Advanced MRI unravels the nature of tissue alterations in early multiple sclerosis.

INTRODUCTION: In patients with multiple sclerosis (MS), conventional magnetic resonance imaging (MRI) provides only limited insights into the nature of brain damage with modest clinic-radiological correlation. In this study, we applied recent advances in MRI techniques to study brain microstructural alterations in early relapsing-remitting MS (RRMS) patients with minor deficits. Further, we investigated the potential use of advanced MRI to predict functional performances in these patients. METHODS: Brain relaxometry (T1, T2, T2*) and magnetization transfer MRI were performed at 3T in 36 RRMS patients and 18 healthy controls (HC). Multicontrast analysis was used to assess for microstructural alterations in normal-appearing (NA) tissue and lesions. A generalized linear model was computed to predict clinical performance in patients using multicontrast MRI data, conventional MRI measures as well as demographic and behavioral data as covariates. RESULTS: Quantitative T2 and T2* relaxometry were significantly increased in temporal normal-appearing white matter (NAWM) of patients compared to HC, indicating subtle microedema (P = 0.03 and 0.004). Furthermore, significant T1 and magnetization transfer ratio (MTR) variations in lesions (mean T1 z-score: 4.42 and mean MTR z-score: -4.09) suggested substantial tissue loss. Combinations of multicontrast and conventional MRI data significantly predicted cognitive fatigue (P = 0.01, Adj-R (2) = 0.4), attention (P = 0.0005, Adj-R (2) = 0.6), and disability (P = 0.03, Adj-R (2) = 0.4). CONCLUSION: Advanced MRI techniques at 3T, unraveled the nature of brain tissue damage in early MS and substantially improved clinical-radiological correlations in patients with minor deficits, as compared to conventional measures of disease.

Concentrations sériques de protéines placentaires au 1er trimestre dans des grossesses monofoetales et multiples après FIV : implications pour le dépistage de la trisomie 21 [First trimester serum concentrations of placental proteins in singleton and multiple IVF pregnancies: implications for Down syndrome screening]

First trimester biochemical trisomy screening is based on serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotrophin (hCG). Our aim was to confirm previously suggested modifications in serum marker concentrations after in vitro fertilisation (IVF) and embryo transfer (ET), and to assess the need of establishing normal medians for trisomy screening in these. We compared 56 singleton pregnancies obtained after ET (of which 40 in gonadotrophin stimulation cycles) with 120 gestation-matched spontaneous controls. For multiple pregnancies, 17 treated cycles were compared with 25 controls. The levels of PAPP-A, hCG, and pregnancy-specific β1-glycoprotein were determined and compared between treated and spontaneous pregnancies. Serum PAPP-A levels were reduced in pregnancies achieved after gonadotrophin-stimulated IVF and ET, and this was more pronounced in earlier gestational stages. SP1 followed the same trend, while hCG tended to be increased, and this not only in pregnancies obtained from gonadotrophin-stimulated but also from oestrogen supported cycles, and with a more pronounced effect in the later gestational ages examined here. Decreased PAPP-A together with increased hCG concentrations produce falsely elevated results in first trimester Down syndrome screening, but we do not recommend the establishment of normal medians for IVF pregnancies due to the variations in stimulation protocols.

Pliocene and Pleistocene diversification and multiple refugia in a Eurasian shrew (Crocidura suaveolens group).

We sequenced 998 base pairs (bp) of mitochondrial DNA cytochrome b and 799 bp of nuclear gene BRCA1 in the Lesser white-toothed shrew (Crocidura suaveolens group) over its geographic range from Portugal to Japan. The aims of the study were to identify the main clades within the group and respective refugia resulting from Pleistocene glaciations. Analyses revealed the Asian lesser white-toothed shrew (C. shantungensis) as the basal clade, followed by a major branch of C. suaveolens, subdivided sensu stricto into six clades, which split-up in the Upper Pliocene and Lower Pleistocene (1.9-0.9 Myr). The largest clade, occurring over a huge range from east Europe to Mongolia, shows evidence of population expansion after a bottleneck. West European clades originated from Iberian and Italo-Balkanic refugia. In the Near East, three clades evolved in an apparent hotspot of refugia (west Turkey, south-west and south-east of the Caucasus). Most clades include specimens of different morphotypes and the validity of many taxa in the C. suaveolens group has to be re-evaluated.

Multiples étiologies de l'angioedème [The multiple etiologies of angioedema]

L'angioedème est une affection fréquente, dont les étiologies sont multiples. Les angioedèmes habituellement associés à une urticaire sont en général dus à une libération d'histamine et répondent en principe aux antihistaminiques et à l'adrénaline. Il s'agit des angioedèmes d'origine allergique, des réactions anaphylactoïdes, souvent d'origine médicamenteuse (AINS), des angioedèmes physiques et de l'angioedème récurrent idiopathique. La bradykinine joue certainement un rôle dans la genèse des angioedèmes associés aux inhibiteurs de l'enzyme de conversion de l'angiotensine et rarement aux antagonistes du récepteur de l'angiotensine II, ainsi que dans celle des rares angioedèmes héréditaires ou liés à un déficit acquis en Ci-inhibiteur. L'urticaire est alors absente et les antihistaminiques ainsi que l'adrénaline sont inefficaces. Angioedema is a frequent disorder with multiple aetiologies. Angioedemas associated with urticaria are usually caused by histamine release and respond to anti-histamines and adrenalin. They include allergic angioedemas, anaphylactoid reactions (mostly drug-induced, e.g. NSAID), physical angioedemas and recurrent idiopathic angioedema. Bradykinin probably plays a causative role in the pathogenesis of ACE-inhibitor or angiotensin II receptor blocker related angioedemas, as well as in the pathogenesis of the rare hereditary or acquired C1-inhibitor deficiency angioedemas. Urticaria is then typically absent and anti-histamines, as well as adrenalin, are ineffective

MP2RAGE provides new clinically-compatible correlates of mild cognitive deficits in relapsing-remitting multiple sclerosis.

Despite that cognitive impairment is a known early feature present in multiple sclerosis (MS) patients, the biological substrate of cognitive deficits in MS remains elusive. In this study, we assessed whether T1 relaxometry, as obtained in clinically acceptable scan times by the recent Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequence, may help identifying the structural correlate of cognitive deficits in relapsing-remitting MS patients (RRMS). Twenty-nine healthy controls (HC) and forty-nine RRMS patients underwent high-resolution 3T magnetic resonance imaging to obtain optimal cortical lesion (CL) and white matter lesion (WML) count/volume and T1 relaxation times. T1 z scores were then obtained between T1 relaxation times in lesion and the corresponding HC tissue. Patient cognitive performance was tested using the Brief Repeatable Battery of Neuro-psychological Tests. Multivariate analysis was applied to assess the contribution of MRI variables (T1 z scores, lesion count/volume) to cognition in patients and Bonferroni correction was applied for multiple comparison. T1 z scores were higher in WML (p < 0.001) and CL-I (p < 0.01) than in the corresponding normal-appearing tissue in patients, indicating relative microstructural loss. (1) T1 z scores in CL-I (p = 0.01) and the number of CL-II (p = 0.04) were predictors of long-term memory; (2) T1 z scores in CL-I (β = 0.3; p = 0.03) were independent determinants of long-term memory storage, and (3) lesion volume did not significantly influenced cognitive performances in patients. Our study supports evidence that T1 relaxometry from MP2RAGE provides information about microstructural properties in CL and WML and improves correlation with cognition in RRMS patients, compared to conventional measures of disease burden.

Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

Pegfilgrastim to accelerate neutrophil engraftment following peripheral blood stem cell transplant and reduce the duration of neutropenia, hospitalization, and use of intravenous antibiotics: a phase II study in multiple myeloma and lymphoma and comparison with filgrastim-treated matched controls.

This trial was aimed to explore the efficacy of pegfilgrastim to accelerate neutrophil engraftment after stem cell autotransplant. Twenty patients with multiple myeloma and 20 with lymphoma received pegfilgrastim 6 mg on day +1. Forty cases treated with daily filgrastim starting at median day +7 (5-7), matched by age, sex, diagnosis, high-dose chemotherapy schedule, CD34 +  cell-dose, and prior therapy lines, were used for comparison. Median time to neutrophil engraftment was 9.5 vs. 11 days for pegfilgrastim and filgrastim, respectively (p < 0.0001). Likewise, duration of neutropenia, intravenous antibiotic use, and hospitalization favored pegfilgrastim, while platelet engraftment, transfusion requirement, and fever duration were equivalent in both groups. No grade  ≥ 3 toxicities were observed. Patients with lymphoma performed similarly to the entire cohort, while patients with myeloma showed faster neutrophil engraftment and shorter neutropenia but not shorter hospitalization and antibiotic use. The possibility of different outcomes for lymphoma and myeloma suggests that stratification by diagnosis may be useful in future phase III studies.

Inversion of multiple intersecting high-resolution crosshole GPR profiles for hydrological characterization at the Boise Hydrogeophysical Research Site

The integration of geophysical data into the subsurface characterization problem has been shown in many cases to significantly improve hydrological knowledge by providing information at spatial scales and locations that is unattainable using conventional hydrological measurement techniques. In particular, crosshole ground-penetrating radar (GPR) tomography has shown much promise in hydrology because of its ability to provide highly detailed images of subsurface radar wave velocity, which is strongly linked to soil water content. Here, we develop and demonstrate a procedure for inverting together multiple crosshole GPR data sets in order to characterize the spatial distribution of radar wave velocity below the water table at the Boise Hydrogeophysical Research Site (BHRS) near Boise, Idaho, USA. Specifically, we jointly invert 31 intersecting crosshole GPR profiles to obtain a highly resolved and consistent radar velocity model along the various profile directions. The model is found to be strongly correlated with complementary neutron porosity-log data and is further corroborated by larger-scale structural information at the BHRS. This work is an important prerequisite to using crosshole GPR data together with existing hydrological measurements for improved groundwater flow and contaminant transport modeling.

A pipeline approach with spatial information for segmenting multiple sclerosis lesions on brain magnetic resonance imaging

Background: Conventional magnetic resonance imaging (MRI) techniques are highly sensitive to detect multiple sclerosis (MS) plaques, enabling a quantitative assessment of inflammatory activity and lesion load. In quantitative analyses of focal lesions, manual or semi-automated segmentations have been widely used to compute the total number of lesions and the total lesion volume. These techniques, however, are both challenging and time-consuming, being also prone to intra-observer and inter-observer variability.Aim: To develop an automated approach to segment brain tissues and MS lesions from brain MRI images. The goal is to reduce the user interaction and to provide an objective tool that eliminates the inter- and intra-observer variability.Methods: Based on the recent methods developed by Souplet et al. and de Boer et al., we propose a novel pipeline which includes the following steps: bias correction, skull stripping, atlas registration, tissue classification, and lesion segmentation. After the initial pre-processing steps, a MRI scan is automatically segmented into 4 classes: white matter (WM), grey matter (GM), cerebrospinal fluid (CSF) and partial volume. An expectation maximisation method which fits a multivariate Gaussian mixture model to T1-w, T2-w and PD-w images is used for this purpose. Based on the obtained tissue masks and using the estimated GM mean and variance, we apply an intensity threshold to the FLAIR image, which provides the lesion segmentation. With the aim of improving this initial result, spatial information coming from the neighbouring tissue labels is used to refine the final lesion segmentation.Results:The experimental evaluation was performed using real data sets of 1.5T and the corresponding ground truth annotations provided by expert radiologists. The following values were obtained: 64% of true positive (TP) fraction, 80% of false positive (FP) fraction, and an average surface distance of 7.89 mm. The results of our approach were quantitatively compared to our implementations of the works of Souplet et al. and de Boer et al., obtaining higher TP and lower FP values.Conclusion: Promising MS lesion segmentation results have been obtained in terms of TP. However, the high number of FP which is still a well-known problem of all the automated MS lesion segmentation approaches has to be improved in order to use them for the standard clinical practice. Our future work will focus on tackling this issue.

Internal arsenite bioassay calibration using multiple reporter cell lines

Bioassays with bioreporter bacteria are usually calibrated with analyte solutions of known concentrations that are analysed along with the samples of interest. This is done as bioreporter output (the intensity of light, fluorescence or colour) does not only depend on the target concentration, but also on the incubation time and physiological activity of the cells in the assay. Comparing the bioreporter output with standardized colour tables in the field seems rather difficult and error-prone. A new approach to control assay variations and improve application ease could be an internal calibration based on the use of multiple bioreporter cell lines with drastically different reporter protein outputs at a given analyte concentration. To test this concept, different Escherichia coli-based bioreporter strains expressing either cytochrome c peroxidase (CCP, or CCP mutants) or β-galactosidase upon induction with arsenite were constructed. The reporter strains differed either in the catalytic activity of the reporter protein (for CCP) or in the rates of reporter protein synthesis (for β-galactosidase), which, indeed, resulted in output signals with different intensities at the same arsenite concentration. Hence, it was possible to use combinations of these cell lines to define arsenite concentration ranges at which none, one or more cell lines gave qualitative (yes/no) visible signals that were relatively independent of incubation time or bioreporter activity. The discriminated concentration ranges would fit very well with the current permissive (e.g. World Health Organization) levels of arsenite in drinking water (10 µg l−1).

Paper 5: Surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases.

BACKGROUND: Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS: Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as "multiple congenital anomaly" cases. RESULTS: A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as "potentially multiple congenital anomalies". After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS: The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research.

Magnetoencephalography demonstrates multiple asynchronous generators during human sleep spindles.

Sleep spindles are approximately 1 s bursts of 10-16 Hz activity that occur during stage 2 sleep. Spindles are highly synchronous across the cortex and thalamus in animals, and across the scalp in humans, implying correspondingly widespread and synchronized cortical generators. However, prior studies have noted occasional dissociations of the magnetoencephalogram (MEG) from the EEG during spindles, although detailed studies of this phenomenon have been lacking. We systematically compared high-density MEG and EEG recordings during naturally occurring spindles in healthy humans. As expected, EEG was highly coherent across the scalp, with consistent topography across spindles. In contrast, the simultaneously recorded MEG was not synchronous, but varied strongly in amplitude and phase across locations and spindles. Overall, average coherence between pairs of EEG sensors was approximately 0.7, whereas MEG coherence was approximately 0.3 during spindles. Whereas 2 principle components explained approximately 50% of EEG spindle variance, >15 were required for MEG. Each PCA component for MEG typically involved several widely distributed locations, which were relatively coherent with each other. These results show that, in contrast to current models based on animal experiments, multiple asynchronous neural generators are active during normal human sleep spindles and are visible to MEG. It is possible that these multiple sources may overlap sufficiently in different EEG sensors to appear synchronous. Alternatively, EEG recordings may reflect diffusely distributed synchronous generators that are less visible to MEG. An intriguing possibility is that MEG preferentially records from the focal core thalamocortical system during spindles, and EEG from the distributed matrix system.