High-affinity, non-peptide agonists for the ORL1 (orphanin FQ/nociceptin) receptor

The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure-activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.     

Increased asthma medication use in association with ambient fine and ultrafine particles.

The association between particulate air pollution and asthma medication use and symptoms was assessed in a panel study of 53 adult asthmatics in Erfurt, Germany in winter 1996/1997. Number concentrations of ultrafine particles, 0.01-0.1 microm in diameter (NC(0.01-0.1), mean 17,300 x cm(-3), and mass concentrations of fine particles 0.01-2.5 microm in diameter (MC(0.01-2.5)), mean 30.3 microg x m(-3), were measured concurrently. They were not highly correlated (r=0.45). The associations between ambient particle concentrations and the prevalence of inhaled beta2-agonist, corticosteroid use and asthma symptoms, were analysed separately with logistic regression models, adjusting for trend, temperature, weekend, holidays, and first order autocorrelation of the error. Cumulative exposures over 14 days of ultrafine and fine particles were associated with corticosteroid use. Beta2-agonist use was associated with 5-day mean NC(0.01-0.1) and MC(0.01-2.5). The prevalence of asthma symptoms was associated with ambient particle concentrations. The results suggest that reported asthma medication use and symptoms increase in association with particulate air pollution and gaseous pollutants such as nitrogen dioxide.     

Impact of early feeding on childhood eczema: development after nutritional intervention compared with the natural course – the GINIplus study up to the age of 6 years

Background Nutritional intervention with hydrolysed infant formulas has been shown efficacious in preventing eczema in children predisposed to allergy. However, this preventive effect has never been related to the natural course of eczema in children with or without a family history of allergy. The aim of this study therefore was to compare the course of eczema in predisposed children after nutritional intervention to the natural course of eczema. Method The prospective German birth cohort study GINIplus includes a total of 5991 children, subdivided into interventional and non‐interventional groups. Children with a familial predisposition for allergy whose parents agreed to participate in the prospective, double‐blind intervention trial (N=2252) were randomly assigned at birth to one of four formulas: partially or extensively hydrolysed whey, extensively hydrolysed casein (eHF‐C) or standard cow's milk formula. Children with or without familial predisposition represented the non‐interventional group (N=3739). Follow‐up data were taken from yearly self‐administered questionnaires from 1 up to 6 years. The outcome was physician‐diagnosed eczema and its symptoms. The cumulative incidence of eczema in predisposed children with or without nutritional intervention was compared with that of non‐predisposed children who did not receive intervention. Cox regression was used to adjust for confounding. Results Predisposed children without nutritional intervention had a 2.1 times higher risk for eczema [95% confidence interval (CI) 1.6–2.7] than children without a familial predisposition. The risk was smaller with nutritional intervention even levelling out to 1.3 (95% CI 0.9–1.9) in children fed eHF‐C formula. Conclusion Although direct comparability is somewhat restricted, the data demonstrate that early intervention with hydrolysed infant formulas can substantially compensate up until the age of 6 years for an enhanced risk of childhood eczema due to familial predisposition to allergy. Cite this as: A. v. Berg, U. Krämer, E. Link, C. Bollrath, J. Heinrich, I. Brockow, S. Koletzko, A. Grübl, B. Filipiak‐Pittroff, H.‐E. Wichmann, C.‐P. Bauer, D. Reinhardt, D. Berdel and the GINIplus study group, Clinical & Experimental Allergy, 2010 (40) 627–636.     

Relationships between MR-imaged total amount of tissue removed, resection scores of specific mediobasal limbic subcompartments and clinical outcome following selective amygdalohippocampectomy

Of 204 patients who underwent a selective amygdalohippocampectomy at our hospital, we studied 30 in whom special pre- and postoperative MR imaging was carried out and who were followed up for at least 1 year postoperatively. We measured the total size of the resection and the extent to which the following specific mediobasal temporal lobe structures had been removed: amygdala, hippocampus, pes hippocampi, dentate gyrus, parahippocampal gyrus, uncus and subiculum. Postoperative seizure control was correlated with the overall size of the resection as well as with the resection scores of the above mentioned limbic subcompartments. The mean size of the removed tissue was 7.2 cm3 (range: 2.1-17.7). The mean resection scores of the limbic subcompartments (in percentages) are: amygdala 92%, hippocampus 46%, pes hippocampi 92%, dentate gyrus 45%, parahippocampal gyrus 32%, uncus 92%, subiculum 40%. Although a small resection did not exclude a good outcome, the general tendency was that a better outcome was obtained from a larger resection. With regard to the resection scores of the limbic subcompartments, a positive correlation emerged between good postoperative outcome and the radicality of the removal of the parahippocampal gyrus (and the subiculum, which has been evaluated separately). These findings support our previously formulated amplifier hypothesis for the parahippocampal gyrus.     

Epidemiological evidence on health effects of ultrafine particles.

Evidence from epidemiologic studies linking ambient concentrations of particulate matter to morbidity and mortality influenced the guidelines for air quality standards worldwide. With the improvement of measurement techniques, clearer effects were observed with smaller particle sizes. Based on these effects and results from animal studies on the potential toxicity of ultrafine particles, recent epidemiologic studies focus on the health effects of particles which are less than 100nm in diameter. However, most of the studies are ongoing and only few results have been available so far. Six panel studies with patients suffering from chronic pulmonary diseases have been performed in Germany, Finland and the United Kingdom. Overall, a decrease of peak expiratory flow (PEF) and an increase of daily symptoms and medication use was found for elevated daily particle concentrations. Effects were seen with both fine and ultrafine particles. One large study on daily mortality from Germany showed comparable effects of fine and ultrafine particles in all size classes considered. However, fine particles showed more immediate effects while ultrafine particles showed more delayed effects on mortality. The limited number of epidemiological studies suggest that there are health effects of fine and ultrafine particles which might be independent of each other. If these effects are confirmed by ongoing research, monitoring and regulation of particulate air pollution may need to be revised.     

Ergebnisse der Diätbehandlung der Hauttuberkulose

Ohne Zusammenfassung     

Laparoscopic gastro-jejunal anastomosis using novel r2 deflectable instruments in an ex vivo model

Objective A novel 5?mm steerable instrument system (r2-DRIVE) was developed with active tip deflection and tip and shaft rotation. The feasibility and training effect of the r2 instruments were determined in a phantom model. Material and methods Experienced laparoscopic surgeons and untrained novices performed laparoscopic gastro-jejunal anastomoses using porcine tissue and r2 DRIVE-instruments. Mean anastomosis time, anastomosis width and burst pressure were measured. Number of stitches, skipped stitches and dropped needles were counted. Results of trained and untrained subjects were compared. Results Mean time for suturing decreased rapidly for all participants, but was more evident for untrained persons. After five anastomoses no relevant improvement in anastomotic time was seen for the skilled group. The ease of use, efficacy of manipulation and swift training effect with the novel r2 instruments for both experienced laparoscopic surgeons and untrained non-surgeons could be demonstrated and after few cases stable anastomosis times and a fast learning curve were obtained. Conclusions This study demonstrates the ease of use, efficacy of manipulation and swift training effect with the novel r2 instruments for both experienced laparoscopic surgeons and untrained non-surgeons. After few cases stable anastomosis times and a fast learning curve were obtained.     

Scanning electron microscopy studies in the detection of apo-B,E receptor activity of the lymphocyte membrane for diagnostic verification of genetically determined disorders of lipid metabolism

We present a scanning electron microscopic method for determining the quantity of the apo B,E-receptors at the surface of lymphocytes. We used human lymphocytes from venous blood. Gold particles, 50 nm in diameter, were conjugated to the receptors by indirect coupling. We visualized the gold particles by means of an electron microscope (JEM 100 S with scanning attachment ASID). The lymphocytes of control persons and of patients with primary hyperlipoproteinaemias were analysed. Scanning electron microscopic assay of labelled apo-B,E-receptors was shown to allow the rapid and accurate identification of patients with autosomal monogenic hypercholesterolaemia.     

Prospective study of device-related complications in intensive care unit detected by virtual autopsy

Background

There has been increasing use of invasive techniques, such as extracorporeal organ support, in intensive care units (ICU), and declining autopsy rates. Thus, new measures are needed to maintain high-quality standards. We investigated the potential of computed tomography (CT)-based virtual autopsy to substitute for medical autopsy in this setting.