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Sol?ne Moulin - Top 30 Publications

Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke.

Background Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. Methods In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. Results A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. Conclusions Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

Reprogramming of rabbit induced pluripotent stem cells toward epiblast and chimeric competency using Krüppel-like factors.

Rabbit induced pluripotent stem cells (rbiPSCs) possess the characteristic features of primed pluripotency as defined in rodents and primates. In the present study, we reprogrammed rbiPSCs using human Krüppel-like factors (KLFs) 2 and 4 and cultured them in a medium supplemented with fetal calf serum and leukemia inhibitory factor. These cells (designated rbEKA) were propagated by enzymatic dissociation for at least 30 passages, during which they maintained a normal karyotype. This new culturing protocol resulted in transcriptional and epigenetic reconfiguration, as substantiated by the expression of transcription factors and the presence of histone modifications associated with naïve pluripotency. Furthermore, microarray analysis of rbiPSCs, rbEKA cells, rabbit ICM cells, and rabbit epiblast showed that the global gene expression profile of the reprogrammed rbiPSCs was more similar to that of rabbit ICM and epiblast cells. Injection of rbEKA cells into 8-cell stage rabbit embryos resulted in extensive colonization of ICM in 9% early-blastocysts (E3.5), epiblast in 10% mid-blastocysts (E4.5), and embryonic disk in 1.4% pre-gastrulae (E6). Thus, these results indicate that KLF2 and KLF4 triggered the conversion of rbiPSCs into epiblast-like, embryo colonization-competent PSCs. Our results highlight some of the requirements to achieve bona fide chimeric competency.

Unintentional Cannabis Ingestion in Children: A Systematic Review.

To analyze published reports of unintentional cannabis ingestions in children to determine presenting signs and symptoms, route of exposure, treatment, and outcome.

A population-based approach to assess the heritability and distribution of renal handling of electrolytes.

The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population-based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m(2), and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m(2). The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population.

Chronic Intermittent Hypoxia Impairs Insulin Sensitivity but Improves Whole-Body Glucose Tolerance by Activating Skeletal Muscle AMPK.

Obstructive sleep apnea syndrome is a highly prevalent disease resulting in transient respiratory arrest and chronic intermittent hypoxia (cIH). cIH is associated with insulin resistance and impaired metabolic homeostasis in both rodents and humans but the exact underlying mechanism(s) remains unclear. In the present study, we investigated the effects of two weeks of cIH (1min cycle, FiO2 21-5%, 8h/day) on whole-body insulin sensitivity and glucose tolerance in lean mice. Although food intake and body weight were reduced when compared to normoxia, cIH induced systemic insulin resistance in a hypoxia-inducible factor-1α-independent manner and impaired insulin signaling in liver, white adipose tissue and skeletal muscle. Unexpectedly, cIH was found to improve whole-body glucose tolerance, independently of changes in body weight and glucose-induced insulin response. This effect was associated with elevated phosphorylation of Thr172-AMP-activated Protein Kinase (AMPK) and Ser237-TBC1 domain family member 1 (TBC1D1) in skeletal muscle, suggesting a tissue-specific AMPK-dependent increase in TBC1D1-driven glucose uptake. Remarkably, although food intake, body weight and systemic insulin sensitivity were still affected, the improvement in glucose tolerance by cIH was abolished in muscle-specific AMPKα1α2-deficient mice. We conclude that cIH impairs insulin sensitivity while improving whole-body glucose tolerance by promoting specific activation of skeletal muscle AMPK pathway.

Management of patients with inflammatory bowel disease and spondyloarthritis.

More than half of the patients with inflammatory bowel disease (IBD) experience at least one extra-intestinal manifestation (EIM). The most common EIM in patients with IBD is spondyloarthritis (SpA). Microscopic intestinal inflammation is documented in almost 50% of the patients with SpA. Areas covered: We give an overview of the classification, the epidemiology and the diagnosis of IBD and SpA. The treatment goals, the pharmacologic management options and the available treatment guidelines in IBD patients with SpA are discussed. Expert Commentary: The coexistence of IBD and SpA generates challenges and opportunities for both the gastroenterologist and the rheumatologist. The potential of drugs with a gut-specific mode of action in the treatment of IBD-related arthritis warrants further exploration.

Exploring Memories of the Self: 2412 Self-image Norms for Adults Aged 17 to 88.

Transcriptome and proteome analysis reveal new insight into proximal and distal responses of wheat to foliar infection by Xanthomonas translucens.

The molecular details of local plant response against Xanthomonas translucens infection is largely unknown. Moreover, there is no knowledge about effects of the pathogen on the root's transcriptome and proteome. Therefore, we investigated the global gene and protein expression changes both in leaves and roots of wheat (Triticum aestivum) 24 h post leaf infection of X. translucens. This simultaneous analysis allowed us to obtain insight into possible metabolic rearrangements in above- and belowground tissues and to identify common responses as well as specific alterations. At the site of infection, we observed the implication of various components of the recognition, signaling, and amplification mechanisms in plant response to the pathogen. Moreover, data indicate a massive down-regulation of photosynthesis and confirm the chloroplast as crucial signaling hub during pathogen attack. Notably, roots responded as well to foliar attack and their response significantly differed from that locally triggered in infected leaves. Data indicate that roots as a site of energy production and synthesis of various secondary metabolites may actively influence the composition and colonisation level of root-associated microbes. Finally, our results emphasize the accumulation of jasmonic acid, pipecolic acid and/or the downstream mediator of hydrogen peroxide as long distal signals from infected leaves to roots.

An algal photoenzyme converts fatty acids to hydrocarbons.

Although many organisms capture or respond to sunlight, few enzymes are known to be driven by light. Among these are DNA photolyases and the photosynthetic reaction centers. Here, we show that the microalga Chlorella variabilis NC64A harbors a photoenzyme that acts in lipid metabolism. This enzyme belongs to an algae-specific clade of the glucose-methanol-choline oxidoreductase family and catalyzes the decarboxylation of free fatty acids to n-alkanes or -alkenes in response to blue light. Crystal structure of the protein reveals a fatty acid-binding site in a hydrophobic tunnel leading to the light-capturing flavin adenine dinucleotide (FAD) cofactor. The decarboxylation is initiated through electron abstraction from the fatty acid by the photoexcited FAD with a quantum yield >80%. This photoenzyme, which we name fatty acid photodecarboxylase, may be useful in light-driven, bio-based production of hydrocarbons.

Fractionating controlled memory processes and recall of context in recognition memory: a case report.

Recollection has been described as both a recognition memory judgment requiring cognitive control and the ability to retrieve contextual information about a prior occurrence. At the core of this article is the question whether or not these two subcomponents of recollection are dissociable in amnesia. In three experiments, we explored the influence of exclusion task instructions on performance in a single case (CJ), with the view to understand the relative contributions of control and source memory to recognition memory decisions. First, contrasting findings were obtained between tasks requiring strategic control or source reports. Second, even though CJ displayed some residual source memory relative to the ability to strategically control this information, his source memory capacity was time-limited. Our findings resonate with the novel proposal that recollection draws heavily upon working memory resources, and provide an example of how amnesic patients might utilize residual working memory capacity to solve episodic memory tasks.

Infectious complications of a rituximab-based immunosuppressive regimen in patients with glomerular disease.

Recent years have seen increasing use of rituximab (RTX) for various types of primary and secondary glomerulopathies. However, there are no studies that specifically address the risk of infection related to this agent in patients with these conditions.

Tumor necrosis factor (TNF) signaling, but not TWEAK (TNF-like weak inducer of apoptosis)-triggered cIAP1 (cellular inhibitor of apoptosis protein 1) degradation, requires cIAP1 RING dimerization and E2 binding.

Hepatitis E virus as a cause of acute hepatitis acquired in Switzerland.

Autochthonous hepatitis E is increasingly recognized as zoonotic infection in western countries. Serological assays have varying sensitivity and specificity.

Alterations in plasma triglycerides lipolysis in patients with history of multifactorial chylomicronemia.

The heterogeneity and mechanisms of multifactorial chylomicronemia (MCM) remain poorly understood. To gain new insights, post heparin lipolysis measured at 60 min (PHLA60), in addition to the more commonly used 10 min (PHLA10), was assessed in patients with history of MCM.

ROCK-1 mediates diabetes-induced retinal pigment epithelial and endothelial cell blebbing: Contribution to diabetic retinopathy.

In diabetic retinopathy, the exact mechanisms leading to retinal capillary closure and to retinal barriers breakdown remain imperfectly understood. Rho-associated kinase (ROCK), an effector of the small GTPase Rho, involved in cytoskeleton dynamic regulation and cell polarity is activated by hyperglycemia. In one year-old Goto Kakizaki (GK) type 2 diabetic rats retina, ROCK-1 activation was assessed by its cellular distribution and by phosphorylation of its substrates, MYPT1 and MLC. In both GK rat and in human type 2 diabetic retinas, ROCK-1 is activated and associated with non-apoptotic membrane blebbing in retinal vessels and in retinal pigment epithelium (RPE) that respectively form the inner and the outer barriers. Activation of ROCK-1 induces focal vascular constrictions, endoluminal blebbing and subsequent retinal hypoxia. In RPE cells, actin cytoskeleton remodeling and membrane blebs in RPE cells contributes to outer barrier breakdown. Intraocular injection of fasudil, significantly reduces both retinal hypoxia and RPE barrier breakdown. Diabetes-induced cell blebbing may contribute to ischemic maculopathy and represent an intervention target.

A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders.

Post-transplant lymphoproliferative disorders arising after kidney transplantation portend an increased risk of morbidity and mortality. Retransplantation of patients who had developed post-transplant lymphoproliferative disorder remains questionable owing to the potential risks of recurrence when immunosuppression is reintroduced. Here, we investigated the feasibility of kidney retransplantation after the development of post-transplant lymphoproliferative disorder.

Comparison of methods available for the identification of Mycobacterium chimaera.

Mycobacterium chimaera is a recently described nontuberculous mycobacterium belonging to the M. avium complex (MAC). Because this species is implicated in a worldwide outbreak due to contaminated heater-cooler unit water tanks during open-heart surgery, it becomes mandatory for clinical microbiology laboratories to be able to differentiate M. chimaera from the other MAC species, especially M. intracellulare. Such identification was so far restricted to specialized laboratories, since it required the analysis of several gene sequences. The aim of this study was to evaluate commercialized methods for identifying M. chimaera with regard to the reference gene sequencing ITS, the internal transcribed spacer 16-23S.

Safety and efficacy of transcatheter embolization with Glubran(®)2 cyanoacrylate glue for acute arterial bleeding: a single-center experience with 104 patients.

To assess the efficacy and the safety of Glubran(®)2 n-butyl cyanoacrylate metacryloxysulfolane (NBCA-MS) transcatheter arterial embolization (TAE) for acute arterial bleeding from varied anatomic sites and to evaluate the predictive factors associated with clinical success and 30-day mortality.

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.

Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis. For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days after subretinal injection using multimodal imaging in 5 NHPs. We revealed prolonged reattachment times in LV-RPE65-injected eyes compared to vehicle-injected eyes. Low- (n = 2) and high-dose (n = 2) LV-RPE65-injected eyes presented a reduction of the outer nuclear and photoreceptor outer segment layer thickness in the macula, that was more pronounced than in vehicle-injected eyes (n = 4). All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite foveal structural changes, full-field electroretinography indicated that the overall retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial, or leucocyte ocular activation between low-dose, high-dose, and vehicle-injected eyes. Moreover, LV-RPE65-injected animals did not show signs of vector shedding or extraocular targeting, confirming the safe ocular restriction of the vector. Our results evidence a limited ocular tolerance to LV-RPE65 after subretinal injection without adjuvant anti-inflammatory prophylaxis, with complications linked to this route of administration necessitating to block this transient inflammatory event.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis.

We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity).

Microbleeds, Cerebral Hemorrhage, and Functional Outcome After Stroke Thrombolysis: Individual Patient Data Meta-Analysis.

We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome.

In-hospital ischaemic stroke treated with intravenous thrombolysis or mechanical thrombectomy.

Patients with in-hospital strokes (IHS) may be eligible for recanalization therapies. The objective of this study is to compare outcomes in patients with IHS and community-onset strokes (COS) treated by recanalization therapy. We analysed data prospectively collected in consecutive patients treated by thrombolysis, thrombectomy, or both for cerebral ischemia at the Lille University Hospital. We compared four outcomes measures at 3 months in patients with IHS and COS: (1) modified Rankin scale (mRS) 0-1, (2) mRS 0-2, (3) death, and (4) symptomatic intracranial haemorrhage (ECASS 2 definition). Of 1209 patients, 64 (5.3%) had IHS, with an increasing proportion over time (p = 0.001). Their median onset-to-needle time was 128 min vs. 145 in COS (p < 0.001). They were more likely to have had a recent TIA [odds ratio (OR) 30.1; 95% confidence interval (CI) 11.5-78.7], to have been treated by vitamin K antagonist before (OR 4.2; 95% CI 1.4-12.0) and to undergo mechanical thrombectomy (45 vs. 10%, p < 0.001). They were less likely to have a pre-stroke mRS 0-1 (OR 0.22; 95% CI 0.09-0.50). After adjustment, IHS was not associated with any of the four outcome measures. Patients with IHS are treated 17 min earlier than patients with COS, but, taking into account that they were already in the hospital, delays are still too long. Their outcome does not differ from that of patients with COS, suggesting room for improvement if delays can be reduced. IHS being frequent, pre-specified pathways should be organised.

Glutaric Aciduria Type 1 and Acute Renal Failure: Case Report and Suggested Pathomechanisms.

Glutaric aciduria type 1 (GA1) is caused by deficiency of the mitochondrial matrix enzyme glutaryl-CoA dehydrogenase (GCDH), leading to accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3OHGA) in tissues and body fluids. During catabolic crises, GA1 patients are prone to the development of striatal necrosis and a subsequent irreversible movement disorder during a time window of vulnerability in early infancy. Thus, GA1 had been considered a pure "cerebral organic aciduria" in the past. Single case reports have indicated the occurrence of acute renal dysfunction in children affected by GA1. In addition, growing evidence arises that GA1 patients may develop chronic renal failure during adulthood independent of the previous occurrence of encephalopathic crises. The underlying mechanisms are yet unknown. Here we report on a 3-year-old GA1 patient who died following the development of acute renal failure most likely due to haemolytic uraemic syndrome associated with a pneumococcal infection. We hypothesise that known GA1 pathomechanisms, namely the endothelial dysfunction mediated by 3OHGA, as well as the transporter mechanisms for the urinary excretion of GA and 3OHGA, are involved in the development of glomerular and tubular dysfunction, respectively, and may contribute to a pre-disposition of GA1 patients to renal disease. We recommend careful differential monitoring of glomerular and tubular renal function in GA1 patients.

Treatment of radioactive liquid effluents by reverse osmosis membranes: From lab-scale to pilot-scale.

The recent use of the reverse osmosis (RO) process at the damaged Fukushima-Daiichi nuclear power plant generated a growing interest in the application of this process for decontamination purposes. This study focused on the development of a robust RO process for decontamination of two kinds of liquid effluents: a contaminated groundwater after a nuclear disaster and a contaminated seawater during a nuclear accident. The SW30 HR membrane was selected among other in this study due to higher retentions (96% for Cs and 98% for Sr) in a true groundwater. Significant fouling and scaling phenomenon, attributed to calcium and strontium precipitation, were evidenced in this work: this underscored the importance of the lab scale experiment in the process. Validation of the separation performances on trace radionuclides concentration was performed with similar retention around 96% between surrogates Cs (inactive) and (137)Cs (radioactive). The scale up to a 2.6 m(2) spiral wound membrane led to equivalent retentions (around 96% for Cs and 99% for Sr) but lower flux values: this underlined that the hydrodynamic parameters (flowrate/cross-flow velocity) should be optimized. This methodology was also applied on the reconstituted seawater effluent: retentions were slightly lower than for the groundwater and the same hydrodynamic effects were observed on the pilot scale. Then, ageing of the membrane through irradiation experiments were performed. Results showed that the membrane active layer composition influenced the membrane resistance towards γ irradiation: the SW30 HR membrane performances (retention and permeability) were better than the Osmonics SE at 1 MGy. Finally, to supplement the scale up approach, the irradiation of a spiral wound membrane revealed a limited effect on the permeability and retention. This indicated that irradiation conditions need to be controlled for a further development of the process.

Vγ9Vδ2 T cell activation by strongly agonistic nucleotidic phosphoantigens.

Human Vγ9Vδ2 T cells can sense through their TCR tumor cells producing the weak endogenous phosphorylated antigen isopentenyl pyrophosphate (IPP), or bacterially infected cells producing the strong agonist hydroxyl dimethylallyl pyrophosphate (HDMAPP). The recognition of the phosphoantigen is dependent on its binding to the intracellular B30.2 domain of butyrophilin BTN3A1. Most studies have focused on pyrophosphate phosphoantigens. As triphosphate nucleotide derivatives are naturally co-produced with IPP and HDMAPP, we analyzed their specific properties using synthetic nucleotides derived from HDMAPP. The adenylated, thymidylated and uridylated triphosphate derivatives were found to activate directly Vγ9Vδ2 cell lines as efficiently as HDMAPP in the absence of accessory cells. These antigens were inherently resistant to terminal phosphatases, but apyrase, when added during a direct stimulation of Vγ9Vδ2 cells, abrogated their stimulating activity, indicating that their activity required transformation into strong pyrophosphate agonists by a nucleotide pyrophosphatase activity which is present in serum. Tumor cells can be sensitized with nucleotide phosphoantigens in the presence of apyrase to become stimulatory, showing that this can occur before their hydrolysis into pyrophosphates. Whereas tumors sensitized with HDMAPP rapidly lost their stimulatory activity, sensitization with nucleotide derivatives, in particular with the thymidine derivative, induced long-lasting stimulating ability. Using isothermal titration calorimetry, binding of some nucleotide derivatives to BTN3A1 intracellular domain was found to occur with an affinity similar to that of IPP, but much lower than that of HDMAPP. Thus, nucleotide phosphoantigens are precursors of pyrophosphate antigens which can deliver strong agonists intracellularly resulting in prolonged and strengthened activity.

A Pilot Study on Ocular Safety and Efficacy of Infliximab as an Antifibrotic Agent After Experimental Glaucoma Filtration Surgery.

Tumor necrosis factor-α (TNF-α) is a multifunctional, proinflammatory cytokine that mediates pleiotropic biological functions, especially inflammation and immunoregulation. We hypothesized that blocking TNF-α with a monoclonal antibody would decrease inflammation and subconjunctival scarring in an animal model of experimental filtration surgery.

Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia.

Fibromyalgia (FM) syndrome is characterized by chronic widespread pain, muscle tenderness and emotional distress. Previous studies found reduced endogenous pain modulation in FM. This deficiency of pain modulation may be related to the attributes of chronic pain and other clinical symptoms experienced in patients with FM. Thus, we tested whether there is a link between the clinical symptoms of FM and functional connectivity (FC) of the periaqueductal gray (PAG), a key node of pain modulation. We acquired resting state 3T functional MRI (rsfMRI) data from 23 female patients with FM and 16 age- and sex- matched healthy controls (HC) and assessed FM symptoms with the Brief Pain Inventory (BPI), Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS) and Pain Catastrophizing Scale (PCS). We found that patients with FM exhibit statistically significant disruptions in PAG FC, particularly with brain regions implicated in negative affect, self-awareness and saliency. Specifically, we found that, compared to HCs, the FM patients had stronger PAG FC with the lingual gyrus and hippocampus but weaker PAG FC with regions associated with motor/executive functions, the salience (SN) and default mode networks (DMN). The attenuated PAG FC was also negatively correlated with FIQ scores, and positively correlated with the magnification subscale of the PCS. These alterations were correlated with emotional and behavioral symptoms of FM. Our study implicates the PAG as a site of dysfunction contributing to the clinical manifestations and pain in FM.

MicroRNA-29b Contributes to Collagens Imbalance in Human Osteoarthritic and Dedifferentiated Articular Chondrocytes.

Decreased expression of collagen type II in favour of collagen type I or X is one hallmark of chondrocyte phenotype changes in osteoarthritic (OA) cartilage. MicroRNA- (miR-) 29b was previously shown to target collagens in several tissues. We studied whether it could contribute to collagen imbalance in chondrocytes with an impaired phenotype.

Pain-related Activity Management Patterns and Function in Patients with Fibromyalgia Syndrome.

To clarify the importance of avoidance, pacing and overdoing pain-related activity management patterns as predictors of adjustment in patients with Fibromyalgia Syndrome (FMS).

The Utility of Gene Expression Profiling from Tissue Samples to Support Drug Safety Assessments.

Originally conceptualized as an integrated approach combining conventional toxicology methods with genome-wide expression profiling, toxicogenomics has promised to provide unequivocal relationships between the molecular changes elicited by a compound or a target pathway and the lesions that appear subsequently in the tissues. However, the discipline has only partially delivered on this promise, and the number of publications and submissions related to toxicogenomics is stagnating. The purpose of this article is to outline key factors contributing to a successful implementation of toxicogenomics in the drug discovery and development process. Paradigms and methods of toxicogenomics are briefly reviewed, and the prominence of biostatistics and its limitations in the particular context of nonclinical toxicology studies are discussed. We present specific approaches for pathophysiological contextualization of gene expression data derived from tissues with lesions at variable incidence and severity: "unmixing" (deconvolution) of molecular expression profiles from complex tissues, the invaluable contribution of reference data, the role of establishing causation between expression signals and pathologic changes (phenotypic anchoring), and especially molecular localization. These approaches compensate for the limitations of biostatistical analysis, which in turn, derive from tissue heterogeneity. Finally, impactful applications of toxicogenomics along the drug discovery and development process are exemplified, from the evaluation of potential target toxicities to the selection of candidate compounds and elucidation of the molecular and cellular mechanisms leading to chronic toxicity.