The effect of mutation on an aggregation-prone protein: An in vivo, in vitro, and in silico analysis.

Aggregation of initially stably structured proteins is involved in more than 20 human amyloid diseases. Despite intense research, however, how this class of proteins assembles into amyloid fibrils remains poorly understood, principally because of the complex effects of amino acid substitutions on protein stability, solubility, and aggregation propensity. We address this question using ß2-microglobulin (ß2m) as a model system, focusing on D76N-ß2m that is involved in hereditary amyloidosis. This amino acid substitution causes the aggregation-resilient wild-type protein to become highly aggregation prone in vitro, although the mechanism by which this occurs remained elusive. Here, we identify the residues key to protecting ß2m from aggregation by coupling aggregation with antibiotic resistance in E. coli using a tripartite ß-lactamase assay (TPBLA). By performing saturation mutagenesis at three different sites (D53X-, D76X-, and D98X-ß2m) we show that residue 76 has a unique ability to drive ß2m aggregation in vivo and in vitro. Using a randomly mutated D76N-ß2m variant library, we show that all of the mutations found to improve protein behavior involve residues in a single aggregation-prone region (APR) (residues 60 to 66). Surprisingly, no correlation was found between protein stability and protein aggregation rate or yield, with several mutations in the APR decreasing aggregation without affecting stability. Together, the results demonstrate the power of the TPBLA to develop proteins that are resilient to aggregation and suggest a model for D76N-ß2m aggregation involving the formation of long-range couplings between the APR and Asn76 in a nonnative state.

Comprehensive analysis of synthetic learning applied to neonatal brain MRI segmentation.

Brain segmentation from neonatal MRI images is a very challenging task due to large changes in the shape of cerebral structures and variations in signal intensities reflecting the gestational process. In this context, there is a clear need for segmentation techniques that are robust to variations in image contrast and to the spatial configuration of anatomical structures. In this work, we evaluate the potential of synthetic learning, a contrast-independent model trained using synthetic images generated from the ground truth labels of very few subjects. We base our experiments on the dataset released by the developmental Human Connectome Project, for which high-quality images are available for more than 700 babies aged between 26 and 45 weeks postconception. First, we confirm the impressive performance of a standard UNet trained on a few volumes, but also confirm that such models learn intensity-related features specific to the training domain. We then confirm the robustness of the synthetic learning approach to variations in image contrast. However, we observe a clear influence of the age of the baby on the predictions. We improve the performance of this model by enriching the synthetic training set with realistic motion artifacts and over-segmentation of the white matter. Based on extensive visual assessment, we argue that the better performance of the model trained on real T2w data may be due to systematic errors in the ground truth. We propose an original experiment allowing us to show that learning from real data will reproduce any systematic bias affecting the training set, while synthetic models can avoid this limitation. Overall, our experiments confirm that synthetic learning is an effective solution for segmenting neonatal brain MRI. Our adapted synthetic learning approach combines key features that will be instrumental for large multisite studies and clinical applications.

Low prevalence of tissue detection of cefepime and daptomycin used as empirical treatment during revision for periprosthetic joint infections: results of a prospective multicenter study.

Data demonstrating that antibiotics administered intraoperatively in patients with surgical revision for periprosthetic joint infection achieve concentrations exceeding minimal inhibitory concentrations of the identified bacteria at the surgical site when the new implant is inserted are lacking. We prospectively included patients with periprosthetic joint infection operated with one- or two-stage replacement during which cefepime (2g)-daptomycin (10mg/kg) combination was administered intravenously as intraoperative empirical antibiotic treatment. Three biopsies (two bones and one synovial membrane) were taken from each patient just before the insertion of the new implant. Eighteen adults of median age 68 years were included. Knee was involved in 10 patients (55.6%) and surgery consisted in one-/two-stage replacement in 11/7 patients. A tourniquet was used during the intervention in the 10 patients with knee prosthesis. Among 54 tissue samples, cefepime and daptomycin were detected respectively in 35 (64.8%) and 21 (38.9%) cases (P=0.01). A total of 17 bacteria dominated by staphylococci (n=14) were identified in 10 patients; tissue inhibitory quotient calculated in 51 samples was >1 in 22 cases (43.1%) for cefepime and in 16 cases (31.4%) for daptomycin. The proportion of tissue samples with detectable antibiotic was significantly higher in hip versus knee prosthesis (P=0.03). The present study suggests that intraoperative empirical administration of cefepime-daptomycin combination during septic prosthetic joint replacement results in a high proportion of tissue samples in which at least one of the two antibiotics was not detected or at a low concentration despite satisfactory concomitant blood serum concentrations.

Introducing cell-free DNA noninvasive testing in a Down syndrome public health screening program: a budget impact analysis.

BACKGROUND: Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma is a high accurate test for prenatal screening for Down syndrome. Although it has been reported to be cost effective as a contingent test, evidence about its budget impact is lacking. OBJECTIVE: To evaluate, using computer simulations, the budget impact of implementing NIPT as a contingent test in the Quebec Program of screening for Trisomy 21. METHODS: A semi-Markov analytic model built to simulate the budget impact of implementing NIPT into the current Quebec Trisomy 21 public Prenatal Screening, Serum Integrated prenatal screening (SIPS). Comparisons were made for a virtual population similar to that of expected Quebec pregnant women in 2015 in terms of size and age. Data input parameters were retrieved from a thorough literature search and in government databases, especially data from Quebec Program of screening for Trisomy 21. The 2015-2016 fiscal year budget impact was estimated from the Quebec healthcare system perspective and was expressed as the difference in the overall costs between the two alternatives (SIPS minus SPS + NIPT). RESULTS: Our study found that, at a baseline cost for NIPT of CAD$ 795, NIPT as a second-tier test offered to high-risk women identified by current screening program (SIPS + NIPT) may be affordable for Quebec health care system. Compared to the current screening program, it would be implemented at a neutral cost, considering a modest annual savings of $ 80,432 (95% CI $ 79, $ 874-$ 81,462). Results were sensitive to the NIPT costs and the uptake-rate of invasive diagnostic tests. CONCLUSION: Introducing NIPT as a contingent test in the Quebec Trisomy 21 screening program is an affordable strategy compared to the current practice. Further research is needed to confirm if our results can be reproduced in other healthcare jurisdictions.

Cell-free DNA noninvasive prenatal screening for aneuploidy versus conventional screening: A systematic review of economic evaluations.

Although noninvasive prenatal testing (NIPT) for aneuploidies using cell-free fetal DNA in maternal blood has been reported to have a high accuracy, only little evidence about its cost-effectiveness is available. We systematically reviewed and assessed quality of economic evaluation studies published between January 1, 2009 and January 1, 2016 where NIPT was compared to the current screening practices consisting of biochemical markers with or without nuchal translucency (NT) and/or maternal age. We included 16 studies and we found that, at current level of NIPT prices, contingent NIPT provide the best value for money, especially for publicly funded screening programs. NIPT as first-line test was found not cost-effective in the majority of studies. The NIPT unit cost, the risk cut-offs for current screening practice, the screening uptake rates (first- and second-line screening) as well as the costs and uptake rates of invasive diagnostic screening were the most common uncertain variables. The overall quality of included studies was fair. Considering a possible drop in prices and an ongoing NIPT expansion to include other chromosomes abnormalities other than T21, T18, T13 and sex chromosomes aneuploidies, future research are needed to examine the potential cost-effectiveness of implementing NIPT as first-line test.

Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.

We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec.

Screening for pre-eclampsia early in pregnancy: performance of a multivariable model combining clinical characteristics and biochemical markers.

OBJECTIVE: To investigate the performance of a multivariable model combining a priori clinical characteristics and biomarkers to detect, early in pregnancy, women at higher risk of developing pre-eclampsia (PE). DESIGN: Nested case-control study. SETTING: University medical centre, Quebec, Canada (CHU de Québec). POPULATION: A total of 7929 pregnant women recruited between 10 and 18 weeks of gestation. In all, 350 developed hypertensive disorders of pregnancy (HDP)-of which 139 had PE, comprising 68 with severe PE and 47 with preterm PE-and were matched with two women with a normal pregnancy. METHODS: We selected a priori clinical characteristics and promising markers to create multivariable logistic regression models: body mass index (BMI), mean arterial pressure (MAP), placental growth factor, soluble Fms-like tyrosine kinase-1, pregnancy-associated plasma protein A and inhibin A. MAIN OUTCOME MEASURES: PE, severe PE, preterm PE, HDP. RESULTS: At false-positive rates of 5 and 10%, the estimated detection rates were between 15% (5-29%) and 32% (25-39%), and between 39% (19-59%) and 50% (34-66%), respectively. Considering the low prevalence of PE in this population, the positive predictive values were 7% (5-9%) to 10% (7-13%) for PE and 2% (1-4%) to 4% (3-6%) in the preterm and severe PE subgroups. The multivariable model yielded areas under the receiver operating characteristics curves (AUC) between 0.72 (0.61-0.81) and 0.78 (0.68-0.88). When only BMI and MAP were included in the model, the AUC were similar to those of the a priori model. CONCLUSIONS: In a population with a low prevalence of preterm PE, a multivariable risk algorithm using an a priori combination of clinical characteristics and biochemical markers did not reach a performance justifying clinical implementation as screening test early in pregnancy.

Zoom in at African country level: potential climate induced changes in areas of suitability for survival of malaria vectors.

BACKGROUND: Predicting anopheles vectors' population densities and boundary shifts is crucial in preparing for malaria risks and unanticipated outbreaks. Although shifts in the distribution and boundaries of the major malaria vectors (Anopheles gambiae s.s. and An. arabiensis) across Africa have been predicted, quantified areas of absolute change in zone of suitability for their survival have not been defined. In this study, we have quantified areas of absolute change conducive for the establishment and survival of these vectors, per African country, under two climate change scenarios and based on our findings, highlight practical measures for effective malaria control in the face of changing climatic patterns. METHODS: We developed a model using CLIMEX simulation platform to estimate the potential geographical distribution and seasonal abundance of these malaria vectors in relation to climatic factors (temperature, rainfall and relative humidity). The model yielded an eco-climatic index (EI) describing the total favourable geographical locations for the species. The EI values were classified and exported to a GIS package. Using ArcGIS, the EI shape points were clipped to the extent of Africa and then converted to a raster layer using Inverse Distance Weighted (IDW) interpolation method. Generated maps were then transformed into polygon-based geo-referenced data set and their areas computed and expressed in square kilometers (km(2)). RESULTS: Five classes of EI were derived indicating the level of survivorship of these malaria vectors. The proportion of areas increasing or decreasing in level of survival of these malaria vectors will be more pronounced in eastern and southern African countries than those in western Africa. Angola, Ethiopia, Kenya, Mozambique, Tanzania, South Africa and Zambia appear most likely to be affected in terms of absolute change of malaria vectors suitability zones under the selected climate change scenarios. CONCLUSION: The potential shifts of these malaria vectors have implications for human exposure to malaria, as recrudescence of the disease is likely to be recorded in several new areas and regions. Therefore, the need to develop, compile and share malaria preventive measures, which can be adapted to different climatic scenarios, remains crucial.

White matter volume is decreased in the brain of patients with neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory disease involving predominantly the spinal cord and optic nerves. Whether patients with NMO have a loss in white or grey matter (GM) volumes remains to be determined. METHODS: Thirty patients with NMO, 30 healthy subjects matched for age and gender, 21 patients with multiple sclerosis (MS) and 20 patients with a clinically isolated syndrome (CIS) were studied. We applied a SIENAX post-treatment software. We compared white matter (WM) and GM volumes between groups and explored correlations of changes in NMO patients with age, gender, duration, disease severity, visual acuity and T2 hyperintensities. We also performed a voxel-based morphometry (VBM) analysis to identify the regions affected by loss of volume. RESULTS: White matter volume was significantly reduced in patients with NMO (764.4 ± 58.3 cm(3) ) compared to healthy subjects (843.1 ± 49.3 cm(3) ) (P < 0.001), whereas no difference was observed for the GM. Patients with CIS also presented an elective atrophy of WM and MS an atrophy of both WM and GM. We did not find any predictive factors of brain atrophy. The decrease in WM volume in NMO was noted even in the absence of visible MRI hypersignals. The VBM analysis found a few regions of WM atrophy (corpus callosum and optic radiations, P < 0.005, uncorrected) and a few regions of GM atrophy (thalamus and prefrontal cortex, P < 0.001, uncorrected). CONCLUSION: These results suggest a significant brain involvement in NMO, especially an involvement of WM which appears not to be limited to secondary degeneration after spinal cord and optic nerve damage.

A gene for achondroplasia-hypochondroplasia maps to chromosome 4p.

Achondroplasia (ACH) is a frequent condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. Milder forms, termed hypochondroplasias (HCH) result in short stature with radiological features similar to those observed in ACH. We report on the mapping of a gene causing ACH/HCH to human chromosome 4p16.3, by linkage to the iduronidase A (IDUA) locus, in 15 informative families (Z max = 3.01 at theta = 0 for ACH; Z max = 4.71 at theta = 0 for ACH/HCH). Multipoint linkage analysis provides evidence for mapping the disease locus telomeric to D4S412 (location score in log 10 = 4.60). Moreover, this study supports the view that ACH and HCH are genetically homogeneous in our series.

UGT2B17 gene deletion associated with an increase in bone mineral density similar to the effect of hormone replacement in postmenopausal women.

UNLABELLED: UGT2B17 is one of the most important enzymes for androgen metabolism. In addition, the UGT2B17 gene is one of the most commonly deleted regions of the human genome. The deletion was previously found associated with higher femoral bone density in men and women, and we replicated this association in a sample of postmenopausal who never used hormone therapy. INTRODUCTION: Deletion of the UGT2B17 gene was previously shown to be associated with a higher hip bone mineral density (BMD). Using a PCR assay, we tried to replicate the association among a large group of 2,379 women. We examined the effect of the deletion on femoral neck BMD and lumbar spine BMD according to the menopausal status and hormone replacement therapy (HRT). METHODS: We used a high-throughput PCR assay to identify the gene and the deletion in a population of well-characterized women. Two additional polymorphisms, UGT2B28 deletion and UGT2B15 rs1902023 G > T were also investigated. RESULTS: Only UGT2B17 deletion was associated with LS and FN BMD. Furthermore, the association was seen only among postmenopausal women who had never used hormone replacement as in the first reported association. CONCLUSIONS: We confirmed the association between UGT2B17 deletion and a higher LS and FN BMD. In addition, we show that the association is observed among postmenopausal women who never used HRT consistent with the enzymatic function of UGT2B17. The analysis shows that those having one or two UGT2B17 alleles benefit from HRT, which is not the case for null carriers.

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1.

Autism is a severe developmental disorder, whose pathogenetic underpinnings are still largely unknown. Temporocortical gray matter from six matched patient-control pairs was used to perform post-mortem biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier (AGC), which participates in the aspartate/malate reduced nicotinamide adenine dinucleotide shuttle and is physiologically activated by calcium (Ca(2+)). AGC transport rates were significantly higher in tissue homogenates from all six patients, including those with no history of seizures and with normal electroencephalograms prior to death. This increase was consistently blunted by the Ca(2+) chelator ethylene glycol tetraacetic acid; neocortical Ca(2+) levels were significantly higher in all six patients; no difference in AGC transport rates was found in isolated mitochondria from patients and controls following removal of the Ca(2+)-containing postmitochondrial supernatant. Expression of AGC1, the predominant AGC isoform in brain, and cytochrome c oxidase activity were both increased in autistic patients, indicating an activation of mitochondrial metabolism. Furthermore, oxidized mitochondrial proteins were markedly increased in four of the six patients. Variants of the AGC1-encoding SLC25A12 gene were neither correlated with AGC activation nor associated with autism-spectrum disorders in 309 simplex and 17 multiplex families, whereas some unaffected siblings may carry a protective gene variant. Therefore, excessive Ca(2+) levels are responsible for boosting AGC activity, mitochondrial metabolism and, to a more variable degree, oxidative stress in autistic brains. AGC and altered Ca(2+) homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.

Screening and instability of FMR1 alleles in a prospective sample of 24,449 mother-newborn pairs from the general population.

To study the instability of FMR1 triplet repeats in the general population, we screened a prospective sample of 24,449 anonymized mother-offspring pairs and analyzed transmissions of intermediate-size (45-54 triplets) and premutation-size (55-200 triplets) alleles. We screened all mothers for alleles > or = 45 triplets by Southern blot and studied transmission of 545 maternal alleles to their offspring using polymerase chain reaction. Out of 21,411 maternal samples with conclusive results, we identified 250 carriers of at least one intermediate-size allele and 39 carrying a premutation-size allele. Out of a subsample of 430 transmissions of normal-size alleles (< 45 triplets), we observed four (< 1%) unstable transmissions. There were 6/90 intermediate-size unstable alleles (7%) and 11/25 unstable premutation-size alleles (44%). Two mothers transmitted a typical full mutation. The incidence of fragile X syndrome was thus 1/12,225 newborns (upper limit of 95% confidence interval: 1/4638 newborns), but larger in males (1/6209) than females (none detected in over 12,000 newborn females). Intermediate-size alleles were more unstable than normal-size alleles (p = 0.0027), but more stable (about sixfold) than premutation-size alleles (p < 0.0001). Unstable premutation-size alleles harbored the major fragile X haplotype (T50-T42-T62), and this haplotype appeared to be a good predictor of instability in premutations (p = 0.02). Incidence and instability are important to determine the feasibility and cost effectiveness of putative FMR1 screening programs. Carriers of FMR1 alleles of 55+ triplets with no family history of the disease may have a significant risk of expansion to a full mutation in a single generation.

The contribution of founder mutations to early-onset breast cancer in French-Canadian women.

In an ethnically-homogeneous population, it is valuable to identify founder mutations in cancer-predisposing genes. Founder mutations have been found in four breast-cancer-predisposing genes in French-Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French-Canadian women with early-onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French-Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7-28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9-67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4-9.1). One-half of the women with a mutation had a first- or second-degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French-Canadian women with early-onset breast cancer. It is reasonable to offer screening for founder mutations to all French-Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population-based screening.

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.

The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island, at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations, and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged, or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression, and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.

Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island.

Yeast artificial chromosomes (YACs) were obtained from a 550-kilobase region that contains three probes previously mapped as very close to the locus of the fragile X syndrome. These YACs spanned the fragile site in Xq27.3 as shown by fluorescent in situ hybridization. An internal 200-kilobase segment contained four chromosomal breakpoints generated by induction of fragile X expression. A single CpG island was identified in the cloned region between markers DXS463 and DXS465 that appears methylated in mentally retarded fragile X males, but not in nonexpressing male carriers of the mutation nor in normal males. This CpG island may indicate the presence of a gene involved in the clinical phenotype of the syndrome.

Development of vegetable farming: a cause of the emergence of insecticide resistance in populations of Anopheles gambiae in urban areas of Benin.

BACKGROUND: A fast development of urban agriculture has recently taken place in many areas in the Republic of Benin. This study aims to assess the rapid expansion of urban agriculture especially, its contribution to the emergence of insecticide resistance in populations of Anopheles gambiae. METHODS: The protocol was based on the collection of sociological data by interviewing vegetable farmers regarding various agricultural practices and the types of pesticides used. Bioassay tests were performed to assess the susceptibility of malaria vectors to various agricultural insecticides and biochemical analysis were done to characterize molecular status of population of An. gambiae. RESULTS: This research showed that:(1) The rapid development of urban agriculture is related to unemployment observed in cities, rural exodus and the search for a balanced diet by urban populations;(2) Urban agriculture increases the farmers' household income and their living standard;(3) At a molecular level, PCR revealed the presence of three sub-species of An. gambiae (An. gambiae s.s., Anopheles melas and Anopheles arabiensis) and two molecular forms (M and S). The kdr west mutation recorded in samples from the three sites and more specifically on the M forms seems to be one of the major resistance mechanisms found in An. gambiae from agricultural areas. Insecticide susceptibility tests conducted during this research revealed a clear pattern of resistance to permethrin (76% mortality rate at Parakou; 23.5% at Porto-Novo and 17% at Cotonou). CONCLUSION: This study confirmed an increase activity of the vegetable farming in urban areas of Benin. This has led to the use of insecticide in an improper manner to control vegetable pests, thus exerting a huge selection pressure on mosquito larval population, which resulted to the emergence of insecticide resistance in malaria vectors.

Global Perturbation of Initial Geometry in a Biomechanical Model of Cortical Morphogenesis.

Cortical folding pattern is a main characteristic of the geometry of the human brain which is formed by gyri (ridges) and sulci (grooves). Several biological hypotheses have suggested different mechanisms that attempt to explain the development of cortical folding and its abnormal evolutions. Based on these hypotheses, biomechanical models of cortical folding have been proposed. In this work, we compare biomechanical simulations for several initial conditions by using an adaptive spherical parameterization approach. Our approach allows us to study and explore one of the most potential sources of reproducible cortical folding pattern: the specification of initial geometry of the brain.

Temporal resolution enhancement of dynamic MRI sequences within a motion-based framework.

Dynamic MRI has made it possible to non-invasively capture the moving human joints in vivo. Real-time Fast Field Echo (FFE) sequences have the potential to reduce the effect of motion artifacts by acquiring the image data within a few milliseconds. However, the short acquisition times affect the temporal resolution of the acquired sequences. In this paper, we propose a post-processing technique to reconstruct the missing frames of the sequence given the reduced amount of acquired data, which leads to recover the entire joint trajectory outside the MR scanner. To do this, we generalize the Log-Euclidean polyrigid registration framework to deal with dynamic three-dimensional articulated structures by adding the time as fourth dimension : we first estimate the rigid motion of each bone from the acquired data using linear intensity-based registration. Then, we fuse these local transformations to compute the non-linear joint deformations between successive images using a spatio-temporal log-euclidean polyrigid framework. The idea is to reconstruct the missing time frames by interpolating the realistic joint deformation fields in the domain of matrix logarithms assuming the motion to be consistent over a short period of time. The algorithm has been applied and validated using dynamic data from five children performing passive ankle dorsi-plantar flexion.

4D in vivo quantification of ankle joint space width using dynamic MRI.

Spatio-temporal evolution of joint space width (JSW) during motion is of great importance to help with making early treatment plans for degenerative joint diseases like osteoarthritis (OA). These diseases can affect people of all ages leading to an acceleration of joint degeneration and to limitations in the activities of daily living. However, only a few studies have attempted to quantify the JSW from moving joints. In this paper, we present a generic pipeline to accurately determine the changes of the JSW during the joint motion cycle. The key idea is to combine spatial information of static MRI with temporal information of low-resolution (LR) dynamic MRI sequences via an intensity-based registration framework, leading to a high-resolution (HR) temporal reconstruction of the joint. This allows the temporal JSW to be measured in the HR domain using an Eulerian approach for solving partial differential equations (PDEs) inside a deforming inter-bone area where the HR reconstructed bone segmentations are considered as temporal Dirichlet boundaries. The proposed approach has been applied and evaluated on in vivo MRI data of five healthy children to non-invasively quantify the spatio-temporal evolution of the JSW of the ankle (tibiotalar joint) during the entire dorsi-plantar flexion motion cycle. Promising results were obtained, showing that this pipeline can be useful to perform large-scale studies containing subjects with OA for different joints like ankle and knee.