Chest High-resolution Computed Tomography Findings in 601 Patients with Inflammatory Bowel Diseases

Publication date: Available online 28 November 2017
Source:Academic Radiology
Author(s): Haruka Sato, Fumito Okada, Shunro Matsumoto, Akira Sonoda, Kazunari Murakami, Tetsuya Ishida, Hajime Takaki, Masaki Wakisaka, Kouhei Tokuyama, Ryuichi Shimada, Hiromu Mori
Rationale and ObjectivesPulmonary involvement in inflammatory bowel disease may reflect the common embryonic origin of the gastrointestinal tract and the bronchial tree. No studies have compared pulmonary high-resolution computed tomography (HRCT) findings between ulcerative colitis (UC) and Crohn disease (CD). This study aimed to assess the relationship between pulmonary HRCT findings and inflammatory bowel disease activity and to compare HRCT findings between UC and CD.Materials and MethodsWe retrospectively identified 601 consecutive patients (350 with UC and 251 with CD) who had undergone chest HRCT examinations at our institutions between April 2004 and April 2016. Parenchymal abnormalities, enlarged lymph nodes, and pleural effusion were evaluated on HRCT.ResultsOne hundred sixty-seven patients (94 men, 73 women; aged 12–86 years, mean: 47.2 years) with UC and 93 patients (61 men, 32 women; aged 12–71 years, mean: 37.9 years) with CD had abnormal findings on chest HRCT. The HRCT findings of UC and CD mainly consisted of centrilobular nodules (in 49.1% and 45.2% of cases, respectively) and bronchial wall thickening (in 31.7% and 54.8%, respectively). There was no relationship between HRCT findings and disease activity. Bronchial wall thickening was significantly more frequent in patients with CD than in those with UC (P < .001).ConclusionThe main chest HRCT findings in UC and CD are centrilobular nodules and bronchial wall thickening. There are differences in HRCT findings between UC and CD.



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Normal Axillary Lymph Node Variability Between White and Black Women on Breast MRI

Publication date: Available online 28 November 2017
Source:Academic Radiology
Author(s): Lars J. Grimm, Neal K. Viradia, Karen S. Johnson
Rationale and ObjectivesThis study aimed to determine if there were differences in the imaging features of normal lymph nodes between white and black women using magnetic resonance imaging.Materials and MethodsFollowing institutional review board approval, we identified white and black women who underwent breast magnetic resonance imaging from November 1, 2008 to December 31, 2013 at our institution. To identify normal lymph nodes for measurement, patients with any benign or malignant causes for lymph node enlargement and patients with any subsequent breast cancer in the following 2 years were excluded. Black and white women were age matched at a 1:2 ratio. The largest lymph node in each axilla was measured for the long-axis length and maximal cortical thickness. Comparisons were made between white and black women using a conditional logistic regression to control for matching.ResultsThere were 55 black women and 110 white women for analysis. The mean lymph node long-axis length was 14.7 ± 5.3 mm for black women and 14.4 ± 6.4 mm for white women (P = .678). The mean maximum cortical thickness was 3.3 ± 1.6 mm for black women and 2.6 ± 1.4 mm for Caucasian women (P < .001). A significantly higher percentage of black than white women had cortical thicknesses greater than threshold values of 3, 4, 5, 6, and 7 mm (P < .01 for all).ConclusionsThe normal lymph node cortical thickness in black women is significantly greater than in white women, which should be considered when deciding to recommend a lymph node biopsy.



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Prognostic value of combining a quantitative image feature from positron emission tomography with clinical factors in oligometastatic non-small cell lung cancer

Oligometastatic non-small cell lung cancer (NSCLC) is a heterogeneous condition with few known risk stratification factors. A quantitative imaging feature (QIF) on positron emission tomography (PET), gray-level co-occurrence matrix energy, has been linked with outcome of nonmetastatic NSCLC. We hypothesized that GLCM energy would enhance the ability of models comprising standard clinical prognostic factors (CPFs) to stratify oligometastatic patients based on overall survival (OS).

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Evaluation of sediment and 137Cs redistribution in the Oginosawa River catchment near the Fukushima Dai-ichi Nuclear Power Plant using integrated watershed modeling

Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Kazuyuki Sakuma, Alex Malins, Hironori Funaki, Hiroshi Kurikami, Tadafumi Niizato, Takahiro Nakanishi, Koji Mori, Kazuhiro Tada, Takamaru Kobayashi, Akihiro Kitamura, Masaaki Hosomi
The Oginosawa River catchment lies 15 km south-west of the Fukushima Dai-ichi nuclear plant and covers 7.7 km². Parts of the catchment were decontaminated between fall 2012 and March 2014 in preparation for the return of the evacuated population. The General-purpose Terrestrial Fluid-flow Simulator (GETFLOWS) code was used to study sediment and ¹³⁷Cs redistribution within the catchment, including the effect of decontamination on redistribution. Fine resolution grid cells were used to model local features of the catchment, such as paddy fields adjacent to the Oginosawa River. The simulation was verified using monitoring data for river water discharge rates (r = 0.92), suspended sediment concentrations, and particulate ¹³⁷Cs concentrations (r = 0.40). Cesium-137 input to watercourses came predominantly from land adjacent to river channels and forest gullies, e.g. the paddy fields in the Ogi and Kainosaka districts, as the ground in these areas saturates during heavy rain and is easily eroded. A discrepancy between the simulation and monitoring results on the sediment discharge rate following decontamination may be explained by fast erosion occurring after decontamination. Forested areas far from the channels only made a minor contribution to ¹³⁷Cs input to watercourses, total erosion of between 0.001 and 0.1 mm from May 2011 to December 2015, as ground saturation is infrequent in these areas. The 2.3–6.9% y⁻¹ decrease in the amount of ¹³⁷Cs in forest topsoil over the study period can be explained by radioactive decay (approximately 2.3% y⁻¹), along with a migration downwards into subsoil and a small amount of export. The amount of ¹³⁷Cs available for release from land adjacent to rivers is expected to be lower in future than compared to this study period, as the simulations indicate a high depletion of inventory from these areas by the end of 2015. However continued monitoring of ¹³⁷Cs concentrations in river water over future years is advised, as recultivation of paddy fields by returnees may again lead to fast erosion rates and release of the remaining inventory.



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Norwegian monitoring (1990–2015) of the marine environment around the sunken nuclear submarine Komsomolets

Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Justin P. Gwynn, Hilde Elise Heldal, Janita K. Flo, Ingrid Sværen, Torbjörn Gäfvert, Hallvard Haanes, Lars Føyn, Anne Liv Rudjord
Norway has monitored the marine environment around the sunken Russian nuclear submarine Komsomolets since 1990. This study presents an overview of 25 years of Norwegian monitoring data (1990–2015). Komsomolets sank in 1989 at a depth of 1680 m in the Norwegian Sea while carrying two nuclear torpedoes in its armament. Subsequent Soviet and Russian expeditions to Komsomolets have shown that releases from the reactor have occurred and that the submarine has suffered considerable damage to its hulls. Norwegian monitoring detected ¹³⁴Cs in surface sediments around Komsomolets in 1993 and 1994 and elevated activity concentrations of ¹³⁷Cs in bottom seawater between 1991 and 1993. Since then and up to 2015, no increased activity concentrations of radionuclides above values typical for the Norwegian Sea have been observed in any environmental sample collected by Norwegian monitoring. In 2013 and 2015, Norwegian monitoring was carried out using an acoustic transponder on the sampling gear that allowed samples to be collected at precise locations, ∼20 m from the hull of Komsomolets. The observed ²³⁸Pu/^239,240Pu activity ratios and ²⁴⁰Pu/²³⁹Pu atom ratios in surface sediments sampled close to Komsomolets in 2013 did not indicate any releases of Pu isotopes from reactor or the torpedo warheads. Rather, these values probably reflect the overprinting of global fallout ratios with fluxes of these Pu isotopes from long-range transport of authorised discharges from nuclear reprocessing facilities in Northern Europe. However, due to the depth at which Komsomolets lies, the collection of seawater and sediment samples in the immediate area around the submarine using traditional sampling techniques from surface vessels is not possible, even with the use of acoustic transponders. Further monitoring is required in order to have a clear understanding of the current status of Komsomolets as a potential source of radioactive contamination to the Norwegian marine environment. Such monitoring should involve the use of ROVs or submersibles in order to obtain samples next to and within the different compartments of the submarine.



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Evidence for associations between PDE4D polymorphisms and a subtype of neuroticism

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Toxicity evaluation of textile effluents and role of native soil bacterium in biodegradation of a textile dye

Abstract

Water pollution caused by the discharge of hazardous textile effluents is a serious environmental problem worldwide. In order to assess the pollution level of the textile effluents, various physico-chemical parameters were analyzed in the textile wastewater and agricultural soil irrigated with the wastewater (contaminated soil) using atomic absorption spectrophotometer and gas chromatography-mass spectrometry (GC-MS) analysis that demonstrated the presence of several toxic heavy metals (Ni, Cu, Cr, Pb, Cd, and Zn) and a large number of organic compounds. Further, in order to get a comprehensive idea about the toxicity exerted by the textile effluent, mung bean seed germination test was performed that indicated the reduction in percent seed germination and radicle-plumule growth. The culturable microbial populations were also enumerated and found to be significantly lower in the wastewater and contaminated soil than the ground water irrigated soil, thus indicating the biotic homogenization of indigenous microflora. Therefore, the study was aimed to develop a cost effective and ecofriendly method of textile waste treatment using native soil bacterium, identified as Arthrobacter soli BS5 by 16S rDNA sequencing that showed remarkable ability to degrade a textile dye reactive black 5 with maximum degradation of 98% at 37 °C and pH in the range of 5–9 after 120 h of incubation.

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Predictors for the Treatment Effect of Sodium Glucose Co-transporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus

Abstract

Introduction

Predictors for the effect of sodium glucose co-transporter 2 (SGLT2) inhibitors at lowering hemoglobin A1c (HbA1c) levels in type 2 diabetes mellitus patients remain unclear. We therefore aimed to elucidate these predictors in type 2 diabetes patients after 3 months of SGLT2 treatment.

Methods

A total of 302 consecutive type 2 diabetes patients who had been treated with SGLT2 inhibitors as monotherapy or add-on therapy to existing antidiabetic treatments were enrolled retrospectively. After excluding 27 patients whose HbA1c levels could not be evaluated 3 months after treatment, the glucose-lowering effects of SGLT2 inhibitors were assessed in 275 patients by measuring HbA1c levels before and 3 months after treatment. The predictors for changes in HbA1c levels after 3 months of treatment were evaluated.

Results

SGLT2 inhibitor treatment for 3 months decreased HbA1c levels from 7.8 ± 1.2% to 7.4 ± 1.0% (p < 0.0001). A multiple regression analysis showed that the independent determinants for SGLT2 inhibitor treatment effect included decreased HbA1c levels after 1 month of treatment, high baseline HbA1c levels, and a high estimated glomerular filtration rate (eGFR).

Conclusion

We show that type 2 diabetes patients who received the greatest glucose-lowering effect with SGLT2 inhibitor treatment were those with preserved renal function (high baseline eGFR) and high baseline HbA1c levels. Moreover, SGLT2 inhibitor treatment efficacy could be predicted by the patients’ initial response to treatment.

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Viruses, Vol. 9, Pages 363: Dynamics of Pathological and Virological Findings During Experimental Calpox Virus Infection of Common Marmosets (Callithrix jacchus)

Viruses, Vol. 9, Pages 363: Dynamics of Pathological and Virological Findings During Experimental Calpox Virus Infection of Common Marmosets (Callithrix jacchus)

Viruses doi: 10.3390/v9120363

Authors: Anne Schmitt Li Gan Ahmed Abd El Wahed Tingchuan Shi Heinz Ellerbrok Franz-Josef Kaup Christiane Stahl-Hennig Kerstin Mätz-Rensing

Experimental intranasal infection of marmosets (Callithrix jacchus) with calpox virus results in fatal disease. Route and dose used for viral inoculation of the test animals mimics the natural transmission of smallpox, thus representing a suitable model to study pathogenesis and to evaluate new vaccines against orthopoxvirus infection. However, the pathogenic mechanisms leading to death are still unclear. Therefore, our study aimed at investigating the kinetics of pathological alterations to clarify the pathogenesis in calpox virus infection. Following intranasal inoculation with two different viral doses, common marmosets were sacrificed on days 3, 5, 7, 10 and 12 post inoculation. Collected tissue was screened using histopathology, immunohistochemistry, transmission electron microscopy, and virological assays. Our data suggest that primary replication took place in nasal and bronchial epithelia followed by secondary replication in submandibular lymph nodes and spleen. Parallel to viremia at day 7, virus was detectable in many organs, mainly located in epithelial cells and macrophages, as well as in endothelial cells. Based on the onset of clinical signs, the histological and ultrastructural lesions and the immunohistochemical distribution pattern of the virus, the incubation period was defined to last 11 days, which resembles human smallpox. In conclusion, the data indicate that the calpox model is highly suitable for studying orthopoxvirus-induced disease.

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A grim winter looms for UK hospitals but there’s an easy cure

Winter crises grip the UK health system with worrying predictability and this year’s could be severe. We can move beyond this seasonal chaos, says Luke Allen

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Giant climate camera will watch how our planet changes

The Visible Infrared Imaging Radiometer Suite will take pictures of Earth to measure the temperatures of the sea and atmosphere and to watch how ice and water move

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Editorial Board and Contents

Publication date: December 2017
Source:Trends in Immunology, Volume 38, Issue 12





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A grim winter looms for UK hospitals but there’s an easy cure

Winter crises grip the UK health system with worrying predictability and this year’s could be severe. We can move beyond this seasonal chaos, says Luke Allen

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Giant climate camera will watch how our planet changes

The Visible Infrared Imaging Radiometer Suite will take pictures of Earth to measure the temperatures of the sea and atmosphere and to watch how ice and water move

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A specialized vascular niche for adult neural stem cells

Stem cells reside in specialized niches that regulate their self-renewal and differentiation. The vasculature is emerging as an important component of stem cell niches. Here, we show that the adult subventricular zone (SVZ) neural stem cell niche contains an extensive planar vascular plexus that has specialized properties. Dividing stem cells and their transit-amplifying progeny are tightly apposed to SVZ blood vessels both during homeostasis and regeneration. They frequently contact the vasculature at sites that lack astrocyte endfeet and pericyte coverage, a modification of the blood-brain barrier unique to the SVZ. Moreover, regeneration often occurs at these sites. Finally, we find that circulating small molecules in the blood enter the SVZ. Thus, the vasculature is a key component of the adult SVZ neural stem cell niche, with SVZ stem cells and transit-amplifying cells uniquely poised to receive spatial cues and regulatory signals from diverse elements of the vascular system.

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Sleep disturbances in Singaporean children with attention deficit hyperactivity disorder

Many studies have reported various levels of association between sleep disorders and attention deficit hyperactivity disorder (ADHD). This study aims to investigate sleep disturbances in children with ADHD prior to treatment and during treatment.; This study recruited 114 child and adolescent patients diagnosed with ADHD and 60 normal patients. Sleep disturbances are assessed using the parent-rated Child Behaviour Checklist (CBCL) questionnaire. In addition, chart reviews and semi-structured clinical interviews were conducted for 54 patients with ADHD who had been seen at the clinic since 2002 to examine the sleep disturbances they experienced during treatment over a 4-year period.; Compared to the normal subjects, parents of children with ADHD reported that their children slept less. The summation score of the sleep items on the CBCL was also significantly higher in the ADHD group. Girls with ADHD also had more "trouble sleeping". When children with ADHD received treatment with medications, they experienced sleep-related side effects. Out of the 54 children with ADHD, 18.5% experienced sleep disturbance related to medication, with 13.0% reporting daytime somnolence and 5.5% reporting insomnia.; Our study showed that there was an increased frequency of sleep disturbances in children with ADHD prior to treatment with medications. The children in our study appeared to sleep less. A significant proportion also experienced sleep disturbance during treatment with medication, of which daytime somnolence and insomnia were the most commonly reported problems. Future research in this area is needed to further examine the range of sleep disorders in ADHD children locally.

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Individual preferences modulate incentive values: Evidence from functional MRI

ABSTRACT:; In most studies on human reward processing, reward intensity has been manipulated on an objective scale (e.g., varying monetary value). Everyday experience, however, teaches us that objectively equivalent rewards may differ substantially in their subjective incentive values. One factor influencing incentive value in humans is branding. The current study explores the hypothesis that individual brand preferences modulate activity in reward areas similarly to objectively measurable differences in reward intensity.; A wheel-of-fortune game comprising an anticipation phase and a subsequent outcome evaluation phase was implemented. Inside a 3 Tesla MRI scanner, 19 participants played for chocolate bars of three different brands that differed in subjective attractiveness.; Parametrical analysis of the obtained fMRI data demonstrated that the level of activity in anatomically distinct neural networks was linearly associated with the subjective preference hierarchy of the brands played for. During the anticipation phases, preference-dependent neural activity has been registered in premotor areas, insular cortex, orbitofrontal cortex, and in the midbrain. During the outcome phases, neural activity in the caudate nucleus, precuneus, lingual gyrus, cerebellum, and in the pallidum was influenced by individual preference.; Our results suggest a graded effect of differently preferred brands onto the incentive value of objectively equivalent rewards. Regarding the anticipation phase, the results reflect an intensified state of wanting that facilitates action preparation when the participants play for their favorite brand. This mechanism may underlie approach behavior in real-life choice situations.

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White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging study

To use a combination of magnetic resonance diffusion-tensor imaging (MR-DTI) and MR imaging of voxel-based morphometry (MR-VBM) in patients with fibromyalgia syndrome (FMS) to determine microstructural and volume changes in the central neuronal networks involved in the sensory-discriminative and affective-motivational characteristics of pain, anxiety, memory, and regulation of the stress response.; Thirty female patients with FMS and 30 healthy female control subjects were studied. Predefined areas of the brain were measured for volume of gray matter by MR-VBM and for diffusivity and fractional anisotropy (FA) by MR-DTI. Higher FA values and reduced diffusivity are thought to reflect increased complexity of brain-tissue microstructure.; MR-VBM and MR-DTI demonstrated a striking pattern of changes in brain morphology in patients with FMS. Both thalami, the thalamocortical tracts, and both insular regions showed significant decreases in FA. In contrast, increases in FA and decreases in gray matter volume were seen in the postcentral gyri, amygdalae, hippocampi, superior frontal gyri, and anterior cingulate gyri. Increased pain intensity scores were correlated with changes in MR-DTI measurements in the right superior frontal gyrus. Increased fatigue was correlated with changes in the left superior frontal and left anterior cingulate gyrus, and self-perceived physical impairment was correlated with changes in the left postcentral gyrus. Higher intensity scores for stress symptoms were correlated negatively with diffusivity in the thalamus and FA in the left insular cortex. No relationship was found between MR-VBM measurements and symptom intensity scores.; MR-DTI allows the visualization of microstructural changes in the brain of patients with FMS, appears to be more sensitive than MR-VBM, and may serve as an additional diagnostic technique in FMS and probably other dysfunctional pain syndromes.

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Serum procalcitonin for discrimination between septic and non-septic arthritis

BACKGROUND: Early differentiation between septic and non-septic arthritis is difficult. A previous study showed promising diagnostic accuracy of serum Procalcitonin (PCT) in septic arthritis, limited by a low sensitive PCT test kit. OBJECTIVE: To investigate the diagnostic value of PCT in patients with septic and non-septic arthritis using a novel test with low detection limit. METHODS: Forty-two patients, 28 with non-septic and 14 with septic arthritis were prospectively included. For each patient, gram stain, culture and polarization microscopy of synovial fluid was done and PCT, C-reactive protein (CRP), white blood cell count, uric acid and blood cultures were taken. Patients with septic arthritis, patients with non-septic arthritis with and without concomitant infection were compared. RESULTS: Patients with septic arthritis had a significant higher PCT concentration than patients with non-septic arthritis (p>0.0001). At a cut-off of 0.1 (0.25) ng/ml, sensitivity for septic arthritis was 100(93)% and specificity 46(75)%. Specificity rose to 93% after exclusion of patients with non-septic arthritis and concomitant infection. Both sensitivity and specificity for the diagnosis of septic arthritis were higher for PCT than CRP. CONCLUSIONS: Our data suggest that PCT seems to be a highly sensitive and specific marker for septic arthritis, depending on the clinical setting. Further studies are warranted.

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Interaction between Tobacco Smoking and Hepatitis B Virus Infection on the Risk of Liver Cancer in a Chinese Population

Abstract

Although tobacco smoking has been reported as a risk factor for liver cancer, few studies have specifically explored the association among Chinese females and the potential interaction between smoking and other risk factors. A population-based case-control study was conducted and 2,011 liver cancer cases and 7,933 healthy controls were enrolled in Jiangsu, China from 2003 to 2010. Epidemiological data were collected, and serum HBsAg and anti-HCV antibody were measured. Unconditional logistic regression was used to examine association and potential interaction, while semi-Bayes method was employed to make estimates more conservative. The prevalence of serum HBsAg positivity was 43.2% among cases and 6.5% among controls. The adjusted odds ratio for ever smoking was 1.62 (95% CI: 1.33 - 1.96) among male and was 0.82 (95% CI: 0.53-1.26) among female. Age at first cigarette, duration of smoking and pack-years of smoking were all significantly associated with liver cancer among men. Compared to HBsAg negative never-smokers, the adjusted OR was 1.25 (95% CI: 1.03-1.52) for HBsAg-negative ever smokers, was 7.66 (95% CI: 6.05-9.71) for HBsAg-positive never smokers, and was 15.68 (95% CI: 12.06-20.39) for HBsAg-positive ever smokers. These different odds indicated super-additive (RERI: 7.77, 95% CI: 3.81-11.73) and super-multiplicative interactions (ROR: 1.64, 95% CI: 1.17-2.30) between HBV infection and tobacco smoking. Most associations and interactions detected remained statistically significant after semi-Bayes adjustments. Tobacco smoking and HBV infection positively interact in the development of liver cancer. This article is protected by copyright. All rights reserved.

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Genes, Vol. 8, Pages 353: Circular RNAs (circRNAs) in Health and Disease

Genes, Vol. 8, Pages 353: Circular RNAs (circRNAs) in Health and Disease

Genes doi: 10.3390/genes8120353

Authors: Shahnaz Haque Lorna Harries

Splicing events do not always produce a linear transcript. Circular RNAs (circRNAs) are a class of RNA that are emerging as key new members of the gene regulatory milieu, which are produced by back-splicing events within genes. In circRNA formation, rather than being spliced in a linear fashion, exons can be circularised by use of the 3′ acceptor splice site of an upstream exon, leading to the formation of a circular RNA species. circRNAs have been demonstrated across species and have the potential to present genetic information in new orientations distinct from their parent transcript. The importance of these RNA players in gene regulation and normal cellular homeostasis is now beginning to be recognised. They have several potential modes of action, from serving as sponges for micro RNAs and RNA binding proteins, to acting as transcriptional regulators. In accordance with an important role in the normal biology of the cell, perturbations of circRNA expression are now being reported in association with disease. Furthermore, the inherent stability of circRNAs conferred by their circular structure and exonuclease resistance, and their expression in blood and other peripheral tissues in association with endosomes and microvesicles, renders them excellent candidates as disease biomarkers. In this review, we explore the state of knowledge on this exciting class of transcripts in regulating gene expression and discuss their emerging role in health and disease.

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Does the Polymorphism in the Length of the Polyalanine Tract of FOXE1 Gene Influence the Risk of Thyroid Dysgenesis Occurrence?

Background. Recent data have suggested that polymorphisms in the length of the polyalanine tract (polyA) of FOXE1 gene may act as a susceptibility factor for thyroid dysgenesis. The main purpose of this study was to investigate the influence of polyA of FOXE1 gene on the risk of thyroid dysgenesis. Method. A case-control study was conducted in a sample of 90 Brazilian patients with thyroid dysgenesis and 131 controls without family history of thyroid disease. Genomic DNA was isolated from peripheral blood samples and the genotype of each individual was determined by automated sequencing. Results. More than 90% of genotypes found in the group of patients with thyroid dysgenesis and in controls subjects were represented by sizes 14 and 16 polymorphisms in the following combinations: 14/14, 14/16, and 16/16. Genotypes 14/16 and 16/16 were more frequent in the control group, while genotype 14/14 was more frequent in the group of patients with thyroid dysgenesis. There was no difference between agenesis group and control group. Genotype 14/14 when compared to genotypes 14/16 and 16/16A showed an association with thyroid dysgenesis. Conclusion. PolyA of FOXE1 gene alters the risk of thyroid dysgenesis, which may explain in part the etiology of this disease.

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The Biocontrol Efficacy of Streptomyces pratensis LMM15 on Botrytis cinerea in Tomato

LMM15, an actinomycete with broad spectrum antifungal activity, was isolated from a diseased tomato leaf using the baiting technique. A phylogenetic tree analysis based on similarity percentage of 16S rDNA sequences showed that the bacterium was 97.0% affiliated with the species Streptomyces pratensis. This strain was therefore coded as S. pratensis LMM15. The ferment filtrate of LMM15 had ability to inhibit mycelia growth of Botrytis cinerea and reduce lesion expansion of gray mold on detached leaves and fruits. In greenhouse experiments, both the fresh and dry weights of tomato seedlings were significantly increased with the increased concentrations of total chlorophyll. The incidence of tomato gray mold decreased by 46.35%; this was associated with the increase of proline content and malondialdehyde (MDA) and the changes in defense-related enzymes on tomato leaves when the strain was sprayed on the tomato leaves 24 h prior to inoculation with pathogens. This study showed that the strain S. pratensis LMM15 could be a potential agent for controlling tomato gray mold.

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Mechanical and Metallurgical Properties of Various Nickel-Titanium Rotary Instruments

The aim of this study was to investigate the effect of thermomechanical treatment on mechanical and metallurgical properties of nickel-titanium (NiTi) rotary instruments. Eight kinds of NiTi rotary instruments with sizes of ISO #25 were selected: ProFile, K3, and One Shape for the conventional alloy; ProTaper NEXT, Reciproc, and WaveOne for the M-wire alloy; HyFlex CM for the controlled memory- (CM-) wire; and TF for the R-phase alloy. Torsional fracture and cyclic fatigue fracture tests were performed. Products underwent a differential scanning calorimetry (DSC) analysis. The CM-wire and R-phase groups had the lowest elastic modulus, followed by the M-wire group. The maximum torque of the M-wire instrument was comparable to that of a conventional instrument, while those of the CM-wire and R-phase instruments were lower. The angular displacement at failure (ADF) for the CM-wire and R-phase instruments was higher than that of conventional instruments, and ADF of the M-wire instruments was lower. The cyclic fatigue resistance of the thermomechanically treated NiTi instruments was higher. DSC plots revealed that NiTi instruments made with the conventional alloy were primarily composed of austenite at room temperature; stable martensite and R-phase were found in thermomechanically treated instruments.

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Strategic WIP Inventory Positioning for Make-to-Order Production with Stochastic Processing Times

It is vital for make-to-order manufacturers to shorten the lead time to meet the customers’ requirements. Holding work-in-process (WIP) inventory at more stations can reduce the lead time, but it also brings about higher inventory holding cost. Therefore, it is important to seek out the optimal set of stations to hold WIP inventory to minimize the total inventory holding cost, while meeting the required due date for the final product at the same time. Since the problem with deterministic processing times at the stations has been addressed, as a natural extension, in this study, we address the problem with stochastic processing times, which is more realistic in the manufacturing environment. Assuming that the processing times follow normal distributions, we propose a solution procedure using genetic algorithm.

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Acute Hypoxic and Refractory Respiratory Failure Induced by an Underlying PFO: An Unusual Case of Platypnea Orthodeoxia and Transient Complication after Transcatheter Closure

Platypnea orthodeoxia (PO) is an infrequent condition of dyspnea with hypoxemia, increased by adopting an upright position and is relieved in decubitus. This condition may occur in patients with hidden intracardiac shunts, usually across a persistent foramen ovale (PFO). The incidence of PFO in general population is quite common, around 27%; however, the concurrent presentation with PO, especially in acute refractory respiratory failure, is extremely rare. PFO closure in this setting is still the treatment of choice with significant improvement or complete resolution of symptoms after closure with an overall periprocedural complication in the first 24 hours of approximately less than 5%. A transient ST-segment elevation in the inferior leads is present in extremely rare occasions and most likely is induced by either an air embolism or a mechanically provoked spasm of coronary arteries. We report a case of an 83-year-old woman in acute hypoxic and refractory respiratory failure in whom PO was identified, most likely induced by a hidden PFO. The patient underwent percutaneous transcatheter closure and developed immediate chest pain, transient hemodynamic instability, and ST-segment elevation in the inferior leads; nevertheless, our patient recovered completely with rapid resolution of respiratory failure with no adverse clinical sequelae.

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Hybrid Solutions of (3 + 1)-Dimensional Jimbo-Miwa Equation

The rational solutions, semirational solutions, and their interactions to the ()-dimensional Jimbo-Miwa equation are obtained by the Hirota bilinear method and long wave limit. The hybrid solutions contain rogue wave, lump solution, and the breather solution, in which the breathers which are manifested as growing and decaying periodic line waves show different dynamics in different planes. Rogue waves are localized in time and are obtained theoretically as a long wave limit of breathers with indefinitely larger periods; they arise from a constant background at and then disappear in the constant background when time goes on. More importantly, the interactions between some hybrid solutions are demonstrated in detail by the three-dimensional figures, such as hybrid solution between the stripe soliton and breather and hybrid solution between stripe soliton and lump solution.

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Overexpression of Cholesteryl Ester Transfer Protein Increases Macrophage-Derived Foam Cell Accumulation in Atherosclerotic Lesions of Transgenic Rabbits

High levels of plasma high-density lipoprotein-cholesterol (HDL-C) are inversely associated with the risk of atherosclerosis and other cardiovascular diseases; thus, pharmacological inhibition of cholesteryl ester transfer protein (CETP) is considered to be a therapeutic method of raising HDL-C levels. However, many CETP inhibitors have failed to achieve a clinical benefit despite raising HDL-C. In the study, we generated transgenic (Tg) rabbits that overexpressed the human CETP gene to examine the influence of CETP on the development of atherosclerosis. Both Tg rabbits and their non-Tg littermates were fed a high cholesterol diet for 16 weeks. Plasma lipids and body weight were measured every 4 weeks. Gross lesion areas of the aortic atherosclerosis along with lesional cellular components were quantitatively analyzed. Overexpression of human CETP did not significantly alter the gross atherosclerotic lesion area, but the number of macrophages in lesions was significantly increased. Overexpression of human CETP did not change the plasma levels of total cholesterol or low-density lipoprotein cholesterol but lowered plasma HDL-C and increased triglycerides. These data revealed that human CETP may play an important role in the development of atherosclerosis mainly by decreasing HDL-C levels and increasing the accumulation of macrophage-derived foam cells.

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Virtual Planning of a Complex Three-Part Bimaxillary Osteotomy

In maxillofacial surgery, every patient presents special problems requiring careful evaluation. Conventional methods to study the deformities are still reliable, but the advent of tridimensional (3D) imaging, especially computed tomography (CT) scan and laser scanning of casts, created the opportunity to better understanding the skeletal support and the soft tissue structures. Nowadays, virtual technologies are increasingly employed in maxillofacial surgery and demonstrated precision and reliability. However, in complex surgical procedures, these new technologies are still controversial. Especially in the less frequent cases of three-part maxillary surgery, the experience is limited, and scientific literature cannot give a clear support. This paper presents the case of a young patient affected by a complex long face dentofacial deformity treated by a bimaxillary surgery with three-part segmentation of the maxilla. The operator performed the surgical study completely with a virtual workflow. Pre- and postoperative CT scan and optical scanning of plaster models were collected and compared. Every postoperatory maxillary piece was superimposed with the presurgical one, and the differences were examined in a color-coded map. Only mild differences were found near the osteotomy lines, when the bony surface and the teeth demonstrated an excellent coincidence.

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DSM-5 personality trait domains and withdrawal versus approach motivational tendencies in response to the perception of other people’s desperation and angry aggression

Publication date: Available online 27 November 2017
Source:Biological Psychology
Author(s): Ilona Papousek, Nilüfer Aydin, Christian Rominger, Kurt Feyaerts, Karin Schmid-Zalaudek, Helmut K. Lackner, Andreas Fink, Günter Schulter, Elisabeth M. Weiss
Expressions of affect communicate social messages, which trigger approach and withdrawal/avoidance motivational tendencies in the observer. The present study investigated relationships between inter-individual differences in the motivational responses to other people's affect expressions and DSM-5 personality trait domains. State-dependent, transient EEG alpha asymmetry responses provided indicators of the relative activation of withdrawal versus approach motivation in the respective social-emotional contexts. The Personality Inventory for the DSM-5 (PID-5) was used for the assessment of personality traits in a non-clinical sample. Individuals with higher levels of Antagonism showed relative activation of approach versus withdrawal motivation (as indicated by less relative right frontal activation) in response to confrontation with auditory expressions of angry aggression, whereas participants with higher levels of Detachment showed relative activation of withdrawal versus approach motivation (as indicated by greater relative right frontal activation) to the perception of other people's desperate crying.



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Lactic Acidosis in Prostate Cancer: Consider the Warburg Effect

Lactic acidosis is a commonly observed clinical condition that is associated with a poor prognosis, especially in malignancies. We describe a case of an 81-year-old patient who presented with symptoms of tachypnea and general discomfort. Arterial blood gas analysis showed a high anion gap acidosis with a lactate level of 9.5 mmol/L with respiratory compensation. CT scanning showed no signs of pulmonary embolism or other causes of impaired tissue oxygenation. Despite treatment with sodium bicarbonate, the patient developed an adrenalin-resistant cardiac arrest, most likely caused by the acidosis. Autopsy revealed Gleason score 5 + 5 metastatic prostate cancer as the most probable cause of the lactic acidosis. Next-generation sequencing indicated a nonsense mutation in the TP53 gene (887delA) and an activating mutation in the PIK3CA gene (1634A#x3e;G) as candidate molecular drivers. This case demonstrates the prevalence and clinical relevance of metabolic reprogramming, frequently referred to as “the Warburg effect,” in patients with prostate cancer.
Case Rep Oncol 2017;10:1085–1091

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Multiple Tumor Induction after Treatment of Temporal Arteritis with Prednisone

A 74-year-old female was diagnosed with the autoimmune inflammatory disease temporal arteritis and treated with high and low doses of prednisone over a period of 6 years. During that time, she developed cancers of the lung and colon as well as a soft tumor mass on lumbar vertebrate L3. She also experienced a series of debilitating and disabling symptoms while on prednisone treatment. A temporal analysis of the association of prednisone therapy and immune markers to the successive appearance of the malignant tumors strongly suggests that in the absence of a functioning natural immune and surveillance system by treatment with the immune knockout drug prednisone, spontaneous, multiple independent mutations occurred in several sites in the organ systems of this patient. Over a period of time, these developed into malignant cancers, including a lung nodule which became cancerous 256 days later, as well as the cancers of the colon and a soft tumor mass on lumbar vertebrate L3.
Case Rep Oncol 2017;10:1076–1084

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Contents Vol. 152, 2017

Cytogenet Genome Res 2017;152:I-IV

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Blowup for nonlinear wave equations describing boson stars

We consider the nonlinear wave equation [image] modeling the dynamics of (pseudorelativistic) boson stars. For spherically symmetric initial data, u0(x) ∈ Cmath image (ℝ3), with negative energy, we prove blowup of u(t, x) in the H1/2-norm within a finite time. Physically this phenomenon describes the onset of “gravitational collapse” of a boson star. We also study blowup in external, spherically symmetric potentials, and we consider more general Hartree-type nonlinearities. As an application, we exhibit instability of ground state solitary waves at rest if m = 0.

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Effects of throughfall and litterfall manipulation on concentrations of methylmercury and mercury in forest-floor percolates

The forest floor was shown to be an effective sink of atmospherically deposited methylmercury (MeHg) but less for total mercury (Hgtotal). We studied factors controlling the difference in dynamics of MeHg and Hgtotal in the forest floor by doubling the throughfall input and manipulating aboveground litter inputs (litter removal and doubling litter addition) in the snow-free period in a Norway spruce forest in NE Bavaria, Germany, for 14 weeks. The MeHg concentrations in the forest-floor percolates were not affected by any of the manipulation and ranged between 0.03 (Oa horizon) and 0.11 (Oi horizon) ng Hg L–1. The Hgtotal concentrations were largest in the Oa horizon (24 ng Hg L–1) and increased under double litterfall (statistically significant in the Oi horizon). Similarly, concentrations of dissolved organic C (DOC) increased after doubling of litterfall. The concentrations of Hgtotal and DOC correlated significantly in forest-floor percolates from all plots. However, we did not find any effect of DOC on MeHg concentrations. The difference in the coupling of Hgtotal and MeHg to DOC might be one reason for the differences in the mobility of Hg species in forest floors with a lower mobility of MeHg not controlled by DOC.

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SuperHirn - a novel tool for high resolution LC-MS-based peptide/protein profiling

Label-free quantification of high mass resolution LC-MS data has emerged as a promising technology for proteome analysis. Computational methods are required for the accurate extraction of peptide signals from LC-MS data and the tracking of these features across the measurements of different samples. We present here an open source software tool, SuperHirn, that comprises a set of modules to process LC-MS data acquired on a high resolution mass spectrometer. The program includes newly developed functionalities to analyze LC-MS data such as feature extraction and quantification, LC-MS similarity analysis, LC-MS alignment of multiple datasets, and intensity normalization. These program routines extract profiles of measured features and comprise tools for clustering and classification analysis of the profiles. SuperHirn was applied in an MS1-based profiling approach to a benchmark LC-MS dataset of complex protein mixtures with defined concentration changes. We show that the program automatically detects profiling trends in an unsupervised manner and is able to associate proteins to their correct theoretical dilution profile.

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Long term radiological features of radiation-induced lung damage

Publication date: Available online 27 November 2017
Source:Radiotherapy and Oncology
Author(s): Catarina Veiga, David Landau, Jamie R. McClelland, Jonathan A. Ledermann, David Hawkes, Sam M. Janes, Anand Devaraj
PurposeTo describe the radiological findings of radiation-induced lung damage (RILD) present on CT imaging of lung cancer patients 12 months after radical chemoradiation.Material and methodsBaseline and 12-month CT scans of 33 patients were reviewed from a phase I/II clinical trial of isotoxic chemoradiation (IDEAL CRT). CT findings were scored in three categories derived from eleven sub-categories: (1) parenchymal change, defined as the presence of consolidation, ground-glass opacities (GGOs), traction bronchiectasis and/or reticulation; (2) lung volume reduction, identified through reduction in lung height and/or distortions in fissures, diaphragm, anterior junction line and major airways anatomy, and (3) pleural changes, either thickening and/or effusion.ResultsSix patients were excluded from the analysis due to anatomical changes caused by partial lung collapse and abscess. All remaining 27 patients had radiological evidence of lung damage. The three categories, parenchymal change, shrinkage and pleural change were present in 100%, 96% and 82% respectively. All patients had at least two categories of change present and 72% all three. GGOs, reticulation and traction bronchiectasis were present in 44%, 52% and 37% of patients.ConclusionsParenchymal change, lung shrinkage and pleural change are present in a high proportion of patients and are frequently identified in RILD. GGOs, reticulation and traction bronchiectasis are common at 12 months but not diagnostic.



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Dynamical collapse of white dwarfs in Hartree- and Hartree-Fock theory

We study finite-time blow-up for pseudo-relativistic Hartree- and Hartree-Fock equations, which are model equations for the dynamical evolution of white dwarfs. In particular, we prove that radially symmetric initial configurations with negative energy lead to finite-time blow-up of solutions. Furthermore, we derive a mass concentration estimate for radial blow-up solutions. Both results are mathematically rigorous and are in accordance with Chandrasekhar’s physical theory of white dwarfs, stating that stellar configurations beyond a certain limiting mass lead to “gravitational collapse” of these objects. Apart from studying blow-up, we also prove local well-posedness of the initial-value problem for the Hartree- and Hartree-Fock equations underlying our analysis, as well as global-in-time existence of solutions with sufficiently small initial data, corresponding to white dwarfs whose stellar mass is below the Chandrasekhar limit.

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Special type of pheromone-induced invasive growth in Saccharomyces cerevisiae

The ability to invade a solid substrate is an important phenomenon due to its connection with pathogenic activity of fungi. We report here on invasion displayed by MATalpha cells of Saccharomyces cerevisiae lacking Isw2p, a subunit of the ISW2 chromatin remodelling complex. We found that on minimal medium, where the isw2Delta MATalpha mutant is not invasive, additional absence of another ISW2 complex subunit, Dls1p or Dpb4p, promoted invasion. Our microarray data showed that derepression of MAT a-specific genes caused by absence of Isw2p is very low. Their expression is increased only by the autocrine activation of the mating pathway. Invasion of isw2Delta MATalpha cells thus resembles the pheromone-induced invasion, including dependence on Fig2p. We show here that another pheromone-induced protein, mating agglutinin Aga1p, can play a role in the agar adhesion necessary for invasion. In contrast with MAT a-cells invading agar under low alpha-pheromone concentration, the invasive growth of isw2Delta cells specifically requires Fus3 kinase. Its function in the invasion of isw2Delta MATalpha cells cannot be completely substituted by Kss1 kinase, which plays a basic role in invasive growth signalling. We suggest that partial dependence of the isw2Delta MATalpha invasion on Fus3p and Aga1p corresponds to a weaker pheromone response of this mutant.

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Semi-classical dynamics in quantum spin systems

We consider two limiting regimes, the large-spin and the mean-field limit, for the dynamical evolution of quantum spin systems. We prove that, in these limits, the time evolution of a class of quantum spin systems is determined by a corresponding Hamiltonian dynamics of classical spins. This result can be viewed as a Egorov-type theorem. We extend our results to the thermodynamic limit of lattice spin systems and continuum domains of infinite size, and we study the time evolution of coherent spin states in these limiting regimes.

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Well-posedness for semi-relativistic Hartree equations of critical type

We prove local and global well-posedness for semi-relativistic, nonlinear Schrödinger equations i∂tu=−Δ+m2 √u+F(u) with initial data in Hs(ℝ3), s⩾1/2. Here F(u) is a critical Hartree nonlinearity that corresponds to Coulomb or Yukawa type self-interactions. For focusing F(u), which arise in the quantum theory of boson stars, we derive global-in-time existence for small initial data, where the smallness condition is expressed in terms of the L2-norm of solitary wave ground states. Our proof of well-posedness does not rely on Strichartz type estimates. As a major benefit from this, our method enables us to consider external potentials of a quite general class.

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Demethylation of dimethylarsinic acid and arsenobetaine in different organic soils

Methylation and demethylation of arsenic may change substantially the toxicity and mobility of arsenic in soils. Little is known about demethylation of organic arsenic species in organic soils. We incubated dimethylarsinic acid (DMA) and arsenobetaine (AsB) in soils and aqueous soil extracts from a forest floor and fen, in order to investigate demethylation processes. Incubations were conducted at 5°C in the dark under oxic or anoxic conditions. Arsenobetaine demethylated rapidly in all soil extracts with half-lives of 3.6–12 days, estimated from first order kinetic. Demethylation of DMA was relatively slow with half-lives of 187 and 46 days in the forest floor extracts and oxic fen extracts, respectively. In comparison, DMA was stable for 100 days in anoxic fen extracts. The apparent half-lives were much shorter in soils for DMA (1.3–12.6 days) and AsB (0.5–1.9 days) than in soil extracts, suggesting also irreversible AsB and DMA adsorption to soils beside demethylation. An unknown arsenic species and DMA were detected as metabolites of AsB demethylation. The results indicate rapid demethylation of AsB probably via the pathway AsB → Dimethylarsenoylacetate → DMA, followed up by slow demethylation of DMA → monomethylarsonic acid → inorganic As species.

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Serum procalcitonin for discrimination of blood contamination from bloodstream infection due to coagulase-negative staphylococci

The diagnostic value of serum procalcitonin (PCT) to distinguish blood contamination from bloodstream infection (BSI) due to coagulase-negative staphylococci was evaluated. Patients with BSI had higher PCT concentration than those with blood contamination at day -1, day 0 and day +1 with regard to blood culture collection (p > 0.05), whereas serum C-reactive protein values were significantly higher only on day +1. At a cutoff of 0.1 ng/dl, PCT had a sensitivity of 86% and 100%, and a specificity of 60% and 80% for the diagnosis of BSI on day -1 and 0, respectively. In addition to clinical and microbiological parameters, PCT may help discriminating blood contamination from BSI due coagulase-negative staphylococci.

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Finite orbits for rational maps

Let K be a number field and φ ∈ K(z) a rational function. Let S be the set of all archimedean places of K and all non-archimedean places associated to the prime ideals of bad reduction for φ. We prove an upper bound for the length of finite orbits for φ in ℙ1 (K) depending only on the cardinality of S.

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Fluxes of inorganic and organic arsenic species in a Norway spruce forest floor

To identify the role of the forest floor in arsenic (As) biogeochemistry, concentrations and fluxes of inorganic and organic As in throughfall, litterfall and forest floor percolates at different layers were investigated. Nearly 40% of total Astotal input (5.3 g As ha−1 yr−1) was retained in Oi layer, whereas Astotal fluxes from Oe and Oa layers exceeded the input by far (10.8 and 20 g As ha−1 yr−1, respectively). Except dimethylarsinic acid (DMA), fluxes of organic As decreased with depth of forest floor so that <10% of total deposition (all <0.3 g As ha−1 yr−1) reached the mineral soil. All forest floor layers are sinks for most organic As. Conversely, Oe and Oa layers are sources of Astotal, arsenite, arsenate and DMA. Significant correlations (r ≥ 0.43) between fluxes of Astotal, arsenite, arsenate or DMA and water indicate hydrological conditions and adsorption–desorption as factors influencing their release from the forest floor. The higher net release of arsenite from Oe and Oa and of DMA from Oa layer in the growing than dormant season also suggests microbial influences on the release of arsenite and DMA.

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Two neighboring residues of loop A of the alpha1 subunit point towards the benzodiazepine binding site of GABAA receptors

Benzodiazepines are widely used drugs exerting sedative, anxiolytic, muscle relaxant, and anticonvulsant effects by acting through specific high affinity binding sites on some GABA(A) receptors. It is important to understand how these ligands are positioned in this binding site. We are especially interested here in the conformation of loop A of the alpha(1)beta(2)gamma(2) GABA(A) receptor containing a key residue for the interaction of benzodiazepines: alpha(1)H101. We describe a direct interaction of alpha(1)N102 with a diazepam- and an imidazobenzodiazepine-derivative. Our observations help to better understand the conformation of this region of the benzodiazepine pocket in GABA(A) receptor.

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Circulating biomarkers as surrogates for bloodstream infections

The use of biomarkers provides a novel approach to diagnosing infection, its severity and treatment response. Biomarkers, especially procalcitonin and, to a lesser extent, C-reactive protein and interleukin 8, can improve the diagnostic and prognostic assessment of bloodstream infections. Both strengths and weaknesses of biomarkers must be recognized for rational and safe use in clinical settings. Cut-off ranges must be chosen within the specific clinical context. Ultrasensitive assays for procalcitonin, capable of measuring low levels in healthy individuals, may help to identify even 'subclinical' inflammatory states before the development of clinically evident sepsis. For immunocompromised patients, the use of biomarkers could lead to an earlier and more targeted antimicrobial therapy for patients at risk of sepsis, whereas those patients with viral illness or a non-infectious aetiology of inflammation who maintain low levels of procalcitonin over time can be withheld from antibiotic exposure. The time has arrived to move beyond the observational reporting of 'promising' biomarkers. Specific cut-off ranges must be proposed and intervention studies conducted to tackle the existing vicious cycle of diagnostic uncertainty, antibiotic overuse and emerging multi-resistance.

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Amiodarone-induced thyrotoxicosis: clinical course and predictors of outcome

OBJECTIVES: This study sought to determine the clinical course and predictors of long-term outcome in patients with documented amiodarone-induced thyrotoxicosis (AIT). BACKGROUND: Amiodarone-induced thyrotoxicosis is a condition that is difficult to manage, in particular because of the long half-life of amiodarone. Data on optimal treatment for AIT are scarce. METHODS: We performed a retrospective review among patients with documented AIT at a tertiary care center. Baseline characteristics, treatment received, laboratory parameters, and events during follow-up were evaluated. The predefined composite end point consisted of the following AIT-associated complications: death, heart transplantation, hospitalization for heart failure, myocardial infarction, stroke, hospitalization for arrhythmia management, or hospitalization for treatment complications. RESULTS: Eighty-four patients were included in the present analysis; 27 patients received prednisone for AIT. There was no difference in time to normalization of free thyroxine between those receiving and those not receiving prednisone. Long-term follow-up showed high morbidity and mortality; 47 patients (56%) reached the primary end point. Patients receiving prednisone had a worse outcome than those not receiving prednisone (p = 0.003). Although patients received prednisone for 84 +/- 65 days, curves started to separate only 12 months after the initial diagnosis. CONCLUSIONS: Patients with AIT have a high event rate during follow-up. Prednisone had no effect on time to normalization of thyroxine levels and was associated with an increased event rate. Importantly, AIT-related problems must be expected late, at a time when thyroid function is under control.

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S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling

S6 kinase 1 (S6K1) acts to integrate nutrient and growth factor signals to promote cell growth but also cell survival as a mitochondria-tethered protein kinase that phosphorylates and inactivates the proapoptotic molecule BAD. Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371. This activates a PP1gamma-dependent negative feedback program that decreases S6K1 activity and BAD phosphorylation, thereby altering the threshold for apoptosis. These findings establish URI and PP1gamma as integral components of an S6K1-regulated mitochondrial pathway dedicated, in part, to oppose sustained S6K1 survival signaling and to ensure that the mitochondrial threshold for apoptosis is set in accord with nutrient and growth factor availability.

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Sirt1 overexpression suppresses fluoride-induced p53 acetylation to alleviate fluoride toxicity in ameloblasts responsible for enamel formation

Abstract

Low-dose fluoride is an effective caries prophylactic, but high-dose fluoride is an environmental health hazard that causes skeletal and dental fluorosis. Treatments to prevent fluorosis and the molecular pathways responsive to fluoride exposure remain to be elucidated. Previously we showed that fluoride activates SIRT1 as an adaptive response to protect cells. Here, we demonstrate that fluoride induced p53 acetylation (Ac-p53) [Lys379], which is a SIRT1 deacetylation target, in ameloblast-derived LS8 cells in vitro and in enamel organ in vivo. Here we assessed SIRT1 function on fluoride-induced Ac-p53 formation using CRISPR/Cas9-mediated Sirt1 knockout (LS8^Sirt/KO) cells or CRISPR/dCas9/SAM-mediated Sirt1 overexpressing (LS8^Sirt1/over) cells. NaF (5 mM) induced Ac-p53 formation and increased cell cycle arrest via Cdkn1a/p21 expression in Wild-type (WT) cells. However, fluoride-induced Ac-p53 was suppressed by the SIRT1 activator resveratrol (50 µM). Without fluoride, Ac-p53 persisted in LS8^Sirt/KO cells, whereas it decreased in LS8^Sirt1/over. Fluoride-induced Ac-p53 formation was also suppressed in LS8^Sirt1/over cells. Compared to WT cells, fluoride-induced Cdkn1a/p21 expression was elevated in LS8^Sirt/KO and these cells were more susceptible to fluoride-induced growth inhibition. In contrast, LS8^Sirt1/over cells were significantly more resistant. In addition, fluoride-induced cytochrome-c release and caspase-3 activation were suppressed in LS8^Sirt1/over cells. Fluoride induced expression of the DNA double strand break marker γH2AX in WT cells and this was augmented in LS8^Sirt1/KO cells, but was attenuated in LS8^Sirt1/over cells. Our results suggest that SIRT1 deacetylates Ac-p53 to mitigate fluoride-induced cell growth inhibition, mitochondrial damage, DNA damage and apoptosis. This is the first report implicating Ac-p53 in fluoride toxicity.

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PD-L1 status does not predict the outcome of BRAF inhibitor therapy in metastatic melanoma

Publication date: January 2018
Source:European Journal of Cancer, Volume 88
Author(s): Katrin Schaper-Gerhardt, Steven Okoye, Rudolf Herbst, Jens Ulrich, Patrick Terheyden, Claudia Pföhler, Jochen S. Utikal, Alexander Kreuter, Peter Mohr, Edgar Dippel, Imke Satzger, Antje Sucker, Dirk Schadendorf, Selma Ugurel, Ralf Gutzmer
BackgroundTargeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients.Patients and methodsWe analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues. The oligocentre cohort 1 included 83 patients whose tumour tissues were analysed retrospectively with the anti-PD-L1 antibody clone E1L3N. The multicentre cohort 2 included 58 patients whose tumour tissues were analysed prospectively within the framework of the “Registry of the Arbeitsgemeinschaft Dermatologische Onkologie” (ADOREG) and “Tissue Registry in Melanoma” (TRIM) project using the anti-PD-L1 antibody clone 28–8.ResultsPD-L1 expression in pre-treatment tumour tissue did not correlate with response or survival to BRAFi-based therapies in both MM patient cohorts. This finding was not influenced by retrospective versus prospective immunohistochemistry analyses, oligocentre versus multicentre cohorts or the different anti-PD-L1 antibody clones used. In cohort 1, PD-L1 positivity was detected in tumour tissue of 41.0% and 18.1% of patients (cut-off 1% and 5%, respectively). In cohort 2, 58.6% and 39.7% of patients showed PD-L1 positivity (cut-off 1% and 5%, respectively).ConclusionIn two independent cohorts including a total of 141 MM patients, PD-L1 expression in tumour tissue did not correlate with the outcome of BRAFi-based treatment. Therefore, PD-L1 cannot be recommended for the use as a predictive biomarker of BRAFi-based therapy in BRAF V600-mutated MM.



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Mammographic density and breast cancer risk in breast screening assessment cases and women with a family history of breast cancer

Publication date: January 2018
Source:European Journal of Cancer, Volume 88
Author(s): Stephen W. Duffy, Oliver W.E. Morrish, Prue C. Allgood, Richard Black, Maureen G.C. Gillan, Paula Willsher, Julie Cooke, Karen A. Duncan, Michael J. Michell, Hilary M. Dobson, Roberta Maroni, Yit Y. Lim, Hema N. Purushothaman, Tamara Suaris, Susan M. Astley, Kenneth C. Young, Lorraine Tucker, Fiona J. Gilbert
BackgroundMammographic density has been shown to be a strong independent predictor of breast cancer and a causative factor in reducing the sensitivity of mammography. There remain questions as to the use of mammographic density information in the context of screening and risk management, and of the association with cancer in populations known to be at increased risk of breast cancer.AimTo assess the association of breast density with presence of cancer by measuring mammographic density visually as a percentage, and with two automated volumetric methods, Quantra™ and VolparaDensity™.MethodsThe TOMosynthesis with digital MammographY (TOMMY) study of digital breast tomosynthesis in the Breast Screening Programme of the National Health Service (NHS) of the United Kingdom (UK) included 6020 breast screening assessment cases (of whom 1158 had breast cancer) and 1040 screened women with a family history of breast cancer (of whom two had breast cancer). We assessed the association of each measure with breast cancer risk in these populations at enhanced risk, using logistic regression adjusted for age and total breast volume as a surrogate for body mass index (BMI).ResultsAll density measures showed a positive association with presence of cancer and all declined with age. The strongest effect was seen with Volpara absolute density, with a significant 3% (95% CI 1–5%) increase in risk per 10 cm³ of dense tissue. The effect of Volpara volumetric density on risk was stronger for large and grade 3 tumours.ConclusionsAutomated absolute breast density is a predictor of breast cancer risk in populations at enhanced risk due to either positive mammographic findings or family history. In the screening context, density could be a trigger for more intensive imaging.



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Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study

Publication date: January 2018
Source:European Journal of Cancer, Volume 88
Author(s): Nathalie Gaspar, Bob-Valéry Occean, Hélène Pacquement, Emmanuelle Bompas, Corine Bouvier, Hervé J. Brisse, Marie-Pierre Castex, Nadir Cheurfa, Nadège Corradini, Jessy Delaye, Natacha Entz-Werlé, Jean-Claude Gentet, Antoine Italiano, Cyril Lervat, Perrine Marec-Berard, Eric Mascard, Françoise Redini, Laure Saumet, Claudine Schmitt, Marie-Dominique Tabone, Cécile Verite-Goulard, Marie-Cécile Le Deley, Sophie Piperno-Neumann, Laurence Brugieres
BackgroundIn most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.MethodsTreatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.Results409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%).ConclusionM-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.



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IJMS, Vol. 18, Pages 2548: Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes

IJMS, Vol. 18, Pages 2548: Human Skin Permeation Studies with PPARγ Agonist to Improve Its Permeability and Efficacy in Inflammatory Processes

International Journal of Molecular Sciences doi: 10.3390/ijms18122548

Authors: Marcelle Silva-Abreu Lupe Espinoza María Rodríguez-Lagunas María-José Fábrega Marta Espina María García Ana Calpena

Rosacea is the most common inflammatory skin disease. It is characterized by erythema, inflammatory papules and pustules, visible blood vessels, and telangiectasia. The current treatment has limitations and unsatisfactory results. Pioglitazone (PGZ) is an agonist of peroxisome proliferator-activated receptors (PPARs), a nuclear receptor that regulates important cellular functions, including inflammatory responses. The purpose of this study was to evaluate the permeation of PGZ with a selection of penetration enhancers and to analyze its effectiveness for treating rosacea. The high-performance liquid chromatography (HPLC) method was validated for the quantitative determination of PGZ. Ex vivo permeation experiments were realized in Franz diffusion cells using human skin, in which PGZ with different penetration enhancers were assayed. The results showed that the limonene was the most effective penetration enhancer that promotes the permeation of PGZ through the skin. The cytotoxicity studies and the Draize test detected cell viability and the absence of skin irritation, respectively. The determination of the skin color using a skin colorimetric probe and the results of histopathological studies confirmed the ability of PGZ-limonene to reduce erythema and vasodilation. This study suggests new pharmacological indications of PGZ and its possible application in the treatment of skin diseases, namely rosacea.

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I due punti nell’italiano contemporaneo: segmentazione e organizzazione del testo

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A rat model of Parkinsonism shows depletion of dopamine in the retina

The retinal dopamine (DA) deficiency is an important feature of the pathogenesis in Parkinson`s disease (PD) visual dysfunction. Systemic inhibition of complex I (rotenone) in rats has been proposed as a model of PD. In this study, we investigated whether systemic inhibition of complex I can induce impairment of DA-ergic cells in the retina, similar to the destruction of retinal cells found in PD patients. Rotenone (2.5mg/kg i.p., daily) was administered over 60 days. Neurochemically, rotenone treated rats showed a depletion of DA in the striatum and substantia nigra (SN). In addition, the number of retinal DA-ergic amacrine cells was significantly reduced in the rotenone treated animals. This study is the first one giving highlight towards a deeper understanding of systemic complex I inhibition (rotenone as an environmental toxin) and the connection between both, DA-ergic degeneration in the nigrostriatal pathway, and in the DA-ergic amacrine cells of the retina.

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Homeostatic regulation of eye-specific responses in visual cortex during ocular dominance plasticity

Experience-dependent plasticity is crucial for the precise formation of neuronal connections during development. It is generally thought to depend on Hebbian forms of synaptic plasticity. In addition, neurons possess other, homeostatic means of compensating for changes in sensory input, but their role in cortical plasticity is unclear. We used two-photon calcium imaging to investigate whether homeostatic response regulation contributes to changes of eye-specific responsiveness after monocular deprivation (MD) in mouse visual cortex. Short MD durations decreased deprived-eye responses in neurons with binocular input. Longer MD periods strengthened open-eye responses, and surprisingly, also increased deprived-eye responses in neurons devoid of open-eye input. These bidirectional response adjustments effectively preserved the net visual drive for each neuron. Our finding that deprived-eye responses were either weaker or stronger after MD, depending on the amount of open-eye input a cell received, argues for both Hebbian and homeostatic mechanisms regulating neuronal responsiveness during experience-dependent plasticity.

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Symptom remission in OCD after discontinuation of pharmacotherapy with fluoxetine: a case for looking beyond serotonin

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Mobile arsenic species in unpolluted and polluted soils

The fate and behaviour of total arsenic (As) and of As species in soils is of concern for the quality of drinking water. To estimate the relevance of organic As species and the mobility of different As species, we evaluated the vertical distribution of organic and inorganic As species in two uncontaminated and two contaminated upland soils. Dimethylarsinic acid (up to 6 ng As g− 1), trimethylarsine oxide (up to 1.5 ng As g− 1), 4 unidentified organic As species (up to 3 ng As g− 1) and arsenobetaine (up to 15 ng As g− 1), were detected in the forest soils. Arsenobetaine was the dominant organic As species in both unpolluted and polluted forest soils. No organic As species were detected in the contaminated grassland soil. The organic As species may account for up to 30% of the mobile fraction in the unpolluted forest floor, but never exceed 9% in the unpolluted mineral soil. Highest concentrations of organic As species were found in the forest floors. The concentrations of extractable arsenite were highest in the surface horizons of all soils and may represent up to 36% of total extractable As. The concentrations of extractable arsenate were also highest in the Oa layers in the forest soils and decreased steeply in the mineral soil. In conclusion, the investigated forest soils contain a number of organic As species. The organic As species in forest soils seem to result from throughfall and litterfall and are retained mostly in the forest floor. The relative high concentrations of extractable arsenite, one of the most toxic As species, and arsenate in the forest floor point to the risk of their transfer to surface water by superficial flow under heavy rain events.

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Biogeochemistry of organic and inorganic arsenic species in a forested catchment in Germany

Little is known about the fate and behavior of diffuse inputs of arsenic (As) species in forested catchments which often are the sources of drinking water. The objective of this study was to investigate the mobility and transformation of different As species in forest ecosystems to assess the environmental risk related to the diffuse pollution of As. We determined concentrations and fluxes in precipitation, litterfall, soil solutions (Oa horizon and 20- and 90-cm depth), and runoff of organic and inorganic As species and Astotal in a forest ecosystem in NE-Bavaria, Germany. The concentrations of Astotal were mostly <1 μg As L-1 in aqueous samples and were highest in forest floor percolates (7.6 μg As L-1). In litterfall, the concentrations of As species never exceeded 0.1 μg As g-1. Arsenate and arsenite were the prevalent As species in all samples. Organic As species, comprising monomethylarsonic acid, dimethylarsinic acid, trimethylarsine oxide, arsenobetaine, and three unidentified organic As species, were mostly found in throughfall reaching up to 45% of Astotal. The total deposition of Astotal (calculated as throughfall + litterfall) was 5.6 g As ha-1 yr-1 with 16% contribution of litterfall. The annual Astotal fluxes were 30 g As ha-1 yr-1 for forest floor percolates, 8.0 g As ha-1 yr-1 at 20-cm soil depth, and 1.4 g As ha-1 yr-1 at 90-cm soil depth. The annual runoff of Astotal from the catchment amounted to 3.8 g As ha-1 yr-1. The annual fluxes of total organic As species was highest in total deposition (1.1 g As ha-1 yr-1) and decreased largely with depth in the soil profile. The annual runoff of total organic As species was only 0.08 g As ha-1 yr-1. Significant correlations in soil solutions and runoff were found between Astotal and dissolved organic C and Fe. Correlations between Astotal concentrations in runoff and water fluxes were seasonally dependent and with a steeper slope in the growing season than in the dormant season. The elevated concentrations of organic As species in throughfall indicate microbial methylation of As in the phyllosphere, but no evidence for methylation in the soil was found. The mass balance of the catchment points out the strong retention and probable degradation or oxidation of organic As species and arsenite but also to mobilizable pools of Astotal and arsenate. The forest floor is presently a source, whereas the mineral soil is a sink for Astotal and arsenate. The As concentrations in runoff seem to be controlled by As mobilization from forest floor and riparian wetland soils during heavy rain events and superficial flow. The risk for excessment of the drinking water threshold concentrations of As in runoff and soil solutions is considered low at our site.

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The aging decision maker: Cognitive aging and the adaptive selection of decision strategies

Are older adults' decision abilities fundamentally compromised by age-related cognitive decline? Or can they adaptively select decision strategies? One study (N = 163) investigated the impact of cognitive aging on the ability to select decision strategies as a function of environment structure. Participants made decisions in either an environment that favored the use of information-intensive strategies or one favoring the use of simple, information-frugal strategies. Older adults tended to (a) look up less information and take longer to process it and (b) use simpler, less cognitively demanding strategies. In accordance with the idea that age-related cognitive decline leads to reliance on simpler strategies, measures of fluid intelligence explained age-related differences in information search and strategy selection. Nevertheless, both young and older adults seem to be equally adapted decision makers in that they adjust their information search and strategy selection as a function of environment structure, suggesting that the aging decision maker is an adaptive one.

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PhosphoPep-a phosphoproteome resource for systems biology research in Drosophila Kc167 cells

The ability to analyze and understand the mechanisms by which cells process information is a key question of systems biology research. Such mechanisms critically depend on reversible phosphorylation of cellular proteins, a process that is catalyzed by protein kinases and phosphatases. Here, we present PhosphoPep, a database containing more than 10 000 unique high-confidence phosphorylation sites mapping to nearly 3500 gene models and 4600 distinct phosphoproteins of the Drosophila melanogaster Kc167 cell line. This constitutes the most comprehensive phosphorylation map of any single source to date. To enhance the utility of PhosphoPep, we also provide an array of software tools that allow users to browse through phosphorylation sites on single proteins or pathways, to easily integrate the data with other, external data types such as protein-protein interactions and to search the database via spectral matching. Finally, all data can be readily exported, for example, for targeted proteomics approaches and the data thus generated can be again validated using PhosphoPep, supporting iterative cycles of experimentation and analysis that are typical for systems biology research.

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Structural biology: analysis of `downhill` protein folding

There is controversy as to whether homologues from the peripheral subunit binding domain family of small proteins fold `downhill` (that is, non-cooperatively, in the absence of free-energy barriers between conformations) and whether they modulate their size for biological function. Sadqi et al. claim that Naf-BBL-a naphthylalanine-labelled, truncated version of this domain-folds in this way, on the grounds that they recorded a wide spread of melting temperatures of individual atoms measured by proton nuclear magnetic resonance (NMR) during their thermal denaturation. But their data are not of adequate quality to distinguish, within experimental error, between downhill folding and folding with a cooperative transition. Accordingly, their results offer no compelling evidence that Naf-BBL folds downhill, particularly as non-truncated, unmodified peripheral subunit binding domains seem to fold cooperatively.

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Distinguishing between cooperative and unimodal downhill protein folding

Conventional cooperative protein folding invokes discrete ensembles of native and denatured state structures in separate free-energy wells. Unimodal noncooperative (`downhill`) folding, however, proposes an ensemble of states occupying a single free-energy well for proteins folding at >/=4 x 10(4) s(-1) at 298 K. It is difficult to falsify unimodal mechanisms for such fast folding proteins by standard equilibrium experiments because both cooperative and unimodal mechanisms can present the same time-averaged structural, spectroscopic, and thermodynamic properties when the time scale used for observation is longer than for equilibration. However, kinetics can provide the necessary evidence. Chevron plots with strongly sloping linear refolding arms are very difficult to explain by downhill folding and are a signature for cooperative folding via a transition state ensemble. The folding kinetics of the peripheral subunit binding domain POB and its mutants fit to strongly sloping chevrons at observed rate constants of >6 x 10(4) s(-1) in denaturant solution, extrapolating to 2 x 10(5) s(-1) in water. Protein A, which folds at 10(5) s(-1) at 298 K, also has a well-defined chevron. Single-molecule fluorescence energy transfer experiments on labeled Protein A in the presence of denaturant demonstrated directly bimodal distributions of native and denatured states.

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Third activity of Bordetella adenylate cyclase (AC) toxin-hemolysin. Membrane translocation of AC domain polypeptide promotes calcium influx into CD11b+ monocytes independently of the catalytic and hemolytic activities

The Bordetella adenylate cyclase toxin-hemolysin (CyaA) targets phagocytes expressing the alpha(M)beta2 integrin (CD11b/CD18), permeabilizes their membranes by forming small cation-selective pores, and delivers into cells a calmodulin-activated adenylate cyclase (AC) enzyme that dissipates cytosolic ATP into cAMP. We describe here a third activity of CyaA that yields elevation of cytosolic calcium concentration ([Ca2+]i) in target cells. The CyaA-mediated [Ca2+]i increase in CD11b+ J774A.1 monocytes was inhibited by extracellular La3+ ions but not by nifedipine, SK&F 96365, flunarizine, 2-aminoethyl diphenylborinate, or thapsigargin, suggesting that influx of Ca2+ into cells was not because of receptor signaling or opening of conventional calcium channels by cAMP. Compared with intact CyaA, a CyaA-AC- toxoid unable to generate cAMP promoted a faster, albeit transient, elevation of [Ca2+]i. This was not because of cell permeabilization by the CyaA hemolysin pores, because a mutant exhibiting a strongly enhanced pore-forming activity (CyaA-E509K/E516K), but unable to deliver the AC domain into cells, was also unable to elicit a [Ca2+]i increase. Further mutations interfering with AC translocation into cells, such as proline substitutions of glutamate residues 509 or 570 or deletion of the AC domain as such, reduced or ablated the [Ca2+]i-elevating capacity of CyaA. Moreover, structural alterations within the AC domain, because of insertion of various oligopeptides, differently modulated the kinetics and extent of Ca2+ influx elicited by the respective AC- toxoids. Hence, the translocating AC polypeptide itself appears to participate in formation of a novel type of membrane path for calcium ions, contributing to action of CyaA in an unexpected manner.

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Segments crucial for membrane translocation and pore-forming activity of Bordetella adenylate cyclase toxin

Bordetella adenylate cyclase toxin-hemolysin (CyaA, AC-Hly, or ACT) permeabilizes cell membranes by forming small cation-selective (hemolytic) pores and subverts cellular signaling by delivering into host cells an adenylate cyclase (AC) enzyme that converts ATP to cAMP. Both AC delivery and pore formation were previously shown to involve a predicted amphipathic alpha-helix(502-522) containing a pair of negatively charged Glu(509) and Glu(516) residues. Another predicted transmembrane alpha-helix(565-591) comprises a Glu(570) and Glu(581) pair. We examined the roles of these glutamates in the activity of CyaA. Substitutions of Glu(516) increased specific hemolytic activity of CyaA by two different molecular mechanisms. Replacement of Glu(516) by positively charged lysine residue (E516K) increased the propensity of CyaA to form pores, whereas proline (E516P) or glutamine (E516Q) substitutions extended the lifetime of open single pore units. All three substitutions also caused a drop of pore selectivity for cations. Substitutions of Glu(570) and Glu(581) by helix-breaking proline or positively charged lysine residue reduced (E570K, E581P) or ablated (E570P, E581K) AC membrane translocation. Moreover, E570P, E570K, and E581P substitutions down-modulated also the specific hemolytic activity of CyaA. In contrast, the E581K substitution enhanced the hemolytic activity of CyaA 4 times, increasing both the frequency of formation and lifetime of toxin pores. Negative charge at position 570, but not at position 581, was found to be essential for cation selectivity of the pore, suggesting a role of Glu(570) in ion filtering inside or close to pore mouth. The pairs of glutamate residues in the predicted transmembrane segments of CyaA thus appear to play a key functional role in membrane translocation and pore-forming activities of CyaA.

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Proximity-accelerated chemical coupling reaction in the benzodiazepine-binding site of gamma-aminobutyric acid type A receptors: superposition of different allosteric modulators

Benzodiazepines are widely used drugs. They exert sedative/hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects and act through a specific high affinity binding site on the major inhibitory neurotransmitter receptor, the gamma-aminobutyric acid type A (GABA(A)) receptor. Ligands of the benzodiazepine-binding site are classified into three groups depending on their mode of action: positive and negative allosteric modulators and antagonists. To rationally design ligands of the benzodiazepine site in different isoforms of the GABA(A) receptor, we need to understand the relative positioning and overlap of modulators of different allosteric properties. To solve these questions, we used a proximity-accelerated irreversible chemical coupling reaction. GABA(A) receptor residues thought to reside in the benzodiazepine-binding site were individually mutated to cysteine and combined with a cysteine-reactive benzodiazepine site ligand. Direct apposition of reaction partners is expected to lead to a covalent reaction. We describe here such a reaction of predominantly alpha(1)H101C and also three other mutants (alpha(1)G157C, alpha(1)V202C, and alpha(1)V211C) with an Imid-NCS derivative in which a reactive isothiocyanate group (-NCS) replaces the azide group (-N(3)) in the partial negative allosteric modulator Ro15-4513. Our results show four contact points of imidazobenzodiazepines with the receptor, alpha(1)H101C being shared by classical benzodiazepines. Taken together with previous data, a similar orientation of these ligands within the benzodiazepine-binding pocket may be proposed.

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Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis

Plasma levels of endothelin-1 (ET-1) and adrenomedullin (ADM), two opposingly acting peptides, correlate with mortality in endotoxemia, but their measurement is cumbersome. New sandwich assays have been introduced that measure more stable precursor fragments. The objective of this study was to investigate the counterplay of their precursor peptides in septic patients and to compare them with disease severity and other biomarkers. Blood samples of an observational study in 95 consecutive critically ill patients admitted to the intensive care unit (ICU) were analyzed. CT-proET-1 and MR-proADM concentrations on admission were measured using new sandwich immunoassays. Depending on the clinical severity of the infection, both CT-proET-1 and MR-proADM levels exhibited a gradual increase from Systemic Inflammatory Response Syndrome (SIRS) to sepsis and septic shock (p > .001). Compared to the group of survivors, the group of nonsurvivors had higher median values of MR-proADM (5.7 nmol/L [range 0.4 to 21.0] versus 1.9 nmol/L [range 0.3 to 17.1], p > .02) and similar CT-proET-1 levels (56.0pmol/L [range 0.5 to 271.0] versus 54.1pmol/L [range 1.0 to 506.0], p = .86). Receiver operating characteristics (ROC) curve analysis showed a higher prognostic accuracy of the calculated ratio of both counteracting substances as compared to CT-proET-1 (p = 0.001) and C-reactive protein (CRP) (p = .001) and in the range of MR-proADM (p = .51), procalcitonin (p = 0.22), and the APACHE II score (p = .61). Endothelin-1 and adrenomedullin precursor peptides gradually increase with increasing severities of infection in critically ill patients. The ratio of the two counteracting peptides correlates with mortality and shows a prognostic accuracy to predict adverse outcome comparable to the APACHE II score.

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Effective dynamics for boson stars

We study solutions close to solitary waves of the pseudo-relativistic Hartree equation describing boson stars under the influence of an external gravitational field. In particular, we analyse the long-time effective dynamics of such solutions. In essence, we establish a (long-time) stability result for solutions describing boson stars that move under the influence of an external gravitational field. The proof of our main result tackles difficulties that are absent when deriving similar results on effective solitary wave motions for nonlinear Schrödinger equations or nonlinear wave equations. This is due to the fact that the pseudo-relativisitic Hartree equation does not exhibit Galilean or Lorentz covariance.

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Biomarkers to improve diagnostic and prognostic accuracy in systemic infections

PURPOSE OF REVIEW: We review the advantages and drawbacks of biomarkers in the diagnostic and prognostic assessment of systemic infections. RECENT FINDINGS: Since the signs and symptoms of severe infections can be ambiguous, biomarkers provide a more reliable tool in ascertaining the presence of a relevant bacterial infection, its severity and treatment response. Procalcitonin and, to a lesser extent, C-reactive protein and interleukin-8 can improve the diagnostic assessment of infections and guide antibiotic therapy. Promising prognostic biomarkers include cortisol, proadrenomedullin, copeptin and natriuretic peptides. The strengths and weaknesses of biomarkers must be recognized in order to use them rationally and safely. Cutoff ranges of biomarkers must be chosen according to the specific clinical context and they should be used as a complementary tool, to reinforce the clinical diagnostic workup. Biomarkers cannot determine the causative organisms and associated patterns of antibiotic susceptibility. SUMMARY: If used in the proper setting, serial measurements of diagnostic biomarkers may allow treatments to be adjusted at an early stage in patients with severe infections. This may involve either intensifying treatment when infection levels stay high or avoiding unnecessary prolonged courses of antibiotics when levels rapidly decrease, thereby improving the allocation of healthcare resources.

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Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock

Arginine vasopressin (AVP) levels are increased in hemorrhagic and septic shock. Measurement of AVP levels has limitations due to its short half-life and cumbersome detection method. Copeptin is a more stable peptide derived from the same precursor molecule. We evaluated the plasma copeptin concentration in two independent studies: first, in an experimental baboon model of hemorrhagic shock, and second, in a prospective observational study of 101 consecutive critically ill patients at a university hospital. Copeptin was measured with a newly developed sandwich immunoassay using two polyclonal antibodies to the C-terminal region (amino acid sequence 132-164) of pre-pro-AVP. Copeptin concentrations in hemorrhagic shock increased markedly from median (range) of 7.5 [2.7-13) to 269 pM (241-456 pM). After reperfusion, copeptin levels dropped within hours to a plateau of 27 pM (15-78 pM). In the critically ill patient cohort, copeptin values increased significantly with the severity of the disease and were in patients without sepsis [27.6 pM [2.3-297 pM]), in sepsis [50.0 pM [8.5-268 pM]), in severe sepsis [73.6 pM [15.3-317 pM]), and in septic shock [171.5 pM (35.1-504 pM] compared with 4.1 pM (1.0-13.8 pM) in healthy controls (P for all vs. controls >0.001). On admission, circulating copeptin levels were higher in nonsurvivors (171.5 pM, 46.5-504.0 pM) as compared with survivors (86.8 pM, 8.5-386.0 pM; P = 0.01). Copeptin levels correlated with basal cortisol levels (r = 0.42; P > 0.001) and osmolality (r = 0.42; P > 0.001). In a logistic regression model including other covariates besides copeptin (e.g., determinants of fluid status) on survival, serum copeptin levels were the only independent significant predictor of outcome (P = 0.03). Copeptin concentrations are elevated in hemorrhagic and septic shock. Copeptin was higher on admission in nonsurvivors as compared with survivors, suggesting copeptin as a prognostic marker in sepsis. The availability of a reliable assay for the measurement of AVP release can also prove useful for the assessment of fluid and osmosis status in various diseases.

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