Leukemic stem cell frequency: a strong biomarker for clinical outcome in acute myeloid leukemia.

INTRODUCTION Treatment failure in acute myeloid leukemia is probably caused by the presence of leukemia initiating cells, also referred to as leukemic stem cells, at diagnosis and their persistence after therapy. Specific identification of leukemia stem cells and their discrimination from normal hematopoietic stem cells would greatly contribute to risk stratification and could predict possible relapses. RESULTS For identification of leukemic stem cells, we developed flow cytometric methods using leukemic stem cell associated markers and newly-defined (light scatter) aberrancies. The nature of the putative leukemic stem cells and normal hematopoietic stem cells, present in the same patient's bone marrow, was demonstrated in eight patients by the presence or absence of molecular aberrancies and/or leukemic engraftment in NOD-SCID IL-2Rγ-/- mice. At diagnosis (n=88), the frequency of the thus defined neoplastic part of CD34+CD38- putative stem cell compartment had a strong prognostic impact, while the neoplastic parts of the CD34+CD38+ and CD34- putative stem cell compartments had no prognostic impact at all. After different courses of therapy, higher percentages of neoplastic CD34+CD38- cells in complete remission strongly correlated with shorter patient survival (n=91). Moreover, combining neoplastic CD34+CD38- frequencies with frequencies of minimal residual disease cells (n=91), which reflect the total neoplastic burden, revealed four patient groups with different survival. CONCLUSION AND PERSPECTIVE Discrimination between putative leukemia stem cells and normal hematopoietic stem cells in this large-scale study allowed to demonstrate the clinical importance of putative CD34+CD38- leukemia stem cells in AML. Moreover, it offers new opportunities for the development of therapies directed against leukemia stem cells, that would spare normal hematopoietic stem cells, and, moreover, enables in vivo and ex vivo screening for potential efficacy and toxicity of new therapies.

Guiding functional connectivity estimation by structural connectivity in MEG: an application to discrimination of mild cognitive impaired conditions

Whole brain resting state connectivity is a promising biomarker that might help to obtain an early diagnosis in many neurological diseases, such as dementia. Inferring resting-state connectivity is often based on correlations, which are sensitive to indirect connections, leading to an inaccurate representation of the real backbone of the network. The precision matrix is a better representation for whole brain connectivity, as it considers only direct connections. The network structure can be estimated using the graphical lasso (GL), which achieves sparsity through l1-regularization on the precision matrix. In this paper, we propose a structural connectivity adaptive version of the GL, where weaker anatomical connections are represented as stronger penalties on the corre- sponding functional connections. We applied beamformer source reconstruction to the resting state MEG record- ings of 81 subjects, where 29 were healthy controls, 22 were single-domain amnestic Mild Cognitive Impaired (MCI), and 30 were multiple-domain amnestic MCI. An atlas-based anatomical parcellation of 66 regions was ob- tained for each subject, and time series were assigned to each of the regions. The fiber densities between the re- gions, obtained with deterministic tractography from diffusion-weighted MRI, were used to define the anatomical connectivity. Precision matrices were obtained with the region specific time series in five different frequency bands. We compared our method with the traditional GL and a functional adaptive version of the GL, in terms of log-likelihood and classification accuracies between the three groups. We conclude that introduc- ing an anatomical prior improves the expressivity of the model and, in most cases, leads to a better classification between groups.

Effects of the build-up and resetting of auditory stream segregation on temporal discrimination

The tendency to hear a tone sequence as 2 or more streams (segregated) builds up, but a sudden change in properties can reset the percept to 1 stream (integrated). This effect has not hitherto been explored using an objective measure of streaming. Stimuli comprised a 2.0-s fixed-frequency inducer followed by a 0.6-s test sequence of alternating pure tones (3 low [L]-high [H] cycles). Listeners compared intervals for which the test sequence was either isochronous or the H tones were slightly delayed. Resetting of segregation should make identifying the anisochronous interval easier. The HL frequency separation was varied (0-12 semitones), and properties of the inducer and test sequence were set to the same or different values. Inducer properties manipulated were frequency, number of onsets (several short bursts vs. one continuous tone), tone:silence ratio (short vs. extended bursts), level, and lateralization. All differences between the inducer and the L tones reduced temporal discrimination thresholds toward those for the no-inducer case, including properties shown previously not to affect segregation greatly. Overall, it is concluded that abrupt changes in a sequence cause resetting and improve subsequent temporal discrimination. (PsycINFO Database Record © 2009 APA, all rights reserved)

Photonic processing for wideband cancellation and spectral discrimination of RF signals

Photonic signal processing is used to implement common mode signal cancellation across a very wide bandwidth utilising phase modulation of radio frequency (RF) signals onto a narrow linewidth laser carrier. RF spectra were observed using narrow-band, tunable optical filtering using a scanning Fabry Perot etalon. Thus functions conventionally performed using digital signal processing techniques in the electronic domain have been replaced by analog techniques in the photonic domain. This technique was able to observe simultaneous cancellation of signals across a bandwidth of 1400 MHz, limited only by the free spectral range of the etalon. © 2013 David M. Benton.

High accuracy discrimination of Parkinson's disease participants from healthy controls using smartphones

The aim of this study is to accurately distinguish Parkinson's disease (PD) participants from healthy controls using self-administered tests of gait and postural sway. Using consumer-grade smartphones with in-built accelerometers, we objectively measure and quantify key movement severity symptoms of Parkinson's disease. Specifically, we record tri-axial accelerations, and extract a range of different features based on the time and frequency-domain properties of the acceleration time series. The features quantify key characteristics of the acceleration time series, and enhance the underlying differences in the gait and postural sway accelerations between PD participants and controls. Using a random forest classifier, we demonstrate an average sensitivity of 98.5% and average specificity of 97.5% in discriminating PD participants from controls. © 2014 IEEE.

Bifurcation and stability in a low-dimensional model for multiple-frequency mode-locked lasers

Recent theoretical investigations have demonstrated that the stability of mode-locked solutions of multiple frequency channels depends on the degree of inhomogeneity in gain saturation. In this article, these results are generalized to determine conditions on each of the system parameters necessary for both the stability and the existence of mode-locked pulse solutions for an arbitrary number of frequency channels. In particular, we find that the parameters governing saturable intensity discrimination and gain inhomogeneity in the laser cavity also determine the position of bifurcations of solution types. These bifurcations are completely characterized in terms of these parameters. In addition to influencing the stability of mode-locked solutions, we determine a balance between cubic gain and quintic loss, which is necessary for the existence of solutions as well. Furthermore, we determine the critical degree of inhomogeneous gain broadening required to support pulses in multiple-frequency channels. © 2010 The American Physical Society.

Fixational saccades during grating detection and discrimination

Copyright © 2015 Elsevier Ltd. All rights reserved. This research was funded by French ANR Grant ANR-2010-BLAN-1432-01 (Visafix). The authors would like to thank Dr. Laurent Madelain and Dr. Claudio Simoncini for the helpful discussions during the development of the study.

Fixational saccades during grating detection and discrimination

Copyright © 2015 Elsevier Ltd. All rights reserved. This research was funded by French ANR Grant ANR-2010-BLAN-1432-01 (Visafix). The authors would like to thank Dr. Laurent Madelain and Dr. Claudio Simoncini for the helpful discussions during the development of the study.

Modeling the impact of social discrimination on the physical and mental health of portuguese gay, lesbian and bisexual people

Background: Despite growing acceptance of same-sex sexuality in Portugal, identity development of lesbian, gay and bisexual (LGB) individuals is still restricted by negative societal attitudes, which maintain the experience of stigmatization and discrimination. The purpose of this study is to document the frequency of discriminatory events experienced by sexual minorities and their association with indicators of physical and mental health in Portugal. Methods: A total of 610 LGB participants completed an online survey (mean age = 34.48, SD = 11.54). Most participants were single and self-identified as gay (73.8%). The survey included five categories of survey items: demographic information, social support, physical health, mental health, and discrimination experiences. Results: Physical and mental health results revealed that bisexual people were more likely to report higher levels of psychological distress than gay men. Overall, between one-fifth and one-fourth of the participants in this sample frequently felt the need to hide their sexual orientation to prevent discrimination experiences across the different settings. Regarding actual discrimination experiences, close to 20% reported having suffered from verbal abuse, followed by close to 10% who suffered from written threats, harassment, and physical threats. A hierarchical multiple regression analysis was performed to assess the effects of anticipated and actual discrimination on mental health. Possible confounding variables were added in the first block – age, sexual orientation, being in a relationship, body mass index, and HIV status. Anticipated and actual discrimination experiences were added in the second block. The first block of the analysis explained 6% of the overall variance, while the second block – discrimination experiences – explained an additional 17%. Conclusion: Portuguese culture and stigma/discrimination create discriminatory experiences which impact LGB people’s health. Unless policies are changed to allow for the acceptance of LGB people, they will continue to experience violence and discrimination as a result of homophobia.

Discrimination in clinical settings and its relationship to depression and anger in women living with HIV

Objectives: To describe the frequency of feared discrimination in various social situations and of perceived discrimination in clinical settings, as well as to study the relationship between discrimination and depression and anger in women living with human immunodeiciency virus (HIV). Material and methods: The scale of Feared and Perceived Discrimination for Women with HIV (DTP-40-MV), the Beck Depression Inventory (BDI-2), and the Anger Expression scale of State-Trait-anger expression inventory (STaXi-2-aX/eX) were applied to a random sample of 200 women living with HIV. Results: These women feared being discriminated against, perceived discrimination upon the review of medical records, but perceived little discrimination in clinical care. a model with good adjustment to the data showed that the fear of being discriminated against creates a disposition toward perception of discrimination in the clinical settings (latent variable with 2 indicators: review of the medical records and clinical care) and increases cognitive/affective depressive symptoms; higher anger control decreases the anger manifestation; greater discrimination perceived in the clinical settings decreases anger control, which facilitates the expression of anger and slows cognitive/affective depressive symptoms; and these latter symptoms sensitize the perception of discrimination before the clinical records. Conclusion: Feared discrimination is a clinically relevant aspect due to its frequency and effect on depressive symptoms and perception of discrimination before the review of medical records.

Elevated Micronucleus Frequency In Patients With Type 2 Diabetes, Dyslipidemia And Periodontitis.

The over-production of reactive oxygen species (ROS) can cause oxidative damage to a large number of molecules, including DNA, and has been associated with the pathogenesis of several disorders, such as diabetes mellitus (DM), dyslipidemia and periodontitis (PD). We hypothesise that the presence of these diseases could proportionally increase the DNA damage. The aim of this study was to assess the micronucleus frequency (MNF), as a biomarker for DNA damage, in individuals with type 2 DM, dyslipidemia and PD. One hundred and fifty patients were divided into five groups based upon diabetic, dyslipidemic and periodontal status (Group 1 - poor controlled DM with dyslipidemia and PD; Group 2 - well-controlled DM with dyslipidemia and PD; Group 3 - without DM with dyslipidemia and PD; Group 4 - without DM, without dyslipidemia and with PD; and Group 5 - without DM, dyslipidemia and PD). Blood analyses were carried out for fasting plasma glucose, HbA1c and lipid profile. Periodontal examinations were performed, and venous blood was collected and processed for micronucleus (MN) assay. The frequency of micronuclei was evaluated by cell culture cytokinesis-block MN assay. The general characteristics of each group were described by the mean and standard deviation and the data were submitted to the Mann-Whitney, Kruskal-Wallis, Multiple Logistic Regression and Spearman tests. The Groups 1, 2 and 3 were similarly dyslipidemic presenting increased levels of total cholesterol, low density lipoprotein cholesterol and triglycerides. Periodontal tissue destruction and local inflammation were significantly more severe in diabetics, particularly in Group 1. Frequency of bi-nucleated cells with MN and MNF, as well as nucleoplasmic bridges, were significantly higher for poor controlled diabetics with dyslipidemia and PD in comparison with those systemically healthy, even after adjusting for age, and considering Bonferroni's correction. Elevated frequency of micronuclei was found in patients affected by type 2 diabetes, dyslipidemia and PD. This result suggests that these three pathologies occurring simultaneously promote an additional role to produce DNA impairment. In addition, the micronuclei assay was useful as a biomarker for DNA damage in individuals with chronic degenerative diseases.

Frequency Of The Allelic Variant C.1150t > C In Exon 10 Of The Fibroblast Growth Factor Receptor 3 (fgfr3) Gene Is Not Increased In Patients With Pathogenic Mutations And Related Chondrodysplasia Phenotypes.

Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch). The p.N540K mutation in the FGFR3 gene occurs in ∼70% of individuals with Hch, and nearly 30% of individuals with the Hch phenotype have no mutations in the FGFR3, which suggests genetic heterogeneity. The identification of a severe case of Hch associated with the typical mutation c.1620C > A and the occurrence of a c.1150T > C change that resulted in a p.F384L in exon 10, together with the suspicion that this second change could be a modulator of the phenotype, prompted us to investigate this hypothesis in a cohort of patients. An analysis of 48 patients with FGFR3 chondrodysplasia phenotypes and 330 healthy (control) individuals revealed no significant difference in the frequency of the C allele at the c.1150 position (p = 0.34). One patient carrying the combination `pathogenic mutation plus the allelic variant c.1150T > C' had a typical achondroplasia (Ach) phenotype. In addition, three other patients with atypical phenotypes showed no association with the allelic variant. Together, these results do not support the hypothesis of a modulatory role for the c.1150T > C change in the FGFR3 gene.

Explosive Synchronization With Partial Degree-frequency Correlation.

Networks of Kuramoto oscillators with a positive correlation between the oscillators frequencies and the degree of their corresponding vertices exhibit so-called explosive synchronization behavior, which is now under intensive investigation. Here we study and discuss explosive synchronization in a situation that has not yet been considered, namely when only a part, typically a small part, of the vertices is subjected to a degree-frequency correlation. Our results show that in order to have explosive synchronization, it suffices to have degree-frequency correlations only for the hubs, the vertices with the highest degrees. Moreover, we show that a partial degree-frequency correlation does not only promotes but also allows explosive synchronization to happen in networks for which a full degree-frequency correlation would not allow it. We perform a mean-field analysis and our conclusions were corroborated by exhaustive numerical experiments for synthetic networks and also for the undirected and unweighed version of a typical benchmark biological network, namely the neural network of the worm Caenorhabditis elegans. The latter is an explicit example where partial degree-frequency correlation leads to explosive synchronization with hysteresis, in contrast with the fully correlated case, for which no explosive synchronization is observed.

Enhanced D1 And D2 Inhibitions Induced By Low-frequency Trains Of Conditioning Stimuli: Differential Effects On H- And T-reflexes And Possible Mechanisms.

Mechanically evoked reflexes have been postulated to be less sensitive to presynaptic inhibition (PSI) than the H-reflex. This has implications on investigations of spinal cord neurophysiology that are based on the T-reflex. Preceding studies have shown an enhanced effect of PSI on the H-reflex when a train of ~10 conditioning stimuli at 1 Hz was applied to the nerve of the antagonist muscle. The main questions to be addressed in the present study are if indeed T-reflexes are less sensitive to PSI and whether (and to what extent and by what possible mechanisms) the effect of low frequency conditioning, found previously for the H-reflex, can be reproduced on T-reflexes from the soleus muscle. We explored two different conditioning-to-test (C-T) intervals: 15 and 100 ms (corresponding to D1 and D2 inhibitions, respectively). Test stimuli consisted of either electrical pulses applied to the posterior tibial nerve to elicit H-reflexes or mechanical percussion to the Achilles tendon to elicit T-reflexes. The 1 Hz train of conditioning electrical stimuli delivered to the common peroneal nerve induced a stronger effect of PSI as compared to a single conditioning pulse, for both reflexes (T and H), regardless of C-T-intervals. Moreover, the conditioning train of pulses (with respect to a single conditioning pulse) was proportionally more effective for T-reflexes as compared to H-reflexes (irrespective of the C-T interval), which might be associated with the differential contingent of Ia afferents activated by mechanical and electrical test stimuli. A conceivable explanation for the enhanced PSI effect in response to a train of stimuli is the occurrence of homosynaptic depression at synapses on inhibitory interneurons interposed within the PSI pathway. The present results add to the discussion of the sensitivity of the stretch reflex pathway to PSI and its functional role.

Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39%), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3% of all patients; and 6 % in the dominantly inherited SCAs. We identified the SCA2 mutation in 6% of all families and in 9% of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 % of all patients; and in the 44% of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.