Instabilities in the dissolution of a porous matrix

A reactive fluid dissolving the surrounding rock matrix can trigger an instability in the dissolution front, leading to spontaneous formation of pronounced channels or wormholes. Theoretical investigations of this instability have typically focused on a steadily propagating dissolution front that separates regions of high and low porosity. In this paper we show that this is not the only possible dissolutional instability in porous rocks; there is another instability that operates instantaneously on any initial porosity field, including an entirely uniform one. The relative importance of the two mechanisms depends on the ratio of the porosity increase to the initial porosity. We show that the "inlet" instability is likely to be important in limestone formations where the initial porosity is small and there is the possibility of a large increase in permeability. In quartz-rich sandstones, where the proportion of easily soluble material (e.g. carbonate cements) is small, the instability in the steady-state equations is dominant.Comment: to be published in Geophysical Research Letter

The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome

The central nervous system of persons with Down syndrome presents cytoarchitectural abnormalities that likely result from gene-dosage effects affecting the expression of key developmental genes. To test this hypothesis, we have investigated the transcriptome of the cerebellum of the Ts1Cje mouse model of Down syndrome during postnatal development using microarrays and quantitative PCR (qPCR). Genes present in three copies were consistently overexpressed, with a mean ratio relative to euploid of 1.52 as determined by qPCR. Out of 63 three-copy genes tested, only five, nine and seven genes had ratios >2 or <1.2 at postnatal days 0 (P0), P15 and P30, respectively. This gene-dosage effect was associated with a dysregulation of the expression of some two-copy genes. Out of 8258 genes examined, the Ts1Cje/euploid ratios differed significantly from 1.0 for 406 (80 and 154 with ratios above 1.5 and below 0.7, respectively), 333 (11 above 1.5 and 55 below 0.7) and 246 genes (59 above 1.5 and 69 below 0.7) at P0, P15 and P30, respectively. Among the two-copy genes differentially expressed in the trisomic cerebellum, six homeobox genes, two belonging to the Notch pathway, were severely repressed. Overall, at P0, transcripts involved in cell differentiation and development were over-represented among the dysregulated genes, suggesting that cell differentiation and migration might be more altered than cell proliferation. Finally, global gene profiling revealed that transcription in Ts1Cje mice is more affected by the developmental changes than by the trisomic state, and that there is no apparent detectable delay in the postnatal development of the cerebellum of Ts1Cje mic

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p&lt;5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p&lt;5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

The safety and clinical effectiveness of rapid infusion with CT-P10 in patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia: A retrospective non-interventional post-authorization safety study in Europe

Rapid infusion (RI) of the rituximab biosimilar CT-P10 is currently only an approved treatment regimen for the treatment of rheumatoid arthritis. Although both CT-P10 and reference rituximab are known to be frequently administered using a RI regimen (≤90&nbsp;min) in clinical practice, published data on the safety of RI of CT-P10 in patients with NHL and CLL are limited. Hence, this study collected real-world safety and effectiveness data on RI-CT-P10 from the medical records of 196 patients with NHL or CLL in 10 European centers, 6&nbsp;months after the date of the first RI (index date); the infusion-related reaction (IRR) rate was compared to previously published data. Ten percent (95% confidence interval 6%–15%; n&nbsp;=&nbsp;20/196) of patients experienced an infusion-related reaction (IRR) on day 1–2 post-index, which was not significantly different (p&nbsp;=&nbsp;0.45) to the IRR rate for rituximab described in a previous meta-analysis (8.8%). During the observation period, 2% of patients experienced grade 3–5 IRRs and 85% (n&nbsp;=&nbsp;166) experienced an adverse event (non-IRR). The most common reason for discontinuation of first-line CT-P10 was planned treatment completion (81%; n&nbsp;=&nbsp;158). Complete response and partial response to CT-P10 was observed in 74% (n&nbsp;=&nbsp;142/192) and 22% (n&nbsp;=&nbsp;42/192) of patients, respectively. The results of this real-world study demonstrate that the safety and effectiveness profile of RI-CT-P10 is similar to RI of reference rituximab and therefore support the current use of RI-CT-P10 in patients with NHL and CLL

Définition des centres experts en endométriose

OBJECTIVES: The Collège national des gynécologues obstétriciens français (CNGOF), in agreement with the Société de chirurgie gynécologique et pelvienne (SCGP), has set up a commission in 2017 to define endometriosis expert centres, with the aim of optimizing endometriosis care in France. METHODS: The committee included members from university and general hospitals as well as private facilities, representing medical, surgical and radiological aspects of endometriosis care. Opinion of endometriosis patients\u27 associations was obtained prior to writing this work. The final text was presented and unanimously validated by the members of the CNGOF Board of Directors at its meeting of October 13, 2017. RESULTS: Based on analysis of current management of endometriosis and the last ten years opportunities in France, the committee has been able to define the contours of endometriosis expert centres. The objectives, production specifications, mode of operation, missions and funding for these centres were described. The following missions have been specifically defined: territorial organization, global and referral care, communication and teaching as well as research and evaluation. CONCLUSION: Because of its daily impact for women and its economic burden in France, endometriosis justifies launching of expert centres throughout the country with formal accreditation by health authorities, ideally as part of the National Health Plan

The definition of Endometriosis Expert Centres

Endometriosis is a common condition that causes pain and infertility. It can lead to absenteeism and also to multiple surgeries with a consequent risk of impaired fertility, and constitutes a major public health cost. Despite the existence of numerous national and international guidelines, the management of endometriosis remains suboptimal. To address this issue, the French College of Gynaecologists and Obstetricians (CNGOF) and the Society of Gynaecological and Pelvic Surgery (SCGP) convened a committee of experts tasked with defining the criteria for establishing a system of care networks, headed by Expert Centres, covering all of mainland France and its overseas territories. This document sets out the criteria for the designation of Expert Centres. It will serve as a guide for the authorities concerned, to ensure that the means are provided to adequately manage patients with endometriosis

Wormhole formation in dissolving fractures

We investigate the dissolution of artificial fractures with three-dimensional, pore-scale numerical simulations. The fluid velocity in the fracture space was determined from a lattice-Boltzmann method, and a stochastic solver was used for the transport of dissolved species. Numerical simulations were used to study conditions under which long conduits (wormholes) form in an initially rough but spatially homogeneous fracture. The effects of flow rate, mineral dissolution rate and geometrical properties of the fracture were investigated, and the optimal conditions for wormhole formation determined.Comment: to be published in J. Geophys Re

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms