Comparative biological evaluation of two ethylene linked mixed binuclear ferrocene/ruthenium organometallic species

Two ethylene linked binuclear mixed ferrocene/ruthenium complexes were biologically investigated in comparison to structurally related mononuclear ferrocene or ruthenium species with styryl substituents or ligands. Results indicated that the electron distribution (but not the redox potential), cellular uptake and (to some minor extent) anti-estrogenic effects were the key contributors to antiproliferative effects observed in tumor cell lines.     

Mobile larynx in Mongolian gazelle: Retraction of the larynx during rutting barks in male Mongolian gazelle (Procapra gutturosa Pallas, 1777)

This study provides the first evidence of pronounced temporary laryngeal descent in a bovid species. An elaborate acoustic display is prominent in male courtship behavior of polygynous Mongolian gazelle. During rut, rounding up of females is accompanied by continuous head‐up barking by dominant males. Throughout the rut their evolutionarily enlarged larynx descends to a low mid‐neck resting position. In the course of each bark the larynx is additionally retracted toward the sternum by 30% of the resting vocal tract length. A geometric model of active larynx movements was constructed by combining results of video documentation, dissection, skeletonization, and behavioral observation. The considerable distance between resting position and maximal laryngeal descent suggests a backward tilting of the hyoid apparatus and an extension of the thyrohyoid connection during the retraction phase. Return to the resting position is effected by strap muscles and by the elastic recoil of the pharynx and the thyrohyoid connection. An intrapharyngeal inflation of the peculiar palatinal pharyngeal pouch of adult males is inferred from a short‐time expansion of the ventral neck region rostral to the laryngeal prominence. The neck of adult dominant males is accentuated by long gray guard hairs during the rut. The passive swinging of the heavy larynx of adult males during locomotion gives the impression of a handicap imposed on rutting males. Apparently, this disadvantage becomes outweighed by the profits for reproductive success. J. Morphol., 2008. © 2008 Wiley‐Liss, Inc.     

Pre-Use Susceptibility to Ceftaroline in Clinical Staphylococcus aureus Isolates from Germany: Is There a Non-Susceptible Pool to be Selected?

Ceftaroline is a new cephalosporin active against Methicillin-resistant Staphylococcus aureus (MRSA). Based on a representative collection of clinical S. aureus isolates from Germany, supplemented with isolates of clonal lineages ST228 and ST239, we demonstrate the in-vitro susceptibility towards ceftaroline prior to its introduction into clinical use for a total of 219 isolates. Susceptibility testing was performed by broth microdilution, disc diffusion and Etest, respectively. Results were interpreted according to EUCAST guidelines and showed considerable variance in dependence on clonal affiliation of the isolates tested. Among isolates of widespread hospital-associated lineages we found a high proportion of clinical isolates with MICs close to the EUCAST breakpoint (MIC_50/90 1.0/1.5 mg/L); currently, interpretation of these “borderline” MICs is complicated by a lack of concordant susceptibility testing methods and reasonable breakpoint determination. Isolates of clonal lineages ST228 and ST239 demonstrated increased MIC_50/90 values of 2.5/3.33 mg/L. Sequencing of mecA revealed no association of resistance to a specific mecA polymorphism, but rather reveals two regions in the non-penicillin-binding domain of PbP2a which displayed different combinations of mutations putatively involved in resistance development. This study provides national baseline data to (i) adjust susceptibility testing methods and current breakpoints to clinical and epidemiological requirements, (ii) evaluate current breakpoints with respect to therapeutic outcome and (iii) monitor further resistance evolution.     

LUMOS - A Sensitive and Reliable Optode System for Measuring Dissolved Oxygen in the Nanomolar Range

Most commercially available optical oxygen sensors target the measuring range of 300 to 2 μmol L^-1. However these are not suitable for investigating the nanomolar range which is relevant for many important environmental situations. We therefore developed a miniaturized phase fluorimeter based measurement system called the LUMOS (Luminescence Measuring Oxygen Sensor). It consists of a readout device and specialized “sensing chemistry” that relies on commercially available components. The sensor material is based on palladium(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin embedded in a Hyflon AD 60 polymer matrix and has a K_SV of 6.25 x 10^-3 ppmv^-1. The applicable measurement range is from 1000 nM down to a detection limit of 0.5 nM. A second sensor material based on the platinum(II) analogue of the porphyrin is spectrally compatible with the readout device and has a measurement range of 20 μM down to 10 nM. The LUMOS device is a dedicated system optimized for a high signal to noise ratio, but in principle any phase flourimeter can be adapted to act as a readout device for the highly sensitive and robust sensing chemistry. Vise versa, the LUMOS fluorimeter can be used for read out of less sensitive optical oxygen sensors based on the same or similar indicator dyes, for example for monitoring oxygen at physiological conditions. The presented sensor system exhibits lower noise, higher resolution and higher sensitivity than the electrochemical STOX sensor previously used to measure nanomolar oxygen concentrations. Oxygen contamination in common sample containers has been investigated and microbial or enzymatic oxygen consumption at nanomolar concentrations is presented.     

Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome''s influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1_{meta-analysis} = 2.4, P = 1.0 x 10⁻³⁶), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, P_{meta-analysis} = 8.4 x 10⁻⁸). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring’s susceptibility to a common human disease.     

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.     

Optimization of SPECT-CT Hybrid Imaging Using Iterative Image Reconstruction for Low-Dose CT: A Phantom Study

Background

Hybrid imaging combines nuclear medicine imaging such as single photon emission computed tomography (SPECT) or positron emission tomography (PET) with computed tomography (CT). Through this hybrid design, scanned patients accumulate radiation exposure from both applications. Imaging modalities have been the subject of long-term optimization efforts, focusing on diagnostic applications. It was the aim of this study to investigate the influence of an iterative CT image reconstruction algorithm (ASIR) on the image quality of the low-dose CT images.

Methodology/Principal Findings

Examinations were performed with a SPECT-CT scanner with standardized CT and SPECT-phantom geometries and CT protocols with systematically reduced X-ray tube currents. Analyses included image quality with respect to photon flux. Results were compared to the standard FBP reconstructed images. The general impact of the CT-based attenuation maps used during SPECT reconstruction was examined for two SPECT phantoms. Using ASIR for image reconstructions, image noise was reduced compared to FBP reconstructions for the same X-ray tube current. The Hounsfield unit (HU) values reconstructed by ASIR were correlated to the FBP HU values(R² ≥ 0.88) and the contrast-to-noise ratio (CNR) was improved by ASIR. However, for a phantom with increased attenuation, the HU values shifted for low X-ray tube currents I ≤ 60 mA (p ≤ 0.04). In addition, the shift of the HU values was observed within the attenuation corrected SPECT images for very low X-ray tube currents (I ≤ 20 mA, p ≤ 0.001).

Conclusion/Significance

In general, the decrease in X-ray tube current up to 30 mA in combination with ASIR led to a reduction of CT-related radiation exposure without a significant decrease in image quality.     

Comparison of the Fluid Resuscitation Rate with and without External Pressure Using Two Intraosseous Infusion Systems for Adult Emergencies,the CITRIN (Comparison of InTRaosseous infusion systems in emergency medicINe)-Study

Introduction

Intraosseous infusion is recommended if peripheral venous access fails for cardiopulmonary resuscitation or other medical emergencies. The aim of this study, using body donors, was to compare a semi-automatic (EZ-IO^®) device at two insertion sites and a sternal intraosseous infusion device (FASTR^™).

Methods

Twenty-seven medical students being inexperienced first-time users were randomized into three groups using EZ-IO and FASTR. The following data were evaluated: attempts required for successful placement, insertion time and flow rates with and without external pressure to the infusion.

Results

The first-pass insertion success of the EZ-IO tibia, EZ-IO humerus and FASTR was 91%, 77%, and 95%, respectively. Insertion times (MW±SD) did not show significant differences with 17±7 (EZ-IO tibia) vs. 29±42 (EZ-IO humerus) vs. 33±21 (FASTR), respectively. One-minute flow rates using external pressures between 0 mmHg and 300 mmHg ranged between 27±5 to 69±54 ml/min (EZ-IO tibia), 16±3 to 60±44 ml/min (EZ-IO humerus) and 53±2 to 112±47 ml/min (FASTR), respectively. Concerning pressure-related increases in flow rates, negligible correlations were found for the EZ-IO tibia in all time frames (c = 0.107–0.366; p≤0.013), moderate positive correlations were found for the EZ-IO humerus after 5 minutes (c = 0.489; p = 0.021) and strong positive correlations were found for the FASTR in all time frames (c = 0.63–0.80; p≤0.007). Post-hoc statistical power was 0.62 with the given sample size.

Conclusions

The experiments with first-time users applying EZ-IO and FASTR in body donors indicate that both devices may be effective intraosseous infusion devices, likely suitable for fluid resuscitation using a pressure bag. Variations in flow rate may limit their reliability. Larger sample sizes will prospectively be required to substantiate our findings.     

Effects of Initial Values and Convergence Criterion in the Two-Parameter Logistic Model When Estimating the Latent Distribution in BILOG-MG 3

Parameters of the two-parameter logistic model are generally estimated via the expectation-maximization algorithm, which improves initial values for all parameters iteratively until convergence is reached. Effects of initial values are rarely discussed in item response theory (IRT), but initial values were recently found to affect item parameters when estimating the latent distribution with full non-parametric maximum likelihood. However, this method is rarely used in practice. Hence, the present study investigated effects of initial values on item parameter bias and on recovery of item characteristic curves in BILOG-MG 3, a widely used IRT software package. Results showed notable effects of initial values on item parameters. For tighter convergence criteria, effects of initial values decreased, but item parameter bias increased, and the recovery of the latent distribution worsened. For practical application, it is advised to use the BILOG default convergence criterion with appropriate initial values when estimating the latent distribution from data.