RTX toxins in Pasteurellaceae

RTX toxins (repeats in the structural toxin) are pore-forming protein toxins produced by a broad range of pathogenic Gram-negative bacteria. In vitro, RTX toxins mostly exhibit a cytotoxic and often also a hemolytic activity. They are particularly widespread in species of the family Pasteurellaceae which cause infectious diseases, most frequently in animals but also in humans. Most RTX toxins are proteins with a molecular mass of 100-200 kDa and are post-translationally activated by acylation via a specific activator protein. The repeated structure of RTX toxins, which gave them their name, is composed of iterative glycine-rich nonapeptides binding Ca2+ on the C-terminal half of the protein. Genetic analysis of RTX toxins of various species of Pasteurellaceae and of a few other Gram-negative bacteria gave evidence of horizontal transfer of genes encoding RTX toxins and led to speculations that RTX toxins might have originated from Pasteurellaceae. The toxic activities of RTX toxins in host cells may lead to necrosis and apoptosis and the underlying detailed mechanisms are currently under investigation. The impact of RTX toxins in pathogenicity and the immune responses of the host were described for several species of Pasteurellaceae. Neutralizing antibodies were shown to significantly reduce the cytotoxic activity of RTX toxins. They constitute a valuable strategy in the development of immuno-prophylactics against several animal diseases caused by pathogenic species of Pasteurellaceae. Although many RTX toxins possess cytotoxic and hemolytic activities toward a broad range of cells and erythrocytes, respectively, a few RTX toxins were shown to have cytotoxic activity only against cells of specific hosts and/or show cell-type specificity. Further evidence exists that RTX toxins play a potential role in host specificity of certain pathogens.

Impact of viral load and the duration of primary infection on HIV transmission

Abstract Objectives: HIV 'treatment as prevention' (TasP) describes early treatment of HIV-infected patients intended to reduce viral load and transmission. Crucial assumptions for estimating TasP's effectiveness are the underlying estimates of transmission risk. We aimed to determine transmission risk during primary infection, and of the relation of HIV transmission risk to viral load. Design: A systematic review and meta-analysis. Methods: We searched PubMed and Embase databases for studies that established a relationship between viral load and transmission risk, or primary infection and transmission risk, in serodiscordant couples. We analysed assumptions about the relationship between viral load and transmission risk, and between duration of primary infection and transmission risk. Results: We found 36 eligible articles, based on six different study populations. Studies consistently found that larger viral loads lead to higher HIV transmission rates, but assumptions about the shape of this increase varied from exponential increase to saturation. The assumed duration of primary infection ranged from 1.5 to 12 months; for each additional month, the log10 transmission rate ratio between primary and asymptomatic infection decreased by 0.40. Conclusion: Assumptions and estimates of the relationship between viral load and transmission risk, and the relationship between primary infection and transmission risk, vary substantially and predictions of TasP's effectiveness should take this uncertainty into account.

A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.

The search for the primary tumor in metastasized gastroenteropancreatic neuroendocrine neoplasm.

Gastroenteropancreatic neuroendocrine tumors (NETs) often present as liver metastasis from a carcinoma of unknown primary. We recently showed that primary NETs from the pancreas, small intestine and stomach as well as their respective liver metastases differ from each other by the expression profile of the three genes CD302, PPWD1 and ABHB14B. The gene and protein expression of CD302, PPWD1, and ABHB14B was studied in abdominal NET metastases to identify the site of the respective primary tumors. Cryopreserved tissue from NET metastases collected in different institutions (group A: 29, group B: 50, group C: 132 specimens) were examined by comparative genomic hybridization (Agilent 105 K), gene expression analysis (Agilent 44 K) (groups A and B) and immunohistochemistry (group C). The data were blindly evaluated, i.e. without knowing the site of the primary. Gene expression analysis correctly revealed the primary in the ileum in 94 % of the cases of group A and in 58 % of group B. A pancreatic primary was predicted in 83 % (group A) and 20 % (group B), respectively. The combined sensitivity of group A and B was 75 % for ileal NETs and 38 % for pancreatic NETs. Immunohistochemical analysis of group C revealed an overall sensitivity of 80 %. Gene and protein expression analysis of CD302 and PPWD1 in NET metastases correctly identifies the primary in the pancreas or the ileum in 80 % of the cases, provided that the tissue is well preserved. Immunohistochemical profiling revealed CD302 as the best marker for ileal and PPWD1 for pancreatic detection.

A g-factor metric for k-t-GRAPPA- and PEAK-GRAPPA-based parallel imaging.

PURPOSE The aim of this work is to derive a theoretical framework for quantitative noise and temporal fidelity analysis of time-resolved k-space-based parallel imaging methods. THEORY An analytical formalism of noise distribution is derived extending the existing g-factor formulation for nontime-resolved generalized autocalibrating partially parallel acquisition (GRAPPA) to time-resolved k-space-based methods. The noise analysis considers temporal noise correlations and is further accompanied by a temporal filtering analysis. METHODS All methods are derived and presented for k-t-GRAPPA and PEAK-GRAPPA. A sliding window reconstruction and nontime-resolved GRAPPA are taken as a reference. Statistical validation is based on series of pseudoreplica images. The analysis is demonstrated on a short-axis cardiac CINE dataset. RESULTS The superior signal-to-noise performance of time-resolved over nontime-resolved parallel imaging methods at the expense of temporal frequency filtering is analytically confirmed. Further, different temporal frequency filter characteristics of k-t-GRAPPA, PEAK-GRAPPA, and sliding window are revealed. CONCLUSION The proposed analysis of noise behavior and temporal fidelity establishes a theoretical basis for a quantitative evaluation of time-resolved reconstruction methods. Therefore, the presented theory allows for comparison between time-resolved parallel imaging methods and also nontime-resolved methods. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Measurement of flow harmonics with multi-particle cumulants in Pb+Pb collisions at √sNN=2.76 TeV with the ATLAS detector

ATLAS measurements of the azimuthal anisotropy in lead–lead collisions at √sNN = 2.76 TeV are shown using a dataset of approximately 7μb−1 collected at the LHC in 2010. The measurements are performed for charged particles with transversemomenta 0.5 < pT < 20 GeV and in the pseudorapidity range |η| < 2.5. The anisotropy is characterized by the Fourier coefficients, vn, of the charged-particle azimuthal angle distribution for n = 2–4. The Fourier coefficients are evaluated using multi-particle cumulants calculated with the generating function method. Results on the transverse momentum, pseudorapidity and centrality dependence of the vn coefficients are presented. The elliptic flow, v2, is obtained from the two-, four-, six- and eight-particle cumulants while higher-order coefficients, v3 and v4, are determined with two- and four-particle cumulants. Flow harmonics vn measured with four-particle cumulants are significantly reduced compared to the measurement involving two-particle cumulants. A comparison to vn measurements obtained using different analysis methods and previously reported by the LHC experiments is also shown. Results of measurements of flow fluctuations evaluated with multiparticle cumulants are shown as a function of transverse momentum and the collision centrality. Models of the initial spatial geometry and its fluctuations fail to describe the flow fluctuations measurements.

Low Yield of Methicillin-Resistant Staphylococcus aureus Screening in Hemodialysis Patients: 10 Years' Experience

OBJECTIVE To determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in hemodialysis patients and to analyze the cost-effectiveness of our screening approach compared with an alternative strategy. DESIGN Screening study and cost-effectiveness analysis. METHODS Analysis of twice-yearly MRSA prevalence studies conducted in the hemodialysis unit of a 950-bed tertiary care hospital from January 1, 2004, through December 31, 2013. For this purpose, nasal swab samples were cultured on MRSA screening agar (mannitol-oxacillin biplate). RESULTS There were 20 mass screenings during the 10-year study period. We identified 415 patients participating in at least 1 screening, with an average of 4.5 screenings per patient. Of 415 screened patients, 15 (3.6%) were found to be MRSA carriers. The first mass screening in 2004 yielded the highest percentage of MRSA (6/101 [6%]). Only 7 subsequent screenings revealed new MRSA carriers, whereas 4 screenings confirmed previously known carriers, and 8 remained negative. None of the carriers developed MRSA bacteremia during the study period. The total cost of our screening approach, that is, screening and isolation costs, was US $93,930. The total cost of an alternative strategy (ie, no mass screening administered) would be equivalent to costs of isolation of index cases and contact tracing was estimated to be US $5,382 (difference, US $88,548). CONCLUSIONS In an area of low MRSA endemicity (<5%), regular nasal screenings of a high-risk population yielded a low rate of MRSA carriers. Twice-yearly MRSA screening of dialysis patients is unlikely to be cost-effective if MRSA prevalence is low. Infect. Control Hosp. Epidemiol. 2015;00(0):1-4.

Structure and dynamics of hybrid zones at different stages of speciation in the common vole (Microtus arvalis)

The genetic structure and dynamics of hybrid zones provide crucial information for understanding the processes and mechanisms of evolutionary divergence and speciation. In general, higher levels of evolutionary divergence between taxa are more likely to be associated with reproductive isolation and may result in suppressed or strongly restricted hybridization. In this study, we examined two secondary contact zones between three deep evolutionary lineages in the common vole (Microtus arvalis). Differences in divergence times between the lineages can shed light on different stages of reproductive isolation and thus provide information on the ongoing speciation process in M. arvalis. We examined more than 800 individuals for mitochondrial (mtDNA), Y-chromosome and autosomal markers and used assignment and cline analysis methods to characterize the extent and direction of gene flow in the contact zones. Introgression of both autosomal and mtDNA markers in a relatively broad area of admixture indicates selectively neutral hybridization between the least-divergent lineages (Central and Eastern) without evidence for partial reproductive isolation. In contrast, a very narrow area of hybridization, shifts in marker clines and the quasi-absence of Y-chromosome introgression support a moving hybrid zone and unidirectional selection against male hybrids between the lineages with older divergence (Central and Western). Data from a replicate transect further support non-neutral processes in this hybrid zone and also suggest a role for landscape history in the movement and shaping of geneflow profiles.

Extraction of spin periods of space debris from optical light curves

The population of space debris increased drastically during the last years. These objects have become a great threat for active satellites. Because the relative velocities between space debris and satellites are high, space debris objects may destroy active satellites through collisions. Furthermore, collisions involving massive objects produce large number of fragments leading to significant growth of the space debris population. The long term evolution of the debris population is essentially driven by so-called catastrophic collisions. An effective remediation measure in order to stabilize the population in Low Earth Orbit (LEO) is therefore the removal of large, massive space debris. To remove these objects, not only precise orbits, but also more detailed information about their attitude states will be required. One important property of an object targeted for removal is its spin period, spin axis orientation and their change over time. Rotating objects will produce periodic brightness variations with frequencies which are related to the spin periods. Such a brightness variation over time is called a light curve. Collecting, but also processing light curves is challenging due to several reasons. Light curves may be undersampled, low frequency components due to phase angle and atmospheric extinction changes may be present, and beat frequencies may occur when the rotation period is close to a multiple of the sampling period. Depending on the method which is used to extract the frequencies, also method-specific properties have to be taken into account. The astronomical Institute of the University of Bern (AIUB) light curve database will be introduced, which contains more than 1,300 light curves acquired over more than seven years. We will discuss properties and reliability of different time series analysis methods tested and currently used by AIUB for the light curve processing. Extracted frequencies and reconstructed phases for some interesting targets, e.g. GLONASS satellites, for which also SLR data were available for the period confirmation, will be presented. Finally we will present the reconstructed phase and its evolution over time of a High-Area-to-Mass-Ratio (HAMR) object, which AIUB observed for several years.

Are suicide attempters wired differently?

Objective: Limited research exists on internal risk processes in suicide attempters and factors that distinguish them from non-suicidal, depressive individuals. In this qualitative study, we investigated Plans, motives, and underlying self-regulatory processes of the two groups and conducted a comparative analysis. Methods: We analyzed narrative interviews of 17 suicide attempters and intake interviews of 17 non-suicidal, depressive patients using Plan Analysis. Then, we developed a prototypical Plan structure for both groups. Results: Suicidal behavior serves various Plans only found in suicide attempters. Plans of this group are especially related to social perfectionism and withdrawal in order to protect their self-esteem. Depressive patients employ several interpersonal control and coping strategies, which might help prevent suicidal behavior. Conclusion: The prototypical Plan structure of suicide attempters may be a valuable tool for clinicians to detect critical Plans and motives in their interaction with patients, which are related to suicide risk.

Prognostic and diagnostic value of EEG signal coupling measures in coma.

OBJECTIVE Our aim was to assess the diagnostic and predictive value of several quantitative EEG (qEEG) analysis methods in comatose patients. METHODS In 79 patients, coupling between EEG signals on the left-right (inter-hemispheric) axis and on the anterior-posterior (intra-hemispheric) axis was measured with four synchronization measures: relative delta power asymmetry, cross-correlation, symbolic mutual information and transfer entropy directionality. Results were compared with etiology of coma and clinical outcome. Using cross-validation, the predictive value of measure combinations was assessed with a Bayes classifier with mixture of Gaussians. RESULTS Five of eight measures showed a statistically significant difference between patients grouped according to outcome; one measure revealed differences in patients grouped according to the etiology. Interestingly, a high level of synchrony between the left and right hemisphere was associated with mortality on intensive care unit, whereas higher synchrony between anterior and posterior brain regions was associated with survival. The combination with the best predictive value reached an area-under the curve of 0.875 (for patients with post anoxic encephalopathy: 0.946). CONCLUSIONS EEG synchronization measures can contribute to clinical assessment, and provide new approaches for understanding the pathophysiology of coma. SIGNIFICANCE Prognostication in coma remains a challenging task. qEEG could improve current multi-modal approaches.

Discovering EEG resting state alterations of Semantic Dementia

Objective Diagnosis of semantic dementia relies on cost-intensive MRI or PET, although resting EEG markers of other dementias have been reported. Yet the view still holds that resting EEG in patients with semantic dementia is normal. However, studies using increasingly sophisticated EEG analysis methods have demonstrated that slightest alterations of functional brain states can be detected. Methods We analyzed the common four resting EEG microstates (A, B, C, and D) of 8 patients with semantic dementia in comparison with 8 healthy controls and 8 patients with Alzheimer’s disease. Results Topographical differences between the groups were found in microstate classes B and C, while microstate classes A and D were comparable. The data showed that the semantic dementia group had a peculiar microstate E, but the commonly found microstate C was lacking. Furthermore, the presence of microstate E was significantly correlated with lower MMSE and language scores. Conclusion Alterations in resting EEG can be found in semantic dementia. Topographical shifts in microstate C might be related to semantic memory deficits. Significance This is the first study that discovered resting state EEG abnormality in semantic dementia. The notion that resting EEG in this dementia subtype is normal has to be revised.

Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

False normal Lung Clearance Index in infants with cystic fibrosis due to software algorithms.

BACKGROUND Lung clearance index (LCI), a marker of ventilation inhomogeneity, is elevated early in children with cystic fibrosis (CF). However, in infants with CF, LCI values are found to be normal, although structural lung abnormalities are often detectable. We hypothesized that this discrepancy is due to inadequate algorithms of the available software package. AIM Our aim was to challenge the validity of these software algorithms. METHODS We compared multiple breath washout (MBW) results of current software algorithms (automatic modus) to refined algorithms (manual modus) in 17 asymptomatic infants with CF, and 24 matched healthy term-born infants. The main difference between these two analysis methods lies in the calculation of the molar mass differences that the system uses to define the completion of the measurement. RESULTS In infants with CF the refined manual modus revealed clearly elevated LCI above 9 in 8 out of 35 measurements (23%), all showing LCI values below 8.3 using the automatic modus (paired t-test comparing the means, P < 0.001). Healthy infants showed normal LCI values using both analysis methods (n = 47, paired t-test, P = 0.79). The most relevant reason for false normal LCI values in infants with CF using the automatic modus was the incorrect recognition of the end-of-test too early during the washout. CONCLUSION We recommend the use of the manual modus for the analysis of MBW outcomes in infants in order to obtain more accurate results. This will allow appropriate use of infant lung function results for clinical and scientific purposes.

Comparison of three strip-type tests and two laboratory methods for salivary buffering analysis

This study evaluated the correlation between three strip-type, colorimetric tests and two laboratory methods with respect to the analysis of salivary buffering. The strip-type tests were saliva-check buffer, Dentobuff strip and CRT(®) Buffer test. The laboratory methods included Ericsson's laboratory method and a monotone acid/base titration to create a reference scale for the salivary titratable acidity. Additionally, defined buffer solutions were prepared and tested to simulate the carbonate, phosphate and protein buffer systems of saliva. The correlation between the methods was analysed by the Spearman's rank test. Disagreement was detected between buffering capacity values obtained with three strip-type tests that was more pronounced in case of saliva samples with medium and low buffering capacities. All strip-type tests were able to assign the hydrogencarbonate, di-hydrogenphosphate and 0.1% protein buffer solutions to the correct buffer categories. However, at 0.6% total protein concentrations, none of the test systems worked accurately. Improvements are necessary for strip-type tests because of certain disagreement with the Ericsson's laboratory method and dependence on the protein content of saliva.