DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases

Calsequestrin as a risk factor in Graves’ hyperthyroidism and Graves’ ophthalmopathy patients

Background: The pathogenesis of Graves’ ophthalmopathy (GO), Graves’ hyperthyroidism (GH) and the mechanisms for its link to thyroid autoimmunity are poorly understood. Our research focuses on the role of the skeletal muscle calcium binding protein calsequestrin (CASQ1) in thyroid. We measured the concentration of the CASQ1 protein correlating levels with parameters of the eye signs, CASQ1 antibody levels and CASQ1 gene polymorphism rs3838284. Methods: CASQ1 protein was measured by quantitative Western Blotting. The protein concentrations were expressed as pmol/mg total protein by reference to CASQ1 standards. Results: Western blot analysis showed the presence of two forms of CASQ1 in the thyroid. The mean concentration of CASQ1 protein was significantly reduced in patients with Graves’ disease, compared to thyroid from control subjects with multi-nodular goitre or thyroid cancer. Although in patients with GO it was lower than that, compared with patients with GH this difference was not significant. Reduced CASQ1 in Graves’ thyroid correlated with the homozygous genotype of the rs3838284 CASQ1 polymorphism. Conclusions: Decreased CASQ1 in the thyroid of patients with Graves’ disease compared to thyroid from control subjects is not explained but may reflect consumption of the protein during an autoimmune reaction against CASQ1 in the thyroid

Prefeasibility study for the Port of Itajai

In southern Brazil, in the province of Santa Catarina, the port of Itajai is situated. The port is located at the mouth of the river Itajai-Acu, about 3 km inland. The Port of Itajai is very important for both the local and national economy because of its role in foreign trade, and due to this prominent role in the community many stakeholders are involved. To allow larger vessels into the harbour of Itajai there has been a constant process of deepening the approach channel and the harbour basin. In order to compete sedimentation process in the harbour basin will change. From a commercial point of view it is very interesting to search for other solutions to keep the river at the required depth besides dredging. There are four main principal solutions to reduce the sedimentation of the harbour basin: reduce the sediment production, reduce the transport capacity of the river, increase the flow velocity and redirect the sediment. All these possibilities have a positive effect on the sedimentation in the harbour. Reducing the transport capacity of the river with the use of a sand trap is expected to have the most effect. with surrounding harbours it is important to allow safe navigation of larger vessels as this results in greater cargo handling at lower cost. Due to recent developments the Port of Itajai is investigating the possibility to receive vessels with a length of 300 m overall, 45 m beam and 14 m draught. The Port of Itajai is facing two different kinds of problems, one concerning the alignment and the other concerning sedimentation. In order to deal with the problems the current situation was mapped. The river, sea and harbour characteristics are given; river discharges, flood events, harbour development, harbour lay out, tide, wind and wave direction. At this moment the approach channel of the harbour deals with some imperfections, which makes it difficult, sometimes even impossible, for the design vessel to sail through the channel. Also the current turning circle is a problem as turning of the new design vessel will be extremely difficult and the safety is questionable. With a cost benefit analysis the best possible location for a larger turning basin is determined and a number of changes for the alignment are given. Without human interventions the estuarine system would be in a dynamic equilibrium. The bathymetry would adjust to varying conditions and oscillate around this dynamic equilibrium depth. This is the depth for which the average annual sedimentation is zero. When the natural dynamic equilibrium is disturbed as a result of deepening the estuary, the system will try to restore itself. This causes sedimentation and maintenance dredging is required to maintain the newly dredged areas. The volume of the required maintenance dredging depends on the extent of the disturbance in relation to the equilibrium situation. A larger deepening will lead to smaller flow velocities and therefore to higher sedimentation rates. The sedimentation that occurs in the Itajai Acu estuary is a complex ensemble of processes, which is influenced by processes at the boundary conditions. The two most important processes are the tidal fluctuations and river discharge. To gain insight in the wet system, hand calculations and a 1D-computer model were made. The effect of a number of human interventions on the Itajai-Acu river are determined with hand calculations. With the 1D-modelling software, SOBEK, the effects of the planned dredging are determined.Hydraulic EngineeringCivil Engineering and Geoscience

Zur Politischen Ökonomie öffentlicher Infrastrukturausgaben*

This article reviews results from the literature on the political-economy determinants of infrastructure investments. I discuss three criteria which may be applied to describe efficiency, redistribution and equity concerns of governments when using infrastructure investments as a means of regional policy. Using the planned investment figures of highway construction in the German federal states, I demonstrate that these criteria often lead to conflicting priorities regarding infrastructure investment allocation across regions. Finally, I summarize the findings of previous studies on the political factors that influence infrastructure investment decisions. Copyright 2007 die Autoren Journal compilation 2007, Verein für Socialpolitik und Blackwell Publishing Ltd.

Verification using simulation

International audienc

Decontamination of the digestive tract and oropharynx in ICU patients.

Contains fulltext : 79996.pdf (publisher's version ) (Open Access)BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.

Ecological effects of selective decontamination on resistant gram-negative bacterial colonization.

Contains fulltext : 88783.pdf (publisher's version ) (Closed access)RATIONALE: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) eradicate gram-negative bacteria (GNB) from the intestinal and respiratory tract in intensive care unit (ICU) patients, but their effect on antibiotic resistance remains controversial. OBJECTIVES: We quantified the effects of SDD and SOD on bacterial ecology in 13 ICUs that participated in a study, in which SDD, SOD, or standard care was used during consecutive periods of 6 months (de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, et al. N Engl J Med 2009;360:20-31). METHODS: Point prevalence surveys of rectal and respiratory samples were performed once monthly in all ICU patients (receiving or not receiving SOD/SDD). Effects of SDD on rectal, and of SDD/SOD on respiratory tract, carriage of GNB were determined by comparing results from consecutive point prevalence surveys during intervention (6 mo for SDD and 12 mo for SDD/SOD) with consecutive point prevalence data in the pre- and postintervention periods. MEASUREMENTS AND MAIN RESULTS: During SDD, average proportions of patients with intestinal colonization with GNB resistant to either ceftazidime, tobramycin, or ciprofloxacin were 5, 7, and 7%, and increased to 15, 13, and 13% postintervention (P < 0.05). During SDD/SOD resistance levels in the respiratory tract were not more than 6% for all three antibiotics but increased gradually (for ceftazidime; P < 0.05 for trend) during intervention and to levels of 10% or more for all three antibiotics postintervention (P < 0.05). CONCLUSIONS: SOD and SDD have marked effects on the bacterial ecology in an ICU, with rising ceftazidime resistance prevalence rates in the respiratory tract during intervention and a considerable rebound effect of ceftazidime resistance in the intestinal tract after discontinuation of SDD