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Objective. A study supported by the EULAR and the ACR being conducted to establish classification criteria for polymyalgia rheumatica (PMR) will include ultrasound examination of the shoulders and hips. Ultrasound (US) depicts glenohumeral joint effusion, biceps tenosynovitis, subdeltoid bursitis, hip joint synovitis, and trochanteric bursitis in PMR. These findings may aid in distinguishing PMR from other diseases. The purpose of this study was to assess standards and US interreader agreement of participants in the PMR classification criteria study. Methods. Sixteen physicians in four groups examined shoulders and hips of 4 patients and 4 healthy adults with ultrasound. Overall agreement and interobserver agreement were calculated. Results. The overall agreement (OA) between groups was 87%. The OA for healthy shoulders was 88.8%, for healthy hips 100%, for shoulders with pathology 85.2%, and 74.3% for hips with pathology, respectively. Conclusion. There was a high degree of agreement found for the examination of healthy shoulders and pathologic hips. Agreement was moderate for pathologic shoulders and perfect for healthy hips. US of shoulder and hips performed by different examiners is a reliable and feasible tool for assessment of PMR related disease pathology and can be incorporated into a classification criteria study.
The lessons from QE and other 'unconventional' monetary policies - evidence from the Bank of England
(2011)
This paper investigates the effectiveness of the ‘quantitative easing’ policy, as implemented by the Bank of England in March 2009. Similar policies had been previously implemented in Japan, the U.S. and the Eurozone. The effectiveness is measured by the impact of Bank of England policies (including, but not limited to QE) on nominal GDP growth – the declared goal of the policy, according to the Bank of England. Unlike the majority of the literature on the topic, the general-to-specific econometric modeling methodology (a.k.a. the ‘Hendry’ or ‘LSE’ methodology) is employed for this purpose. The empirical analysis indicates that QE as defined and announced in March 2009 had no apparent effect on the UK economy. Meanwhile, it is found that a policy of ‘quantitative easing’ defined in the original sense of the term (Werner, 1994) is supported by empirical evidence: a stable relationship between a lending aggregate (disaggregated M4 lending, i.e. bank credit for GDP transactions) and nominal GDP is found. The findings imply that BoE policy should more directly target the growth of bank credit for GDP-transactions.
The unintended consequences of the debt ... will increased government expenditure hurt the economy?
(2011)
In 2008, governments in many countries embarked on large fiscal expenditure programmes, with the intention to support the economy and prevent a more serious recession. In this study, the overall impact of a substantial increase in fiscal expenditure is considered by providing a novel analysis of the most relevant recent experience in similar circumstances, namely that of Japan in the 1990s. Then a weak economy with risk-averse banks seemed to require some of the largest peacetime fiscal stimulation programmes on record, albeit with disappointing results. The explanations provided by the literature and their unsatisfactory empirical record are reviewed. An alternative explanation, derived from early Keynesian models on the ineffectiveness of fiscal policy is presented in the form of a modified Fisher-equation, which incorporates the recent findings in the credit view literature. The model postulates complete quantity crowding out. It is subjected to empirical tests, which were supportive. Thus evidence is found that fiscal policy, if not supported by suitable monetary policy, is likely to crowd out private sector demand, even in an environment of falling or near-zero interest rates. As a policy conclusion it is pointed out that by changing the funding strategy, complete crowding out can be avoided and a positive net effect produced. The proposed framework creates common ground between proponents of Keynesian views (as held, among others, by Blinder and Solow), monetarist views (as held in particular by Milton Friedman) and those of leading contemporary macroeconomists (such as Mankiw).
Central banks have recently introduced new policy initiatives, including a policy called ‘Quantitative Easing’ (QE). Since it has been argued by the Bank of England that “Standard economic models are of limited use in these unusual circumstances, and the empirical evidence is extremely limited” (Bank of England, 2009b), we have taken an entirely empirical approach and have focused on the QE-experience, on which substantial data is available, namely that of Japan (2001-2006). Recent literature on the effectiveness of QE has neglected any reference to final policy goals. In this paper, we adopt the view that ultimately effectiveness will be measured by whether it will be able to “boost spending” (Bank of England, 2009b) and “will ultimately be judged by their impact on the wider macroeconomy” (Bank of England, 2010). In line with a widely held view among leading macroeconomists from various persuasions, while attempting to stay agnostic and open-minded on the distribution of demand changes between real output and inflation, we have thus identified nominal GDP growth as the key final policy goal of monetary policy. The empirical research finds that the policy conducted by the Bank of Japan between 2001 and 2006 makes little empirical difference while an alternative policy targeting credit creation (the original definition of QE) would likely have been more successful.
Schistosomiasis is a severe neglected tropical disease caused by trematodes and transmitted by freshwater snails. Snails are known to be highly tolerant to agricultural pesticides. However, little attention has been paid to the ecological consequences of pesticide pollution in areas endemic for schistosomiasis, where people live in close contact with non-sanitized freshwaters. In complementary laboratory and field studies on Kenyan inland areas along Lake Victoria, we show that pesticide pollution is a major driver in increasing the occurrence of host snails and thus the risk of schistosomiasis transmission. In the laboratory, snails showed higher insecticide tolerance to commonly found pesticides than associated invertebrates, in particular to the neonicotinoid Imidacloprid and the organophosphate Diazinon. In the field, we demonstrated at 48 sites that snails were present exclusively in habitats characterized by pesticide pollution and eutrophication. Our analysis revealed that insensitive snails dominated over their less tolerant competitors. The study shows for the first time that in the field, pesticide concentrations considered “safe” in environmental risk assessment have indirect effects on human health. Thus we conclude there is a need for rethinking the environmental risk of low pesticide concentrations and of integrating agricultural mitigation measures in the control of schistosomiasis.
Bei den im Rahmen des Forschungsverbundes erfolgten faunistischen Untersuchungen stand die Charakterisierung der unterschiedlichen, vor allem aber der wertvollen Biotoptypen der Braunkohlenfolgelandschaft mit Hilfe der dort lebenden Tierarten bzw. Artengemeinschaften im Vordergrund. Es wurden Tiergruppen bearbeitet, die zum einen ein hohes indikatorisches Potential besitzen, zum anderen unterschiedliche ökologische Hierachieebenen repräsentieren. Eine Auswertung der Ergebnisse erfolgte zumeist auf der Ebene der Biotoptypengruppen (siehe Heyde; Jakob; Köck; Reuter im gleichen Heft).
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
Hepatocellular carcinoma (HCC) is highly resistant to anticancer therapy and novel therapeutic strategies are needed. Chronotherapy may become a promising approach because it may improve the efficacy of antimitotic radiation and chemotherapy by considering timing of treatment. To date little is known about time‐of‐day dependent changes of proliferation and DNA damage in HCC. Using transgenic c‐myc/transforming growth factor (TGFα) mice as HCC animal model, we immunohistochemically demonstrated Ki67 as marker for proliferation and γ‐H2AX as marker for DNA damage in HCC and surrounding healthy liver (HL). Core clock genes (Per1, Per2, Cry1, Cry2, Bmal 1, Rev‐erbα and Clock) were examined by qPCR. Data were obtained from samples collected ex vivo at four different time points and from organotypic slice cultures (OSC). Significant differences were found between HCC and HL. In HCC, the number of Ki67 immunoreactive cells showed two peaks (ex vivo: ZT06 middle of day and ZT18 middle of night; OSC: CT04 and CT16). In ex vivo samples, the number of γ‐H2AX positive cells in HCC peaked at ZT18 (middle of the night), while in OSC their number remained high during subjective day and night. In both HCC and HL, clock gene expression showed a time‐of‐day dependent expression ex vivo but no changes in OSC. The expression of Per2 and Cry1 was significantly lower in HCC than in HL. Our data support the concept of chronotherapy of HCC. OSC may become useful to test novel cancer therapies.
Within the SEASTAR project at RIKEN-RIBF, 66Cr and 70,72Fe have been produced via protonknockout reactions, and their first excited 2+ and 4+ states have been discovered. The combination of the liquid-hydrogen target and TPC system MINOS has been used in combination with the DALI2 detector array for the first time. A 345 MeV/u 238U beam with a mean intensity of about 12 pnA impinged on a Be target. Fission fragments were separated and identified using the BigRIPS spectrograph, and reaction products were analyzed using the ZeroDegree spectrograph. A plateau of excitation energies, with a small change in the systematic trends past N = 44, reveals an extension of the N = 40 region of collectivity toward N = 50. Hence, the isotopes of interest are located within the N = 40 island of inversion. An interpretation of the observed trends is offered through large scale shell model calculations.
This study presents a comprehensive and critical assessment of the meteorological conditions and atmospheric flow during the Lagrangian-type "Hill Cap Cloud Thuringia 2010" experiment (HCCT-2010). HCCT-2010 was performed in September and October 2010 at Mt. Schmücke in the Thuringian forest, Germany, applying three measurements sites (upwind, in-cloud, downwind) to study physical and chemical aerosol-cloud-interactions. A Lagrangian-type hill cap cloud experiment requires suitable cloud and particularly connected airflow conditions, i.e. representative air masses at the different measurement sites. Therefore, the present study aimed at the identification of time periods during the 6-weeks duration of the campaign, where such conditions were fulfilled and which can be used in further data examinations.
The following topics were studied in detail: (i) the general synoptic weather situations including the mesoscale flow conditions by means of a classification of advected air masses and calculation of non-dimensional flow parameters (e.g. Froude number), (ii) local meteorological conditions, including synoptic front passages, the presence of orographic or frontal cloudiness, cloud base heights and vertical stratification, and (iii) local flow conditions by means of statistical analyses using the quasi-inert trace gas ozone and selected size bins of particle number size distributions as well as SF6 tracer experiments in the campaign area. A comprehensive analyses using statistical measures such as the COD (Coefficient Of Divergence) and cross-correlation have been carried out for the first time in the context of a Lagrangian-type hill cap cloud experiment. Suitable criteria for the aimed statistical analyses were thus developed and applied in the present study to characterise the local flow connectivity in detail.
The comprehensive examination resulted in a total of 14 so-called "Full Cloud Events" (FCE), which are shown to conform to the Lagrange-type experimental philosophy of HCCT-2010. In addition, 15 so-called "Non-Cloud Events" (NCEs) could be established, which can be used as reference cases as they provide similarly suitable flow conditions but no cloud at the summit site. Orographic cloudiness was identified for approx. one third of the FCE periods, while about two thirds were associated to synoptic fronts. The statistical flow analyses indicate the existence of a strong link between the sites during the events, particularly under constant south-westerly flow conditions, high wind speeds and slightly stable stratification. The COD analyses using continuously measured concentrations of ozone and the 49 nm diameter particle bin revealed particularly for COD values below 0.1 very consistent time series, i.e. closely linked air masses between the different sites. The cross-correlation analysis revealed under connected flow conditions typical overflow times of about 15 to 30 min between the two valley sites. Additionally, the performed SF6 tracer experiments during the campaign clearly demonstrate that under appropriate meteorological conditions a Lagrangian-type approach is valid and that the connected flow validation procedure developed in this work is suitable for identifying such conditions. Finally, an overall evaluation of the identified FCEs is presented, which provides the basis for subsequent investigations of the measured chemical and physical data during HCCT-2010.
This paper presents an analysis of the recent tropospheric molecular hydrogen (H2) budget with a particular focus on soil uptake and European surface emissions. A variational inversion scheme is combined with observations from the RAMCES and EUROHYDROS atmospheric networks, which include continuous measurements performed between mid-2006 and mid-2009. Net H2 surface flux, then deposition velocity and surface emissions and finally, deposition velocity, biomass burning, anthropogenic and N2 fixation-related emissions were simultaneously inverted in several scenarios. These scenarios have focused on the sensibility of the soil uptake value to different spatio-temporal distributions. The range of variations of these diverse inversion sets generate an estimate of the uncertainty for each term of the H2 budget. The net H2 flux per region (High Northern Hemisphere, Tropics and High Southern Hemisphere) varies between −8 and +8 Tg yr−1. The best inversion in terms of fit to the observations combines updated prior surface emissions and a soil deposition velocity map that is based on bottom-up and top-down estimations. Our estimate of global H2 soil uptake is −59±9 Tg yr−1. Forty per cent of this uptake is located in the High Northern Hemisphere and 55% is located in the Tropics. In terms of surface emissions, seasonality is mainly driven by biomass burning emissions. The inferred European anthropogenic emissions are consistent with independent H2 emissions estimated using a H2/CO mass ratio of 0.034 and CO emissions within the range of their respective uncertainties. Additional constraints, such as isotopic measurements would be needed to infer a more robust partition of H2 sources and sinks.
Highlights
• 153 chemicals of emerging concern detected in complex multi-component mixtures.
• 108 possible mixture risk assessment scenarios were investigated.
• Non-detects, QSARs, and experimental ecotoxicological data were integrated for risk assessment.
• 8 chemicals were the main risk drivers in at least one site across the River Aconcagua basin.
Abstract
Environmental risk assessments strategies that account for the complexity of exposures are needed in order to evaluate the toxic pressure of emerging chemicals, which also provide suggestions for risk mitigation and management, if necessary. Currently, most studies on the co-occurrence and environmental impacts of chemicals of emerging concern (CECs) are conducted in countries of the Global North, leaving massive knowledge gaps in countries of the Global South.
In this study, we implement a multi-scenario risk assessment strategy to improve the assessment of both the exposure and hazard components in the chemical risk assessment process. Our strategy incorporates a systematic consideration and weighting of CECs that were not detected, as well as an evaluation of the uncertainties associated with Quantitative Structure-Activity Relationships (QSARs) predictions for chronic ecotoxicity. Furthermore, we present a novel approach to identifying mixture risk drivers. To expand our knowledge beyond well-studied aquatic ecosystems, we applied this multi-scenario strategy to the River Aconcagua basin of Central Chile. The analysis revealed that the concentrations of CECs exceeded acceptable risk thresholds for selected organism groups and the most vulnerable taxonomic groups. Streams flowing through agricultural areas and sites near the river mouth exhibited the highest risks. Notably, the eight risk drivers among the 153 co-occurring chemicals accounted for 66–92 % of the observed risks in the river basin. Six of them are pesticides and pharmaceuticals, chemical classes known for their high biological activity in specific target organisms.
Proteins of the secretin family form large macromolecular complexes, which assemble in the outer membrane of Gram-negative bacteria. Secretins are major components of type II and III secretion systems and are linked to extrusion of type IV pili (T4P) and to DNA uptake. By electron cryo-tomography of whole Thermus thermophilus cells, we determined the in situ structure of a T4P molecular machine in the open and the closed state. Comparison reveals a major conformational change whereby the N-terminal domains of the central secretin PilQ shift by ∼30 Å, and two periplasmic gates open to make way for pilus extrusion. Furthermore, we determine the structure of the assembled pilus.
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
Strong dose response after immunotherapy with PQ grass using conjunctival provocation testing
(2019)
Background: Pollinex Quattro Grass (PQ Grass) is an effective, well-tolerated, short pre-seasonal subcutaneous immunotherapy to treat seasonal allergic rhinoconjunctivitis (SAR) due to grass pollen. In this Phase II study, 4 cumulative doses of PQ Grass and placebo were evaluated to determine its optimal cumulative dose.
Methods: Patients with grass pollen-induced SAR were randomised to either a cumulative dose of PQ Grass (5100, 14400, 27600 and 35600 SU) or placebo, administered as 6 weekly subcutaneous injections over 31–41 days (EudraCT number 2017-000333-31). Standardized conjunctival provocation tests (CPT) using grass pollen allergen extract were performed at screening, baseline and post-treatment to determine the total symptom score (TSS) assessed approximately 4 weeks after dosing. Three models were pre-defined (Emax, logistic, and linear in log-dose model) to evaluate a dose response relationship.
Results: In total, 95.5% of the 447 randomized patients received all 6 injections. A highly statistically significant (p < 0.0001), monotonic dose response was observed for all three pre-specified models. All treatment groups showed a statistically significant decrease from baseline in TSS compared to placebo, with the largest decrease observed after 27600 SU (p < 0.0001). The full course of 6 injections was completed by 95.5% of patients. Treatment-emergent adverse events were similar across PQ Grass groups, and mostly mild and transient in nature.
Conclusions: PQ Grass demonstrated a strong curvilinear dose response in TSS following CPT without compromising its safety profile.
Background: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development.
Methods: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins.
Results: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A.
Conclusion: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.
β-barrel proteins mediate nutrient uptake in bacteria and serve vital functions in cell signaling and adhesion. For the 14-strand outer membrane protein G of Escherichia coli, opening and closing is pH-dependent. Different roles of the extracellular loops in this process were proposed, and X-ray and solution NMR studies were divergent. Here, we report the structure of outer membrane protein G investigated in bilayers of E. coli lipid extracts by magic-angle-spinning NMR. In total, 1847 inter-residue 1H–1H and 13C–13C distance restraints, 256 torsion angles, but no hydrogen bond restraints are used to calculate the structure. The length of β-strands is found to vary beyond the membrane boundary, with strands 6–8 being the longest and the extracellular loops 3 and 4 well ordered. The site of barrel closure at strands 1 and 14 is more disordered than most remaining strands, with the flexibility decreasing toward loops 3 and 4. Loop 4 presents a well-defined helix.
Renal cell carcinoma alters endothelial receptor expression responsible for leukocyte adhesion
(2016)
Renal cell carcinoma (RCC) escapes immune recognition. To elaborate the escape strategy the influence of RCC cells on endothelial receptor expression and endothelial leukocyte adhesion was evaluated. Human umbilical vein endothelial cells (HUVEC) were co-cultured with the RCC cell line, Caki-1, with and without tumor necrosis factor (TNF)-alpha. Intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial (E)-selectin, standard and variants (V) of CD44 were then analysed in HUVEC, using flow cytometry and Western blot analysis. To determine which components are responsible for HUVEC-Caki-1 interaction causing receptor alteration, Caki-1 membrane fragments versus cell culture supernatant were applied to HUVECS. Adhesion of peripheral blood lymphocytes (PBL) and polymorphonuclear neutrophils (PMN) to endothelium was evaluated by co-culture adhesion assays. Relevance of endothelial receptor expression for adhesion to endothelium was determined by receptor blockage. Co-culture of RCC and HUVECs resulted in a significant increase in endothelial ICAM-1, VCAM-1, E-selectin, CD44 V3 and V7 expression. Previous stimulation of HUVECs with TNF-alpha and co-cultivation with Caki-1 resulted in further elevation of endothelial CD44 V3 and V7 expression, whereas ICAM-1, VCAM-1 and E-selectin expression were significantly diminished. Since Caki-1 membrane fragments also caused these alterations, but cell culture supernatant did not, cell-cell contact may be responsible for this process. Blocking ICAM-1, VCAM-1, E-selectin or CD44 with respective antibodies led to a significant decrease in PBL and PMN adhesion to endothelium. Thus, exposing HUVEC to Caki-1 results in significant alteration of endothelial receptor expression and subsequent endothelial attachment of PBL and PMN.