Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. ...There are limited data on prevalence of FD and stroke risk in unselected stroke patients.
A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males-enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3.
986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02-0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08-2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables.
The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Individual identification is crucial for studying animal ecology and evolution. In birds this is often achieved by capturing and tagging. However, these methods are insufficient for ...identifying individuals/species that are secretive or difficult to catch. Here, we employ an automatic analytical approach to predict the identity of bird females based on the appearance of their eggs, using the common cuckoo (Cuculus canorus) as a model species. We analysed 192 cuckoo eggs using digital photography and spectrometry. Cuckoo females were identified from genetic sampling of nestlings, allowing us to determine the accuracy of automatic (unsupervised and supervised) and human assignment. Finally, we used a novel analytical approach to identify eggs that were not genetically analysed. Our results show that individual cuckoo females lay eggs with a relatively constant appearance and that eggs laid by more genetically distant females differ more in colour. Unsupervised clustering had similar cluster accuracy to experienced human observers, but supervised methods were able to outperform humans. Our novel method reliably assigned a relatively high number of eggs without genetic data to their mothers. Therefore, this is a cost-effective and minimally invasive method for increasing sample sizes, which may facilitate research on brood parasites and other avian species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The goal of this paper is to compare two selected statistical techniques used for identification of archeological materials merely on the base of their spectra obtained by stand-off laser-induced ...breakdown spectroscopy (stand-off LIBS). Data processing using linear discriminant analysis (LDA) and artificial neural networks (ANN) were applied on spectra of 18 different samples, some of them archeological and some recent, containing 7 types of material (i.e. shells, mortar, bricks, soil pellets, ceramic, teeth and bones). As the input data PCA scores were taken. The intended aim of this work is to create a database for simple and fast identification of archeological or paleontological materials in situ. This approach can speed up and simplify the sampling process during archeological excavations that nowadays tend to be quite damaging and time-consuming.
► We use statistical techniques for identification of archeological materials. ► Input data for LDA and ANN are PC scores counted from stand-off LIBS spectra. ► The method used for identification of archeological materials provides good results. ► After recording more spectra we can get useful tool for rapid analysis in situ.
A growing body of studies highlights involvement of neutrophils in cancer development and progression. Our aim was to assess the phenotypic and functional properties of circulating neutrophils from ...patients with chronic lymphocytic leukemia (CLL). The percentage of CD54+ and CD64+ neutrophils as well as CD54 expression on these cells were higher in CLL patients than in age-matched healthy controls. Neutrophils from CLL produced more reactive oxygen species (ROS) compared to controls in both resting and activated conditions. Lipopolysaccharide-induced production of IL-1β and TNF-a as well as reduced TLR2 expression in neutrophils from CLL than in neutrophils from controls suggesting their tolerant state. Finally, phenotypic alterations of neutrophils, particularly elevation of CD64 and CD54 markers, correlated with disease activity and treatment, and low percentage of neutrophils. Taken together, the alterations in percentage and functional characteristics of neutrophils reflect the clinical course of CLL. Our data provide first evidence that neutrophils in CLL are permanently primed and have functional defects.
Understanding egg-laying behaviour of brood parasites in space and time can improve our knowledge of interactions between hosts and parasites. However, no studies have combined information on the ...laying activity of an obligate brood parasite with detailed information on the distribution of host nests within an area and time period. Here, we used molecular methods and analysis of egg phenotypes to determine maternal identity of common cuckoo, Cuculus canorus, eggs and chicks found in the nests of four species of Acrocephalus warblers in consecutive years. The median size of a cuckoo female laying area (calculated as a minimum convex polygon) was correlated negatively with the density of host nests and positively with the number of eggs assigned to a particular female. Cuckoo female laying areas overlapped to a large extent and their size and location did not change between years. Cuckoo females preferentially parasitized host nests located close to their previously parasitized nests and were mostly host specific except for two that parasitized two host species. Future studies should focus on sympatric host and parasite communities with variable densities across different brood-parasitic systems to investigate how population density of hosts affects fitness and evolution of brood parasites. For instance, it remains unknown whether female parasites moving to new sites need to meet a threshold density of a potential host. In addition, young females may be more limited in their egg laying, particularly with respect to the activity of other parasites and hosts, than older females.
•Cuckoo egg-laying areas varied in size and overlapped to a large extent.•Cuckoo egg-laying areas were smaller when density of host nests was higher.•Size and location of laying areas remained similar between years.•Cuckoos laid eggs in host nests closest to previously parasitized nests.•Majority of cuckoos parasitized only one host species.
The objective of this work was to assess a part of echelle Laser-Induced Plasma spectra (ranging from 200 to 1000nm) that could be most effectively employed for rocks classification. Therefore, a ...60nm wide spectral window mask was iteratively moved over the broadband echelle spectra. Each created narrow artificial spectral windows (60nm) was used for the classification of rock samples using various Multivariate Data Analysis (MVDA) algorithms, reaching more than 99% of the overall accuracy in certain cases. Afterwards, the Czerny-Turner spectrometer (having higher sensitivity compared to the echelle spectrometer) was aligned to the a priori selected and the most effective spectral regions and rocks samples were re-measured. Consequently the MVDA analyses were utilized again, providing also satisfying classification results yielding more than 99% of the overall accuracy. Measurements of 28 sedimentary ores (certified reference materials) were done utilizing commercially available X-Trace device (AtomTrace), where spectrometers in both configurations (echelle and Czerny-Turner) were exploited.
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•Stand-off analysis of sedimentary rocks•Utilization of echelle vs. Czerny-Turner spectrometers•Multivariate classification using linear and non-linear algorithms•Limiting the necessary spectral window and improving detection limits
Background: Frontline therapy of Hodgkin lymphoma (HL) is strictly stage-adapted. Staging systems used are based on historical variables which only indirectly reflects tumor load (Ann Arbor stage) or ...lymphoma cytokine activity (systemic symptoms, erytrocyte sedimentation rate). With new, abbreviated interim PET-tailored chemotherapy schemes (2+2) and reduced radiotherapy protocols, there is a clinical need for precise staging tools. Last years have brought new insight into the prognostic role of metabolic quantitative PET parameters and HL-associated biomarkers. Total metabolic tumor volume (TMTV) measured using fluoro-deoxyglucose PET (FDG-PET) was found to be a predictor of therapy failure after frontline treatment (Kanoun 2014). Interestingly, TMTV was found capable of identifying poor responders within one (intermediate) staging group (Akhtari, 2018; Cottereau 2018). Serum concentrations of thymus and activation-regulated chemokine (TARC) and other cytokines have been proved to have prognostic significance in the patients treated both in the frontline and relapse setting (Moskowitz, 2015; Guidetti 2017). A relationship between pretreatment TMTV, baseline cytokines levels, and current staging systems has not been analyzed yet.
Aim: To analyzed quantitative metabolic PET parameters and selected soluble biomarkers in the context of the staging systems used in the U.S. and Europe
Methods: We have analyzed a prospectively enrolled cohort of forty-eight patients with HL who were diagnosed in two large university medical centers from 5/2015 to 2/2018. All pts have undergone pretreatment FDG-PET/CT with quantitative analysis of TMTV, Total Lesion Glycolysis (TLG), Maximum Standardized Uptake Volume (SUVmax.) and the Largest Tumor Diameter (LD) and were sampled for cytokine analysis within 16 (median) days from the PET/CT. We have analyzed a set of four serum biomarkers: CD30 (sCD30), CD163 (sCD163), TARC, and interleukin 6 (sIL6), which were measured using ELISA assays.
Results: A cohort consisted of 22 males and 26 females with median age of 42 years (range 21-75). Histology subtype was known in all but one case: nodular sclerosis in 23, mixed cellularity 15, lymphocyte-rich in 5 and nodular-lymphocyte predominant (NLPHL) in four. Ann Arbor stages were as follows: I in 5, II in 20, III in 13 and IV in 10 of the pts with systemic symptoms in 20 (42%) of them. All pts were classified according to the German Hodgkin Study Group (GHSG) and NCCN staging systems. GHSG stages - limited, intermediate and advanced were seen in 8 (17%), 10 (21%) and 30 (62%) pts, respectively. NCCN stages were distributed into early favorable in 8 (17%), early unfavorable in 17 (35%) and advanced in 23 (48%) of the pts. Chemotherapy was applied in all but four pts using: BEACOPPesc, combined BEACOPP+ABVD, ABVD and ABV/COPP protocols in 7, 15, 16 and six pts respectively. Of four pts without chemo one case was treated with local radiotherapy and three with WaW (all of them with NLPHL). Treatment response was known in 41 (85%) of the cases with CR, PR, and PD in 33 (80.5%), 6 (14.6%) and two (4.9%) pts, respectively. Relationships between disease stages and PET-parameters are summarized in Table 1. Briefly, metabolic tumor burden (TMTV, TLG) identified two markedly different groups: low and intermediate/high risk. Similarly, cytokines levels were significantly lower in low-risk patients compared to those with intermediate-high risk (Table 2). Treatment outcome did not correlate either with GHSG nor NCCN stage. We found correlation of sIL-6 (p=0.03) but not sCD30 (p=0.09), sCD163 (p=0.14) and TARC (p=0.57) with CR achievement. In terms of PET-parameters the high TMTV>104 cm3 (P=0.046) and TLG>798 (P=0.003) were associated with not achieving of CR with NPV, PPV and test accuracy of 94.4, 22.0, 58.5 for TMTV and 100%, 36,4%, 66% for TLG, respectively.
Conclusion: Adequate frontline treatment policy is vital for achieving an optimal balance between efficacy and toxicity. Current staging systems have a weak correlation with metabolic tumor burden: one-third of those recognized as advanced stage have the low burden, and vice versa about a half of intermediate-risk pts have high tumor burden. Combination of TMTV/TLG and cytokines can be currently used for decision making in borderline stage cases and probably could serve as a backbone for a new staging system in the future.
Acknowledgment: IGA_LF_2018_004, MH CZ-DRO (FNOL, 00098892)
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No relevant conflicts of interest to declare.
Hosts have evolved a multiplicity of defensive responses against avian brood parasites. One of them is mobbing behaviour which often includes direct contact attacks. These aggressive strikes may not ...only distract the parasites but may also be fatal to them, as documented by cases of dead brood parasite females found near host nests. Here, we present the first video-recording of a great reed warbler (Acrocephalus arundinaceus) host whose vigorous nest defence appears to directly lead to the death of a female common cuckoo (Cuculus canorus). We suggest that the chance of parasite death probably rises with the presence of unfavourable factors, such as water below the nest. Our observation supports previous suggestions that hosts may pose a lethal danger to their parasites.
The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of ...current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use.
We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2.
AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection.
The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy.
The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s.
We and others have shown that deregulation of microRNAs (miRNAs) is associated with the biology of B cell malignancies, including regulation of B cell proliferation and survival (Musilova & Mraz, ...Leukemia, 2015). We focused on studying miRNAs that associate with the aggressiveness of FL and its transformation to diffuse large B cell lymphoma (DLBCL).
First, we analyzed the expression of 380 miRNAs (TaqMan Arrays, ABI) in 8 paired primary samples of FL that subsequently transformed to DLBCL. We identified statistically significant changes (P<0.05, fold change >1.8) in the expression of 5 miRNAs. The most significant change was the down-regulation of miR-150 (~5 fold, P=0.01). Similarly, we observed significantly reduced miR-150 levels in an independent cohort of non-paired samples of FL before vs. after transformation to DLBCL, and miR-150 was significantly less expressed in de novo DLBCL in comparison with FL. MicroRNA miR-150 is of particular interest as we have shown that its expression determines BCR signaling propensity in chronic lymphocytic leukemia (CLL) B cells, and low levels associated with worse survival (Mraz et al., Blood, 2014). Therefore, we analyzed miR-150 expression in a cohort of 89 FL samples. We noticed that miR-150 expression was lower in samples from patients with a FLIPI score ≥3 (P=0.03), and with high Ki67 positivity (>20%; P=0.003). Moreover, FL patients with low miR-150 levels (<median) had significantly shorter survival (median survival 6.2 years vs. not reached; P=0.007; HR 3.0 CI: 1.3-6.8).
To determine the potential reason for variable miR-150 levels in FL B cells, we tested the effect of microenvironmental interactions on its expression. In this experiment, a short term (48hrs) co-culture of B cell lymphoma cells with stromal cells (HS-5) led to down-regulation of miR-150 levels (P<0.05). Next we investigated the functional role of miR-150 by silencing its newly identified target, namely GAB1, in lymphoma B cells. The transfection of siGAB1 resulted in a significant reduction of BCR signaling after anti-IgM treatment (10ug/ml, assessed by calcium influx). We further showed that GAB1 is an adaptor molecule that allows for higher activity of the PI3K/AKT signaling pathway.
Low miR-150 levels associate with a shorter overall survival in FL. This could be used as a reasonable prognostic marker since high miRNA stability allows reliable analyses of miR-150 levels from formalin-fixed, paraffin-embedded (FFPE) samples. Interactions with stromal cells and/or soluble microenvironmental factors down-modulate miR-150 levels in B cells, which support their BCR signalling potential. We are further investigating to what extent the miR-150 down-regulation is causally connected with the aggressiveness and/or transformation of FL.
the Ministry of Education, Youth and Sports of the Czech Republic under the project CEITEC 2020 (LQ1601); the European Union's Horizon 2020 research and innovation programme under grant agreement No. 692298; the research grant GACR (16-13334Y); the Ministry of Health of the Czech Republic, grant nr. 16-29622A. All rights reserved. This work was financed from the SoMoPro II Programme (project No. 4SGA8684), co-financed by European Union and the South-Moravian Region. This publication reflects only the author's views and the Union is not liable for any use that may be made of the information contained therein; Masaryk university as part of the project "New approaches in research, diagnostics and therapy of hematological malignancies III", number MUNI/A/1028/2015 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2016; the Ministry of Health of the Czech Republic - conceptual development of research organization (FNBr, 65269705, Sup 3/16); the Ministry of Education, Youth and Sports of the Czech Republic, grant nr. LD15144 (COST CZ); the research grant TACR (TEO2000058/2014-2019); and EHA Research Fellowship award granted by the European Hematology Association. G.P. is a city of Ostrava scholarship holder.
No relevant conflicts of interest to declare.
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