Tackle your Tics:pilot findings of a brief, intensive group-based exposure therapy program for children with tic disorders

Tourette syndrome (TS) and other chronic tic disorders (CTD) are prevalent neurodevelopmental disorders, which can have a huge burden on families and society. Behavioral treatment is a first-line intervention for tic disorders. Despite demonstrated efficacy, tic reduction and utilization rates of behavioral treatment remain relatively low. Patient associations point to an urgent need for easy-to-undergo treatments that focus both on tic reduction and improvement of quality of life. To enhance treatment outcome and overcome treatment barriers, this pilot study's aim was to investigate the feasibility and preliminary results of a brief, intensive group-based treatment. Tackle your Tics is a 4-day intensive and comprehensive group-based program for children and adolescents (9-17 years) with a tic disorder, consisting of exposure and response prevention (ERP) treatment and additional supporting components, such as coping strategies, relaxing activities and parent support. Assessments were performed pre- and post-treatment and at 2 months follow-up, to test outcomes on tic severity and quality of life, and explore premonitory urges, emotional and behavioral functioning and treatment satisfaction (N = 14, of whom 13 completed the treatment). Parents and children rated this treatment positive on a treatment satisfaction questionnaire. On tic severity (Yale Global Tic Severity Scale) and quality of life (Gilles de la Tourette Syndrome Quality of Life Scale for children and adolescents), improvements between pre-treatment and follow-up were found. Intensive ERP in group format is promising as a feasible treatment to improve both tic severity as well as quality of life. Larger controlled trials are needed to establish its effectiveness

Increased Liver Uptake and Reduced Hepatic Stellate Cell Activation with a Cell-Specific Conjugate of the Rho-kinase Inhibitor Y27632

Rho-kinase regulates activation of hepatic stellate cells (HSC) during liver fibrosis, but the ubiquitous presence of this kinase may hinder examination of its exact role and the therapeutic use of inhibitors. We therefore coupled the Rho-kinase inhibitor Y27632 to a drug carrier that binds the mannose-6-phosphate insulin-like growth factor II (M6P/IGFII)-receptor which is upregulated on activated HSC. Y27632 was coupled to mannose-6-phosphate human serum albumin (M6PHSA), and in vitro experiments were performed on primary rat HSC. Biodistribution and effect studies were performed in an acute CCl(4) model in mice. Y27-conjugate remained stable in serum, while drug was efficiently released in liver homogenates. Receptor-blocking studies revealed that it was specifically taken up through the M6P/IGFII-receptor on fibroblasts, and it inhibited expression of fibrotic markers in activated HSC. In vivo, liver drug levels were significantly higher after injection of Y27-conjugate as compared to Y27632, and the conjugate accumulated specifically in HSC. After acute CCl(4)-induced liver injury, Y27-conjugate reduced the local activation of HSC, whereas an equimolar dose of free drug did not. We conclude that specific targeting of a Rho-kinase inhibitor to HSC leads to enhanced accumulation of the drug in HSC, reducing early fibrogenesis in the liver

Revisiting the Local Scaling Hypothesis in Stably Stratified Atmospheric Boundary Layer Turbulence: an Integration of Field and Laboratory Measurements with Large-eddy Simulations

The `local scaling' hypothesis, first introduced by Nieuwstadt two decades ago, describes the turbulence structure of stable boundary layers in a very succinct way and is an integral part of numerous local closure-based numerical weather prediction models. However, the validity of this hypothesis under very stable conditions is a subject of on-going debate. In this work, we attempt to address this controversial issue by performing extensive analyses of turbulence data from several field campaigns, wind-tunnel experiments and large-eddy simulations. Wide range of stabilities, diverse field conditions and a comprehensive set of turbulence statistics make this study distinct

Forecasting global atmospheric CO_2

A new global atmospheric carbon dioxide (CO_2) real-time forecast is now available as part of the pre-operational Monitoring of Atmospheric Composition and Climate – Interim Implementation (MACC-II) service using the infrastructure of the European Centre for Medium-Range Weather Forecasts (ECMWF) Integrated Forecasting System (IFS). One of the strengths of the CO_2 forecasting system is that the land surface, including vegetation CO_2 fluxes, is modelled online within the IFS. Other CO_2 fluxes are prescribed from inventories and from off-line statistical and physical models. The CO_2 forecast also benefits from the transport modelling from a state-of-the-art numerical weather prediction (NWP) system initialized daily with a wealth of meteorological observations. This paper describes the capability of the forecast in modelling the variability of CO_2 on different temporal and spatial scales compared to observations. The modulation of the amplitude of the CO_2 diurnal cycle by near-surface winds and boundary layer height is generally well represented in the forecast. The CO_2 forecast also has high skill in simulating day-to-day synoptic variability. In the atmospheric boundary layer, this skill is significantly enhanced by modelling the day-to-day variability of the CO_2 fluxes from vegetation compared to using equivalent monthly mean fluxes with a diurnal cycle. However, biases in the modelled CO_2 fluxes also lead to accumulating errors in the CO_2 forecast. These biases vary with season with an underestimation of the amplitude of the seasonal cycle both for the CO_2 fluxes compared to total optimized fluxes and the atmospheric CO_2 compared to observations. The largest biases in the atmospheric CO_2 forecast are found in spring, corresponding to the onset of the growing season in the Northern Hemisphere. In the future, the forecast will be re-initialized regularly with atmospheric CO_2 analyses based on the assimilation of CO_2 products retrieved from satellite measurements and CO_2 in situ observations, as they become available in near-real time. In this way, the accumulation of errors in the atmospheric CO_2 forecast will be reduced. Improvements in the CO_2 forecast are also expected with the continuous developments in the operational IFS

Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFβ-receptor in the fibrotic kidney

Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFβR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFβR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFβR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14 days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA

Homing in on the hepatic scar:recent advances in cell-specific targeting of liver fibrosis

Despite the high prevalence of liver disease globally, there are currently no approved anti-fibrotic therapies to treat patients with liver fibrosis. A major goal in anti-fibrotic therapy is the development of drug delivery systems that allow direct targeting of the major pro-scarring cell populations within the liver (hepatic myofibroblasts) whilst not perturbing the homeostatic functions of other mesenchymal cell types present within both the liver and other organ systems. In this review we will outline some of the recent advances in our understanding of myofibroblast biology, discussing both the origin of myofibroblasts and possible myofibroblast fates during hepatic fibrosis progression and resolution. We will then discuss the various strategies currently being employed to increase the precision with which we deliver potential anti-fibrotic therapies to patients with liver fibrosis

Tackle your Tics: pilot findings of a brief, intensive group-based exposure therapy program for children with tic disorders

Tourette syndrome (TS) and other chronic tic disorders (CTD) are prevalent neurodevelopmental disorders, which can have a huge burden on families and society. Behavioral treatment is a first-line intervention for tic disorders. Despite demonstrated efficacy, tic reduction and utilization rates of behavioral treatment remain relatively low. Patient associations point to an urgent need for easy-to-undergo treatments that focus both on tic reduction and improvement of quality of life. To enhance treatment outcome and overcome treatment barriers, this pilot study’s aim was to investigate the feasibility and preliminary results of a brief, intensive group-based treatment. Tackle your Tics is a 4-day intensive and comprehensive group-based program for children and adolescents (9–17 years) with a tic disorder, consisting of exposure and response prevention (ERP) treatment and additional supporting components, such as coping strategies, relaxing activities and parent support. Assessments were performed pre- and post-treatment and at 2 months follow-up, to test outcomes on tic severity and quality of life, and explore premonitory urges, emotional and behavioral functioning and treatment satisfaction (N = 14, of whom 13 completed the treatment). Parents and children rated this treatment positive on a treatment satisfaction questionnaire. On tic severity (Yale Global Tic Severity Scale) and quality of life (Gilles de la Tourette Syndrome Quality of Life Scale for children and adolescents), improvements between pre-treatment and follow-up were found. Intensive ERP in group format is promising as a feasible treatment to improve both tic severity as well as quality of life. Larger controlled trials are needed to establish its effectiveness

Pharmacokinetics of a sustained release formulation of PDGFβ-receptor directed carrier proteins to target the fibrotic liver

Liver fibrogenesis is associated with excessive production of extracellular matrix by myofibroblasts that often leads to cirrhosis and consequently liver dysfunction and death. Novel protein-based antifibrotic drugs show high specificity and efficacy, but their use in the treatment of fibrosis causes a high burden for patients, since repetitive and long-term parenteral administration is required as most proteins and peptides are rapidly cleared from the circulation. Therefore, we developed biodegradable polymeric microspheres for the sustained release of proteinaceous drugs. We encapsulated the drug carrier pPB-HSA, which specifically binds to the PDGF beta R that is highly upregulated on activated myofibroblasts, into microspheres composed of hydrophilic multi-block copolymers composed of poly(L-lactide) and poly ethylene glycol/poly(is an element of-caprolactone), allowing diffusion-controlled release. Firstly, we estimated in mice with acute fibrogenesis induced by a single CCl4 injection the half-life of I-125-labeled pPB-HSA at 40 min and confirmed the preferential accumulation in fibrotic tissue. Subsequently, we determined in the Mdr2-/- mouse model of advanced biliary liver fibrosis how the subcutaneously injected microspheres released pPB-HSA into both plasma and fibrotic liver at 24 h after injection, which was maintained for six days. Although the microspheres still contained protein at day seven, pPB-HSA plasma and liver concentrations were decreased. This reduction was associated with an antibody response against the human albumin-based carrier protein, which was prevented by using a mouse albumin-based equivalent (pPB-MSA). In conclusion, this study shows that our polymeric microspheres are suitable as sustained release formulation for targeted protein constructs such as pPB-HSA. These formulations could be applied for the long-term treatment of chronic diseases such as liver fibrosis

The antifibrotic potential of a sustained release formulation of a PDGFβ-receptor targeted rho kinase inhibitor

Rho kinase activity in hepatic stellate cells (HSCs) is associated with activation, transformation and contraction of these cells, leading to extracellular matrix production and portal hypertension in liver cirrhosis. Inhibition of rho kinase activity can reduce these activities, but may also lead to side effects, for instance systemic hypotension. This can be circumvented by liver-specific delivery of a rho kinase inhibitor to effector cells. Therefore, we targeted the rho kinase inhibitor Y27632 to the key pathogenic cells in liver fibrosis, i.e. myofibroblasts including activated HSCs that highly express the PDGF beta-receptor, using the drug carrier pPB-MSA. This carrier consists of mouse serum albumin (MSA) covalently coupled to several PDGF beta-recognizing moieties (pPB). We aimed to create a prolonged release system of such a targeted construct, by encapsulating pPB-MSA-Y27632 in biodegradable polymeric microspheres, thereby reducing short-lasting peak concentrations and the need for frequent administrations. Firstly, we confirmed the vasodilating potency of PDGF beta-receptor targeted Y27632 in vitro in a contraction assay using HSCs seeded on a collagen gel. We subsequently demonstrated the in vivo antifibrotic efficacy of pPB-MSA-Y27632-loaded microspheres in the Mdr2 - / - mouse model of progressive biliary liver fibrosis. A single subcutaneous microsphere administration followed by organ harvest one week later clearly attenuated liver fibrosis progression and significantly suppressed the expression of fibrosis related genes, such as several collagens, profibrotic cytokines and matrix metalloproteinases. In conclusion, we demonstrate that polymeric microspheres are suitable as drug delivery system for the sustained systemic delivery of targeted protein constructs with antifibrotic potential, such as pPB-MSA-Y27632. This formulation appears suitable for the sustained treatment of liver fibrosis and possibly other chronic diseases

Evapotranspiration estimation considering anthropogenic heat based on remote sensing in urban area

Urbanization influences hydrologic cycle significantly on local, regional even global scale. With urbanization the water resources demand for dense population sharpened, thus it is a great challenge to ensure water supply for some metropolises such as Beijing. Urban area is traditionally considered as the area with lower evapotranspiration (ET) on account of the impervious surface and the lower wind speed. For most remote sensing models, the ET, defined as latent heat in energy budget, is estimated as the difference between net radiation and sensible heat. The sensible heat is generally higher in urban area due to the high surface temperature caused by heat island, therefore the latent heat (i.e. the ET) in urban area is lower than that in other region. We estimated water consumption from 2003 to 2012 in Beijing based on water balance method and found that the annual mean ET in urban area was about 654 mm. However, using Surface Energy Balance System (SEBS) model, the annual mean ET in urban area was only 348 mm. We attributed this inconsistence to the impact of anthropogenic heat and quantified this impact on the basis of the night-light maps. Therefore, a new model SEBS-Urban, coupling SEBS model and anthropogenic heat was developed to estimate the ET in urban area. The ET in urban area of Beijing estimated by SEBS-Urban showed a good agreement with the ET from water balance method. The findings from this study highlighted that anthropogenic heat should be included in the surface energy budget for a highly urbanized area