Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization

Pollen grains induce allergies in susceptible individuals by release of allergens upon contact with mucosal membranes of the upper respiratory tract. We recently demonstrated that pollen not only function as allergen carriers but also as rich sources of bioactive lipids that attract cells involved in allergic inflammation such as neutrophils and eosinophils. Here we demonstrate that soluble factors from birch (Betula alba L.) pollen activate human dendritic cells (DCs) as documented by phenotypical and functional maturation and altered cytokine production. Betula alba L. aqueous pollen extracts (Bet.-APE) selectively inhibited interleukin (IL)-12 p70 production of lipopolysaccharide (LPS)- or CD40L-activated DC, whereas IL-6, IL-10, and TNFalpha remained unchanged. Presence of Bet.-APE during DC activation resulted in DC with increased T helper type 2 (Th2) cell and reduced Th1 cell polarizing capacity. Chemical analysis of Bet.-APE revealed the presence of phytoprostanes (dinor isoprostanes) with prostaglandin E(1)-, F(1)-, A(1)-, or B(1)-ring systems of which only E(1)-phytoprostanes dose dependently inhibited the LPS-induced IL-12 p70 release and augmented the Th2 cell polarizing capacity of DC. These results suggest that pollen-derived E(1)-phytoprostanes not only resemble endogenous prostaglandin E(2) structurally but also functionally in that they act as regulators that modulate human DC function in a fashion that favors Th2 cell polarization.     

"Ideal PEEP" is superior to high dose partial liquid ventilation with low PEEP in experimental acute lung injury

OBJECTIVE: To determine the effects of a high dose partial liquid ventilation (PLV) approximating the amount of the functional residual capacity (FRC) with low levels of positive end-expiratory pressure (PEEP) compared to a lung-protective strategy with volume-controlled mechanical ventilation (vcMV) with a PEEP level above the lower inflection point (LIP) on pulmonary gas exchange, haemodynamics, respiratory mechanics and lung injury in an experimental model of acute lung injury (ALI). DESIGN: Prospective, randomised, controlled study. METHODS: Twenty-four anaesthetised, tracheotomised and mechanically ventilated (FIO(2) 1.0) pigs underwent induction of ALI by repeated saline wash-out of surfactant. Animals were randomly assigned to receive either PLV ( PLV, n=8) with 30 ml/kg of perfluorocarbons (PF 5080, 3 M, Germany) and a PEEP level of 5 cmH(2)O, to receive vcMV with a PEEP level of 1 cmH(2)O above the LIP ( (ideal) PEEP, n=8), or to receive vcMV with a PEEP level of 5 cmH(2)O ( Controls, n=8). MEASUREMENTS AND RESULTS: Measurements of pulmonary gas exchange, respiratory mechanics and haemodynamics were performed hourly for a 6 h period. In the (ideal) PEEP group, intra-pulmonary shunt (Qs/Qt) decreased from 55+/-5% after induction of ALI to 10+/-3% ( p<0.05 versus Controls and versus PLV) and PaO(2) increased from 52+/-4 to 566+/-19 mmHg after 6 h of treatment ( p<0.05 versus Controls and versus PLV). In the PLV group, Qs/Qt decreased from 50+/-5% after induction of ALI to 24+/-3% ( p<0.05 versus Controls) and PaO(2) increased from 59+/-5 to 306+/-35 mmHg after 6 h of treatment ( p<0.05 versus Controls). In the PLV group and in Controls, mean pulmonary artery pressure (MPAP) was significantly increased from 27+/-2 to 38+/-2 mmHg and from 29+/-1 to 40+/-1 mmHg, respectively, 6 h after induction of ALI ( p<0.05 versus (ideal) PEEP), while in the (ideal) PEEP group, MPAP was maintained between 26+/-1 and 31+/-2 mmHg for 6 h after ALI. Cardiac output (CO) decreased significantly in the (ideal) PEEP group compared to Controls ( p<0.05), while CO did not change in the PLV group and in Controls. The compliance of the respiratory system (C(RS)) increased in the (ideal) PEEP group after induction of ALI from 11+/-2 to 22+/-5 ml/mbar ( p<0.05 versus Controls and versus PLV) and in the PLV group from 10+/-2 to 13+/-3 ml/mbar after 6 h of treatment ( p<0.05 versus Controls). On histological examination, the highest total injury scores were found in animals of the PLV group ( p<0.05 versus Controls and versus (ideal) PEEP), while the lowest total lung injury score was found in the dependent lung regions of the (ideal) PEEP group ( p<0.05 versus Controls). CONCLUSION: In this porcine model of ALI, vcMV with a PEEP level of 1 cmH(2)O above the LIP was superior to high dose PLV with a PEEP of 5 cmH(2)O in improving gas exchange and lung mechanics. In terms of lung damage, the treatment in the (ideal) PEEP group resulted in the lowest total lung injury scores.     

Case Report. Mycotic arteritis due to Aspergillus fumigatus in a diabetic with retrobulbar aspergillosis and mycotic meningitis

A 74-year-old man with diabetes mellitus type II, retinopathy and polyneuropathy suffered from exophthalmus, ptosis and diplopia. Magnetic resonance imaging and computer tomography showed a space-occupying process in the right orbital apex. An extranasal ethmoidectomy accompanied by an orbitotomia revealed the presence of septated hyphae. Aspergillus fumigatus was grown from the tissue. After surgical removal of the fungal masses, therapy with amphotericin B (1 mg kg(-1) body weight) plus itraconazole (Sempera, 200 mg per day) over 6 weeks was initiated. Five months later the patient's condition deteriorated again, with vomiting, nausea and pain behind the right eye plus increasing exophthalmus. Antifungal therapy was started again with amphotericin B and 5-fluorocytosine. Neutropenia did not occur. The patient became somnolent and deteriorated, a meningitis was suggested. Aspergillus antigen (titre 1:2, Pastorex) was detected in liquor. Anti-Aspergillus antibodies were not detectable. Both the right eye and retrobulbar fungal masses were eradicated by means of an exenteratio bulbi et orbitae. However, renal insufficiency and an apallic syndrome developed and the patient died. At autopsy, a mycotic aneurysm of the arteria carotis interna dextra was detected. The mycotic vasculitis of this aneurysm had caused a rupture of the blood vessel followed by a massive subarachnoidal haemorrhage. In addition, severe mycotic sphenoidal sinusitis and aspergillosis of the right orbit were seen, which had led to a bifrontal meningitis.     

Nucleus accumbens projections: Validity and reliability of fiber reconstructions based on high‐resolution diffusion‐weighted MRI

Clinical effects of deep brain stimulation are largely mediated by the activation of myelinated axons. Hence, increasing attention has been paid in the past on targeting white matter tracts in addition to gray matter. Aims of the present study were: (i) visualization of discrete afferences and efferences of the nucleus accumbens (NAc), supposed to be a major hub of neural networks relating to mental disorders, using probabilistic fiber tractography and a data driven approach, and (ii) validation of the applied methodology for standardized routine clinical applications. MR‐data from 11 healthy subjects and 7 measurement sessions each were acquired on a 3T MRI‐scanner. For probabilistic fiber tracking the NAc as a seed region and the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), amygdala (AMY), hippocampus (HPC), dorsomedial thalamus (dmT) and ventral tegmental area (VTA) as target regions were segmented for each subject and both hemispheres. To quantitatively assess the reliability and stability of the reconstructions, we filtered and clustered the individual fiber‐tracts (NAc to target) for each session and subject and performed a point‐by‐point calculation of the maximum cluster distances for intra‐subject comparison. The connectivity patterns formed by the obtained fibers were in good concordance with published data from tracer and/or fiber‐dissection studies. Furthermore, the reliability assessment of the (NAc to target)‐fiber‐tracts yielded to high correlations between the obtained clustered‐tracts. Using DBS with directional lead technology, the workflow elaborated in this study may guide selective electrical stimulation of NAc projections.     

ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma

Background  

Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes by focal hypermethylation. In turn, altered DNA methylation patterns have been used to identify putative tumor suppressor genes.