Molecular Profile of Sensitization to Dermatophagoides pteronyssinus Dust Mite in Portugal.

BACKGROUND AND OBJECTIVES: To analyze component-resolved diagnosis of sensitization to Dermatophagoides pteronyssinus (Der p) in patients with respiratory allergy and the association between diagnostic findings and clinical severity in different geographical areas. METHODS: The study population comprised 217 patients (mean age, 25.85 [12.7] years; 51.16% female) selected from 13 centers in Portugal (5 from the North, n=65). All had allergic rhinitis with or without asthma and positive skin prick test results to at least 1 dust mite. Specific IgE (sIgE) to Der p, Dermatophagoides farinae, Lepidoglyphus destructor, Der p 1, Der p 2, Der p 10, and Der p 23 was determined using ImmunoCAP. The Mann-Whitney test was applied for the following comparisons: rhinitis vs rhinitis and asthma; mild vs moderate-to-severe rhinitis; North vs South. RESULTS: The prevalence of sensitization was 98.2% for Der p, and 72.4%, 89.4%, 9.7%, and 77% for Der p 1, Der p 2, Der p 10, and Der p 23, respectively. The corresponding median sIgE levels were 8.56, 17.7, 0.01, and 3.95 kUA/L. sIgE to all allergens was higher in patients with moderate-to-severe rhinitis and rhinitis with asthma (nonsignficant). Concentrations of sIgE to Der p 2 were significantly higher in the South than in the North (P=.0496). CONCLUSION: The most common sensitization in Portugal was to Der p. The highest prevalence and median sIgE level were observed for Der p 2. All sIgE values for molecular components were higher in more symptomatic patients (nonsignificant). Concentrations of sIgE to Der p 2 were higher in the South, probably because of the warmer temperature and/or the larger sample size.

Early Cerebrovascular Ultrasonography as a Predictor of Hemorrhagic Transformation After Thrombectomy.

OBJECTIVES: To determine the predictive value of early transcranial color-coded sonography (TCCS) for intracranial hemorrhage (ICH) in patients with large artery occlusion (LAO) stroke of carotid circulation, who were submitted to endovascular therapy (EVT) with successful reperfusion. MATERIALS AND METHODS: Retrospective study evaluating a cohort of consecutive stroke patients with LAO of the carotid circulation that were recanalyzed with EVT. We measured angle-corrected peak systolic velocities, end-diastolic velocities and mean flow velocities (PSV, EDV and MFV) of the symptomatic and asymptomatic middle cerebral artery (MCA). The ratio between MFV of the symptomatic MCA and MFV of the asymptomatic MCA (MCA-Ra) was calculated. Parenchymal hematoma in the 24 hours control CT was considered as ICH. Univariate associations and multivariate analyses were used to identify early independent predictors for ICH among TCCS findings. RESULTS: We included 234 patients, mean age 72.5 (SD 12.6) years, 52.1% male. The mean time between recanalization and TCCS was 12.3 hours (range 3-22). Patients who developed postinterventional ICH showed a higher MCA-Ra (1.02 ± 0.26 vs 1.16 ± 0,21, p = 0.036). In multivariate analysis, only higher MCA-Ra remained independently associated with postinterventional ICH (OR: 6.778, 95%CI: 1.152-39.892, p = 0.034). A value of MCA-Ra ≥ 1,05 was associated with ICH, showing a sensitivity of 81.3% and a specificity of 65.9%; the AUC based of the ROC analysis was 0.688 (95% CI 0.570-0.806). CONCLUSION: TCCS performed within the first 24 hours after stroke onset can help to predict hemorrhagic transformation in patients with LAO.

Cost-effectiveness of five prenatal screening strategies for trisomies and other unbalanced chromosomal abnormalities: model-based analysis.

OBJECTIVE: To evaluate the cost-effectiveness of five prenatal screening strategies for trisomies (13/18/21) and other unbalanced chromosomal abnormalities (UBCA), following the introduction of cell-free DNA (cfDNA) analysis. METHODS: A model-based cost-effectiveness analysis was performed to estimate prevalence, safety, screening-program costs and healthcare costs of five different prenatal screening strategies, using a virtual cohort of 652 653 pregnant women in France. Data were derived from the French Biomedicine Agency and published articles. Uncertainty was addressed using one-way sensitivity analysis. The five strategies compared were: (i) cfDNA testing for women with a risk following first-trimester screening of ≥ 1/250; (ii) cfDNA testing for women with a risk of ≥ 1/1000 (currently recommended); (iii) cfDNA testing in the general population (regardless of risk); (iv) invasive testing for women with a risk of ≥ 1/250 (historical strategy); and (v) invasive testing for women with a risk of ≥ 1/1000. RESULTS: In our virtual population, at similar risk thresholds, cfDNA testing compared with invasive testing was cheaper but less effective. Compared with the historical strategy, cfDNA testing at the ≥ 1/1000 risk threshold was a more expensive strategy that detected 158 additional trisomies, but also 175 fewer other UBCA. Implementation of cfDNA testing in the general population would give an incremental cost-effectiveness ratio of €9 166 689 per additional anomaly detected compared with the historical strategy. CONCLUSION: Extending cfDNA to lower risk thresholds or even to all pregnancies would detect more trisomies, but at greater expense and with lower detection rate of other UBCA, compared with the historical strategy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Relación costo-eficacia de cinco estrategias de cribado prenatal para trisomías y otras anomalías cromosómicas no equilibradas: un análisis basado en modelos OBJETIVO: Evaluar la eficacia en función de los costos de cinco estrategias de cribado prenatal para trisomías (13/18/21) y otras anomalías cromosómicas no equilibradas (UBCA, por sus siglas en inglés), tras la introducción del análisis de ADN fetal (cfDNA, por sus siglas en inglés). MÉTODOS: Se realizó un análisis de la relación costo-eficacia basado en modelos para estimar la prevalencia, la seguridad, los costos de los programas de cribado y los costos sanitarios de cinco estrategias diferentes de cribado prenatal, para lo cual se usó una cohorte virtual de 652 653 mujeres embarazadas en Francia. Los datos se obtuvieron de la Agencia Francesa de Biomedicina y de artículos publicados. La incertidumbre se abordó mediante un análisis de sensibilidad unidireccional. Las cinco estrategias comparadas fueron: (i) pruebas de cfDNA para mujeres con un riesgo ≥1/250 después del examen del primer trimestre; (ii) pruebas de cfDNA para mujeres con un riesgo ≥1/1000 (las recomendadas actualmente); (iii) pruebas de cfDNA en la población general (independientemente del riesgo); (iv) pruebas invasivas para mujeres con un riesgo ≥1/250 (estrategia histórica); y (v) pruebas invasivas para mujeres con un riesgo ≥1/1000. RESULTADOS: En esta población virtual, con umbrales de riesgo similares, la prueba de cfDNA fue más barata pero menos efectiva en comparación con la prueba invasiva. En comparación con la estrategia histórica, la prueba de cfDNA para el umbral de riesgo de ≥1/1000 fue una estrategia más costosa que detectó 158 trisomías adicionales, pero también 175 menos de otras UBCA. La aplicación de las pruebas de cfDNA en la población general daría una relación costo-eficacia incremental de 9 166 689 EUR por cada anomalía adicional detectada en comparación con la estrategia histórica. CONCLUSIÓN: Extender las pruebas de cfDNA a umbrales de riesgo más bajos o incluso a todos los embarazos detectaría más trisomías, pero a un costo mayor y con una tasa de detección más baja de otras UBCA, en comparación con la estrategia histórica.

Molecular View on Supramolecular Chain and Association Dynamics.

The chain and association dynamics of supramolecular polymer ensembles decisively determines their properties. Using neutron spin echo (NSE) spectroscopy we present molecular insight into the space and time evolution of this dynamics. Studying a well characterized ensemble of linearly associating telechelic poly(ethylene glycol) melts carrying triple H-bonding end groups, we show that H-bond breaking significantly impacts the mode spectrum of the associates. The breaking affects the mode contributions and not the relaxation times as was assumed previously. NSE spectra directly reveal the so far intangible H-bond lifetimes in the supramolecular melt and demonstrate that for both the microscopic and the macroscopic dynamics of the supramolecular ensemble the instantaneous average of the M_{w} distribution governs the system response at least as long as the Rouse picture applies.

Self-healing dynamic bond-based rubbers: understanding the mechanisms in ionomeric elastomer model systems.

While it is traditionally accepted that the chain interactions responsible for the elastic response in an elastomeric network are ideally permanent and instantaneously active, the ongoing investigation of self-healing materials reveals that the introduction of self-healing properties into elastomers requires high mechanical integrity under dynamic load conditions, while on long timescales (or at extended temperatures), the chain and bond dynamics must allow for an intrinsic repair of micro cracks occurring during operation and aging. Based on an acrylate-based amorphous ionomer model system with pendant carboxylate groups allowing the systematic variation of the composition and the nature of the counter ion, we demonstrate the interrelation between the morphological, thermal, and mechanical properties, and identify the prerequisites and tools for property adjustment and optimization of self-healing efficiency. While the ion fraction is directly related to the effective network density and elastic performance, the crossover frequency between viscous and elastic behavior is influenced by the nature of the counter ion. In order to achieve reliable elastic response and optimal damage repair, the ion fraction in these systems should be in the range of 5 mol% and the chain dynamics should be appropriate to allow for excellent self-healing behavior at moderate healing temperatures.

Molecular scale dynamics of large ring polymers.

We present neutron scattering data on the structure and dynamics of melts from polyethylene oxide rings with molecular weights up to ten times the entanglement mass of the linear counterpart. The data reveal a very compact conformation displaying a structure approaching a mass fractal, as hypothesized by recent simulation work. The dynamics is characterized by a fast Rouse relaxation of subunits (loops) and a slower dynamics displaying a lattice animal-like loop displacement. The loop size is an intrinsic property of the ring architecture and is independent of molecular weight. This is the first experimental observation of the space-time evolution of segmental motion in ring polymers illustrating the dynamic consequences of their topology that is unique among all polymeric systems of any other known architecture.

Anesthesia management in a patient with Churg-Strauss syndrome in the ambulatory setting: A case report.

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a rare type of vasculitis with multisystemic involvement. Very few authors have described the anaesthesia technique in these patients. We present the first report on ambulatory surgery in a patient with EGPA. This case dispels concerns about the safety of day surgery and reports successful regional anaesthesia management in a patient with EGPA.

Surgical or Endovascular Treatment of MCA Aneurysms: An Agreement Study.

BACKGROUND AND PURPOSE: MCA aneurysms are still commonly clipped surgically despite the recent development of a number of endovascular tools and techniques. We measured clinical uncertainty by studying the reliability of decisions made for patients with middle cerebral artery (MCA) aneurysms. MATERIALS AND METHODS: A portfolio of 60 MCA aneurysms was presented to surgical and endovascular specialists who were asked whether they considered surgery or endovascular treatment to be an option, whether they would consider recruitment of the patient in a randomized trial, and whether they would provide their final management recommendation. Agreement was studied using κ statistics. Intrarater reliability was assessed with the same, permuted portfolio of cases of MCA aneurysm sent to the same specialists 1 month later. RESULTS: Surgical management was the preferred option for neurosurgeons (n = 844/1320; [64%] responses/22 raters), while endovascular treatment was more commonly chosen by interventional neuroradiologists (1149/1500 [76.6%] responses/25 raters). Interrater agreement was only "slight" for all cases and all judges (κ = 0.094; 95% CI, 0.068-0.130). Agreement was no better within specialties or with more experience. On delayed requestioning, 11 of 35 raters (31%) disagreed with themselves on at least 20% of cases. Surgical management and endovascular treatment were always judged to be a treatment option, for all patients. Trial participation was offered to patients 65% of the time. CONCLUSIONS: Individual clinicians did not agree regarding the best management of patients with MCA aneurysms. A randomized trial comparing endovascular with surgical management of patients with MCA aneurysms is in order.

Molecular mobility of nematic E7 confined to molecular sieves with a low filling degree.

The nematic liquid crystalline mixture E7 was confined with similar filling degrees to molecular sieves with constant composition but different pore diameters (from 2.8 to 6.8 nm). Fourier transform infrared analysis proved that the E7 molecules interact via the cyanogroup with the pore walls of the molecular sieves. The molecular dynamics of the system was investigated by broadband dielectric spectroscopy (10(-2)-10(9) Hz) covering a wide temperature range of approximately 200 K from temperatures well above the isotropic-nematic transition down to the glass transition of bulk E7. A variety of relaxation processes is observed including two modes that are located close to the bulk behavior in its temperature dependence. For all confined samples, two relaxation processes, at frequencies lower than the processes observed for the bulk, were detected. At lower temperatures, their relaxation rates have different temperature dependencies whereas at higher temperatures, they seem to collapse into one chart. The temperature dependence of the slowest process (S-process) obeys the Vogel-Fulcher-Tammann law indicating a glassy dynamics of the E7 molecules anchored to the pore surface. The pore size dependence of both the Vogel temperature and fragility revealed a steplike transition around 4 nm pore size, which indicates a transition from a strong to a fragile behavior. The process with a relaxation rate in between the bulklike and the S-process (I-process) shows no dependence on the pore size. The agreement of the I-process with the behavior of a 5CB surface layer adsorbed on nonporous silica leads to the assignment of E7 molecules anchored at the outer surface of the microcrystals of the molecular sieves.

DWI-Based Algorithm to Predict Disability in Patients Treated with Thrombectomy for Acute Stroke.

BACKGROUND AND PURPOSE: The reasons for poor clinical outcome after thrombectomy for acute stroke, concerning around half of all patients, are misunderstood. We developed a hierarchic algorithm based on DWI to better identify patients at high risk of disability. MATERIALS AND METHODS: Our single-center, retrospective study included consecutive patients with acute ischemic stroke who underwent thrombectomy for large anterior artery occlusion and underwent pretreatment DWI. The primary outcome was the mRS at 3 months after stroke onset. Multivariable regression was used to identify independent clinical and imaging predictors of poor prognosis (mRS > 2) at 3 months, and a hierarchic algorithm predictive of disability was developed. RESULTS: A total of 149 patients were analyzed. In decreasing importance, DWI lesion volume of >80 mL, baseline NIHSS score of >14, age older than 75 years, and time from stroke onset to groin puncture of >4 hours were independent predictors of poor prognosis. The predictive hierarchic algorithm developed from the multivariate analysis predicted the risk of disability at 3 months for up to 100% of patients with a high predictive value. The area under the receiver operating characteristic curve was 0.87. CONCLUSIONS: The DWI-based hierarchic algorithm we developed is highly predictive of disability at 3 months after thrombectomy and is easy to use in routine practice.

Confinement and surface effects on the molecular dynamics of a nematic mixture investigated by dielectric relaxation spectroscopy.

Broadband dielectric spectroscopy (10(-2)-10(9) Hz) was employed to investigate the molecular dynamics of the liquid crystalline mixture E7 confined in both untreated and lecithin-treated 20 nm Anopore membranes. Because E7 does not crystallize, it was possible to cover a temperature range of more than 200 K, providing an exhaustive dielectric characterization of a liquid crystal confined to Anopore membranes for the first time. In the nematic state, the tumbling (alpha-) and the delta-relaxation are observed, also under confinement conditions. The analysis of their relative intensities give that the orientation of the E7 molecules is preferentially axial in untreated but opposite radial in lecithin-treated pores. The radial alignment of the liquid crystals in the modified membrane is understood as a tail-to-tail conformation of E7 molecules imposed by the adsorbed lecithin molecules. The relaxation rate of the alpha-process is enhanced for E7 confined in native Anopore compared with the bulk and E7 in treated pores. This is interpreted as resulting from a less dense molecular packing of E7 in the middle of the pore compared to the bulk. In both untreated and treated membranes, the relaxation rate of the delta-process is higher than in the bulk, and the values of the respective Vogel-Fulcher-Tammann temperatures depend on the actual surface treatment. Additionally, a surface process, due to molecular fluctuations of molecules within an adsorbed layer at the pore wall, was detected.

Asynchronous DNA replication detected by fluorescence in situ hybridisation as a possible indicator of genetic damage in human lymphocytes.

The present study aimed to correlate the DNA replication timing of different genes with genetic damage and frequency of cancer. Using a fluorescence in situ hybridisation (FISH) approach, the replication timing of three loci, two human genes possessing transcriptional capability and involved in both the cellular response to genetic damage and cancer development (TP53 and RB1) and the non-coding locus D22S163, was evaluated. The data obtained show that normal human lymphocytes exposed in vitro to known DNA-damaging agents, e.g. H2O2, ionizing radiation and mitomycin C, exhibit an asynchronous replication of the genes TP53 and RB1. In vivo studies were performed in three different populations from Kazakhstan. In two of these populations that are living in polluted areas and have higher cancer mortalities than people living in a control area, a DNA replication behaviour similar to that observed in human lymphocytes exposed in vitro to known genotoxic agents was detected. The results obtained further indicate that DNA damage hampers replication and FISH represents a fast and accurate method of assessing asynchronous replication by providing an important tool to evaluate DNA damage at a populational level.

Automated database-guided expert-supervised orientation for immunophenotypic diagnosis and classification of acute leukemia.

Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide towards the relevant classification panel (T-cell acute lymphoblastic leukemia (T-ALL), B-cell precursor (BCP)-ALL and/or acute myeloid leukemia (AML)) and final diagnosis. Now we built a reference database with 656 typical AL samples (145 T-ALL, 377 BCP-ALL, 134 AML), processed and analyzed via standardized protocols. Using principal component analysis (PCA)-based plots and automated classification algorithms for direct comparison of single-cells from individual patients against the database, another 783 cases were subsequently evaluated. Depending on the database-guided results, patients were categorized as: (i) typical T, B or Myeloid without or; (ii) with a transitional component to another lineage; (iii) atypical; or (iv) mixed-lineage. Using this automated algorithm, in 781/783 cases (99.7%) the right panel was selected, and data comparable to the final WHO-diagnosis was already provided in >93% of cases (85% T-ALL, 97% BCP-ALL, 95% AML and 87% mixed-phenotype AL patients), even without data on the full-characterization panels. Our results show that database-guided analysis facilitates standardized interpretation of ALOT results and allows accurate selection of the relevant classification panels, hence providing a solid basis for designing future WHO AL classifications.

Origin of glassy dynamics in a liquid crystal studied by broadband dielectric and specific heat spectroscopy.

A combination of broadband dielectric (10{-2}Hz-10{9}Hz) and specific heat (10{-3}Hz-2 x 10{3}Hz) spectroscopy is employed to study the molecular dynamics of the glass-forming nematic liquid crystal E7 in a wide temperature range. In the region of the nematic phase the dielectric spectra show two relaxation processes which are expected theoretically: the delta relaxation which corresponds to rotational fluctuations of the molecules around its short axis and the tumbling mode at higher frequencies than the former one. For both processes the temperature dependence of the relaxation rates follows the Vogel-Fulcher-Tammann formula which is characteristic for glassy dynamics. By applying a detailed data analysis, it is shown that close to the glass transition the tumbling mode has a much steeper temperature dependence than the delta process. The former has a Vogel temperature which is by 30K higher than that of the delta relaxation. Specific heat spectroscopy gives one relaxation process in its temperature and frequency dependence which has to be assigned to the alpha relaxation (dynamic glass transition). The unique and detailed comparison of the temperature dependence of the dielectric and the thermal relaxation rates delivers unambiguously that the dielectric tumbling mode has to be related to the dynamic glass transition.

Ceramide-induced cell death is independent of the Fas/Fas ligand pathway and is prevented by Nur77 overexpression in A20 B cells.

The role of ceramide in triggering apoptosis is still a matter of debate. While in some experimental systems, ceramide was shown to mediate Fas-induced cell death, in other instances it was claimed to induce the expression of Fas ligand (FasL), killing cells in a caspase-dependent fashion. We found that, in mature A20 B cells, ceramide-induced apoptosis is independent of the caspase pathway, since we observed no ICE-like, CPP32-like and Mch2 activities and no PARP proteolysis. Moreover, we were unable to protect these cells from ceramide-induced apoptosis using caspase inhibitors, while they blocked Fas-induced apoptosis and no FasL induction could be detected following ceramide treatment. These results suggest that ceramide does not induce apoptosis through the Fas/FasL pathway. We also found that overexpression of Nur77, a zinc-finger transcription factor described to upregulate FasL, antagonizes ceramide-induced apoptosis, but not Fas-induced apoptosis. This further supports the hypothesis that Fas and ceramide death pathways are independent in A20 cells. Ceramide-induced cell death was associated with increased c-myc, p53, Bax and p27kip1 levels; in contrast, cells transfected with Nur77 (A20Nur77), resistant to ceramide-induced apoptosis, showed a marked downregulation of p53 after ceramide treatment, with neither Bax nor p27kip1 induction. In conclusion, our results suggest that, in the A20 B cell line, Fas and ceramide trigger two distinct pathways and that Nur77 overexpression confers protection against ceramide-mediated apoptosis which correlates with inhibition of p53, Bax and p27kip1 induction.

Optimal MRI sequence for identifying occlusion location in acute stroke: which value of time-resolved contrast-enhanced MRA?

BACKGROUND AND PURPOSE: Identifying occlusion location is crucial for determining the optimal therapeutic strategy during the acute phase of ischemic stroke. The purpose of this study was to assess the diagnostic efficacy of MR imaging, including conventional sequences plus time-resolved contrast-enhanced MRA in comparison with DSA for identifying arterial occlusion location. MATERIALS AND METHODS: Thirty-two patients with 34 occlusion levels referred for thrombectomy during acute cerebral stroke events were consecutively included from August 2010 to December 2012. Before thrombectomy, we performed 3T MR imaging, including conventional 3D-TOF and gradient-echo T2 sequences, along with time-resolved contrast-enhanced MRA of the extra- and intracranial arteries. The 3D-TOF, gradient-echo T2, and time-resolved contrast-enhanced MRA results were consensually assessed by 2 neuroradiologists and compared with prethrombectomy DSA results in terms of occlusion location. The Wilcoxon test was used for statistical analysis to compare MR imaging sequences with DSA, and the κ coefficient was used to determine intermodality agreement. RESULTS: The occlusion level on the 3D-TOF and gradient-echo T2 images differed significantly from that of DSA (P < .001 and P = .002, respectively), while no significant difference was observed between DSA and time-resolved contrast-enhanced MRA (P = .125). κ coefficients for intermodality agreement with DSA (95% CI, percentage agreement) were 0.43 (0.3%-0.6; 62%), 0.32 (0.2%-0.5; 56%), and 0.81 (0.6%-1.0; 88%) for 3D-TOF, gradient-echo T2, and time-resolved contrast-enhanced MRA, respectively. CONCLUSIONS: The time-resolved contrast-enhanced MRA sequence proved reliable for identifying occlusion location in acute stroke with performance superior to that of 3D-TOF and gradient-echo T2 sequences.

Normal genetic response to gamma irradiation in familial adenomatous polyposis.

The present study, a co-operative project between three European institutes, was aimed at elucidating whether the APC gene in carriers of familial adenomatous polyposis coli (FAP) also causes some genetic sensitivity revealed by DNA damage and the yield of chromosome aberrations in peripheral blood lymphocytes exposed to gamma rays. In addition, it seemed of interest to study whether DNA repair is modified after irradiation of lymphocytes from FAP patients compared to controls. To this end, we have used the inhibition of the poly(ADP-ribose) polymerase (ADPRP) by 3-aminobenzamide (3ABA) and studied the effect of 3ABA on the frequency of DNA strand breaks and chromosome aberrations. The data indicate that FAP is not associated with an increased chromosomal sensitivity towards ionising radiation.

Apoptosis as a scaffold for building up the B cell repertoire.

Control of cell number is determined by a balance between cell proliferation and cell death, both of which are highly regulated processes, with numerous checks and balances. Cells control their own death through activation of an internally coded suicide program that, when activated, initiates a characteristic form of cell death called apoptosis. This type of regulation allows elimination of cells that have been produced in excess, that have developed improperly, or that have sustained genetic damage. Apoptosis is, therefore, the most common physiological form of cell death and occurs during embryonic development, tissue remodeling, immune regulation, cell activation and tumor regression.