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Find video protocols related to scientific articles indexed in Pubmed.
Parental Cannabis Abuse and Accidental Intoxications in Children: Prevention by Detecting Neglectful Situations and At-Risk Families.
Pediatr Emerg Care
PUBLISHED: 11-20-2014
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Cannabis intoxication in toddlers is rare and mostly accidental. Our objectives were to focus on the characteristics and management of children under the age of 6 years who were admitted to our emergency department with cannabis poisoning reported as accidental by parents, and to point out the need to consider accidental cannabis ingestions as an indicator of neglect.
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Spontaneous gastrointestinal perforation in cats: a retrospective study of 13 cases.
J. Feline Med. Surg.
PUBLISHED: 11-20-2014
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To describe the clinical characteristics and the frequency of malignant vs non-malignant causes for spontaneous gastrointestinal perforation in cats.
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Loss of the thyroid hormone binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease.
Hum. Mol. Genet.
PUBLISHED: 11-16-2014
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The mechanisms underlying preferential atrophy of the striatum in Huntington's disease (HD) are unknown. One hypothesis is that a set of gene products preferentially expressed in the striatum could determine the particular vulnerability of this brain region to mutant huntingtin (mHtt). Here, we studied the striatal protein Crym (µ-crystallin). Crym is the NADPH-dependent p38 cytosolic T3-binding protein (p38CTBP), a key regulator of thyroid hormone T3 (3,5,3'-triiodo-L-thyronine) transportation. It has been also recently identified as the enzyme that reduces the sulphur-containing cyclic ketimines, which are potential neurotransmitters. Here, we confirm the preferential expression of the Crym protein in the rodent and macaque striatum. Crym expression was found to be higher in the macaque caudate than in the putamen. Expression of Crym was reduced in the BACHD and Knock-in 140CAG mouse models of HD before onset of striatal atrophy. We show that overexpression of Crym in striatal medium-size spiny neurons using a lentiviral-based strategy in mice is neuroprotective against the neurotoxicity of an N-terminal fragment of mHtt in vivo. Thus, reduction of Crym expression in HD could render striatal neurons more susceptible to mHtt suggesting that Crym may be a key determinant of the vulnerability of the striatum. In addition our work points to Crym as a potential molecular link between striatal degeneration and the thyroid hormones deregulation reported in HD patients.
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The Lymphoid Variant of Hypereosinophilic Syndrome: Study of 21 Patients With CD3-CD4+ Aberrant T-Cell Phenotype.
Medicine (Baltimore)
PUBLISHED: 11-15-2014
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The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5-75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35?G/L (range, 0.01-28.3), with a clonal TCR?? rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n?=?18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.
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Exhaled air dispersion during non-invasive ventilation via helmets and a total facemask.
Chest
PUBLISHED: 11-14-2014
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Non-invasive ventilation via helmet or total facemask is an option for managing patients with respiratory infections in respiratory failure. However the risk of nosocomial infection is unknown.
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Association between Morphologic CT Imaging Traits and Prognostically Relevant Gene Signatures in Women with High-Grade Serous Ovarian Cancer: A Hypothesis-generating Study.
Radiology
PUBLISHED: 11-11-2014
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Purpose To investigate associations among imaging traits observed on computed tomographic (CT) images, Classification of Ovarian Cancer ( CLOVAR Classification of Ovarian Cancer ) gene signatures, and survival in women with high-grade serous ovarian cancer ( HGSOC high-grade serous ovarian carcinoma ). Materials and Methods The institutional review board approved this HIPAA-compliant retrospective study of CT images obtained before cytoreductive surgery in 46 women with HGSOC high-grade serous ovarian carcinoma , whose tumors were subjected to molecular analysis performed by the Cancer Genome Atlas Research Network. Two readers independently evaluated the CT features of the primary ovarian mass and sites of metastatic spread if present, including size, outline, and texture. Fisher exact test was used to examine the relationship between imaging traits and CLOVAR Classification of Ovarian Cancer subtypes ( CLOVAR Classification of Ovarian Cancer differentiated, immunoreactive, mesenchymal, and proliferative). Kaplan-Meier and Cox proportional hazards regression survival analyses were performed. Results The presence of mesenteric infiltration and diffuse peritoneal involvement by tumor at CT were significantly associated with CLOVAR Classification of Ovarian Cancer subtype (P = .002-.004 for reader 1 and P = .005-.012 for reader 2). Mesenteric infiltration at CT was associated with CLOVAR Classification of Ovarian Cancer mesenchymal subtype. Patients with mesenteric infiltration had shorter median progression-free survival than patients without mesenteric involvement (14.7 months vs 25.6 months according to both readers; P = .019 for reader 1 and .015 for reader 2) and overall survival (49.0 vs 58.2 months; P = .014 [reader 1] and 50.0 vs 59.1 months; P = .015 [reader 2]). No other imaging features were significantly associated with CLOVAR Classification of Ovarian Cancer subtype or survival. Conclusion Specific CT imaging traits were associated with the CLOVAR Classification of Ovarian Cancer subtypes and survival in patients with HGSOC high-grade serous ovarian carcinoma . © RSNA, 2014.
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High-Resolution Mass Spectrometry Associated with Data Mining Tools for the Detection of Pollutants and Chemical Characterization of Honey Samples.
J. Agric. Food Chem.
PUBLISHED: 11-11-2014
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Analytical methods for food control are mainly focused on restricted lists of well-known contaminants. This paper shows that liquid chromatography-high-resolution mass spectrometry (LC/ESI-HRMS) associated with the data mining tools developed for metabolomics can address this issue by enabling (i) targeted analyses of pollutants, (ii) detection of untargeted and unknown xenobiotics, and (iii) detection of metabolites useful for the characterization of food matrices. A proof-of-concept study was performed on 76 honey samples. Targeted analysis indicated that 35 of 83 targeted molecules were detected in the 76 honey samples at concentrations below regulatory limits. Furthermore, untargeted metabolomic-like analyses highlighted 12 chlorinated xenobiotics, 1 of which was detected in lavender honey samples and identified as 2,6-dichlorobenzamide, a metabolite of dichlobenil, a pesticide banned in France since 2010. Lastly, multivariate statistical analyses discriminated honey samples according to their floral origin, and six discriminating metabolites were characterized thanks to the MS/MS experiments.
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In vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to SL-401, an interleukin-3 receptor targeted biologic agent.
Haematologica
PUBLISHED: 11-09-2014
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Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. Today, no standard of care is accepted to treat blastic plasmacytoid dendritic cell neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of IL-3 receptor ? chain (IL3-R? or CD123), antitumor effects of the IL-3R-targeted drug SL-401 against Blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. Cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. Cytotoxic effects of SL-401 were compared to several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 vs. 17 days, p <0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support the rationale to further evaluate SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.
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[Knowledge, attitudes and practices of emergency contraceptive among female students at Parakou University (Benin)].
Sante Publique
PUBLISHED: 11-08-2014
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This study was designed to assess emergency contraception knowledge, attitude and practices among female students at Parakou University.
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[Oral hygiene of children and adolescents participating in the dental examination programme].
Sante Publique
PUBLISHED: 11-08-2014
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This study was designed to analyse the dental care needs of young people aged 6, 9, 12, 15 and 18 years based on dental examination, assess their compliance with the dental care programme and improvement of their dental status during the nine months following the dental examination programme, in 2007 and 2010.
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Hind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging.
FASEB J.
PUBLISHED: 11-08-2014
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Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6, 13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5- to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis.-Lescale, C., Schenten, V., Djeghloul, D., Bennabi, M., Gaignier, F., Vandamme, K., Strazielle, C., Kuzniak, I., Petite, H., Dosquet, C., Frippiat, J.-P., Goodhardt, M. Hind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging.
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Posaconazole Treatment of Extensive Skin and Nail Dermatophytosis Due to Autosomal Recessive Deficiency of CARD9.
JAMA Dermatol
PUBLISHED: 11-06-2014
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Deep dermatophytosis is a disease that involves dermatophytic infection of the dermis and/or lymph nodes and sometimes the central nervous system. Autosomal recessive deficiency of the CARD9 (caspase recruitment domain 9) protein has been described in 17 patients with deep dermatophytosis from Algeria, Tunisia, and Morocco.
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Ischemic Stroke Activates Hematopoietic Bone Marrow Stem Cells.
Circ. Res.
PUBLISHED: 11-02-2014
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Rationale: The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood. Objective: To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells. Methods and Results: Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (p<0.05 versus pre tMCAO). FACS and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19 to 7.32±0.52 after tMCAO (p<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (p<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (p<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the ?3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, p=0.51). Conclusions: Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6Chigh monocytes.
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Canine Distemper Virus Envelope Protein Interactions Modulated by Hydrophobic Residues in the Fusion Protein Globular Head.
J. Virol.
PUBLISHED: 10-31-2014
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Membrane fusion for morbillivirus cell entry relies on critical interactions between the viral fusion (F) and attachment (H) envelope glycoproteins. Through extensive mutagenesis of an F-cavity recently proposed to contribute to the interaction with the H-protein, we identified two neighboring hydrophobic residues responsible for severe F-to-H-binding and fusion-triggering deficiencies when mutated in combination. Since both residues reside on one side of the F-cavity, the data suggest that H binds the F-globular head domain sideway.
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Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors.
Blood
PUBLISHED: 10-30-2014
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The acquisition of growth signal self-sufficiency is one of the hallmarks of cancer. We previously reported that the murine IL-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the JAK-STAT pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3 or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation, and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short term assays. However, resistant clones occur upon long term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the ATP-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas, cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T cell transformation, and represent a new mechanism of acquisition of resistance against JAK inhibitors.
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Distinct Roles of the Anaphylatoxins C3a and C5a in Dendritic Cell-Mediated Allergic Asthma.
J. Immunol.
PUBLISHED: 10-29-2014
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Conventional dendritic cells (cDC) are necessary and sufficient to drive mixed maladaptive Th2/Th17 immune responses toward aeroallergens in experimental allergy models. Previous studies suggest that the anaphylatoxin C3a promotes, whereas C5a protects from the development of maladaptive immunity during allergen sensitization. However, only limited evidence exists that such effects are directly mediated through anaphylatoxin-receptor signaling in cDCs. In this study, we assessed the impact of C3a and C5a on cDC-mediated induction pulmonary allergy by adoptively transferring house dust mite (HDM)-pulsed bone marrow-derived DCs (BMDC) from wild-type (WT) C3aR(-/-), C5aR1(-/-), or C3aR(-/-)/C5aR1(-/-) into WT mice. Transfer of HDM-pulsed WT BMDCs promoted a strong asthmatic phenotype characterized by marked airway resistance, strong Th2 cytokine, and mucus production, as well as mixed eosinophilic and neurophilic airway inflammation. Surprisingly, C3aR(-/-) cDCs induced a strong allergic phenotype, but no IL-17A production, whereas HDM-pulsed C5aR1(-/-) cDCs failed to drive pulmonary allergy. Transfer of C3aR(-/-)/C5aR1(-/-) cDCs resulted in a slightly reduced allergic phenotype associated with increased IFN-? production. Mechanistically, C3aR and C5aR1 signaling is required for IL-23 production from HDM-pulsed BMDCs in vitro. Furthermore, C3aR(-/-) BMDCs produced less IL-1?. The mechanisms underlying the failure of C5aR1(-/-) BMDCs to induce experimental allergy include a reduced capability to migrate into the lung tissue and a decreased potency to direct pulmonary homing of effector T cells. Thus, we uncovered a crucial role for C5a, but only a minor role for C3a in BMDC-mediated pulmonary allergy, suggesting that BMDCs inappropriately reflect the impact of complement on lung cDC-mediated allergic asthma development.
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High-Content Screening (HCS) technology combined with a human granuloma model as a new approach to evaluate the activity of drugs against M. tuberculosis.
Antimicrob. Agents Chemother.
PUBLISHED: 10-29-2014
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Tuberculosis remains a major health problem due the emergence of drug resistant strains. Some models have provided valuable information about drug resistance, and efficacy; however, the translation of these results into effective human treatments has proven mostly unsuccessful. In this study, we adapted HCS technology to investigate the activity of anti-tubercular compounds in the context of an in vitro granuloma model. We observed significant shifts in MIC50 between extracellular and granuloma conditions.
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Is there a linear relationship between the dose of ruminant trans-fatty acids and cardiovascular risk markers in healthy subjects: results from a systematic review and meta-regression of randomised clinical trials.
Br. J. Nutr.
PUBLISHED: 10-28-2014
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The effects of ruminant (R) trans-fatty acids (TFA) on the risk of CVD are still under debate. It could be argued that the lack of the effect of R-TFA may be the result of the small amount of their intake. Taking into consideration the growing available data from intervention studies, we carried out a systematic review and meta-regression to assess the impact of R-TFA intake levels on changes in the total cholesterol: HDL-cholesterol (TC:HDL-C) ratio. A systematic review of the literature was conducted and thirteen randomised clinical trials were included, yielding a total of twenty-three independent experimental groups of subjects. A univariate random-effects meta-regression approach was used to quantify the relationship between the dose of R-TFA and changes in the TC:HDL-C ratio. To consider several potential modifiers such as subject and dietary characteristics, a multivariate regression analysis was performed. We found no relationship between R-TFA intake levels of up to 4·19 % of daily energy intake (EI) and changes in cardiovascular risk factors such as TC:HDL-C and LDL-cholesterol (LDL-C):HDL-C ratios. In addition, a multivariate regression analysis that included other dietary variables, as well as subject baseline characteristics, confirmed that doses of R-TFA did not significantly influence the changes in the lipid ratio. Our findings showed that doses of R-TFA did not influence the changes in the ratios of plasma TC:HDL-C and LDL-C:HDL-C. These data suggest that TFA from natural sources, at least at the current levels of intake and up to 4·19 % EI, have no adverse effects on these key CVD risk markers in healthy people.
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Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors.
FASEB J.
PUBLISHED: 10-25-2014
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Type 4 metabotropic glutamate (mGlu4) receptors are emerging targets for the treatment of various disorders. Accordingly, numerous mGlu4-positive allosteric modulators (PAMs) have been identified, some of which also display agonist activity. To identify the structural bases for their allosteric action, we explored the relationship between the binding pockets of mGlu4 PAMs with different chemical scaffolds and their functional properties. By use of innovative mGlu4 biosensors and second-messenger assays, we show that all PAMs enhance agonist action on the receptor through different degrees of allosteric agonism and positive cooperativity. For example, whereas VU0155041 and VU0415374 display equivalent efficacies [log(?B) = 1.15 ± 0.38 and 1.25 ± 0.44, respectively], they increase the ability of l-AP4 to stabilize the active conformation of the receptor by 4 and 39 times, respectively. Modeling and docking studies identify 2 overlapping binding pockets as follows: a first site homologous to the pocket of natural agonists of class A GPCRs linked to allosteric agonism and a second one pointing toward a site topographically homologous to the Na(+) binding pocket of class A GPCRs, occupied by PAMs exhibiting the strongest cooperativity. These results reveal that intrinsic efficacy and cooperativity of mGlu4 PAMs are correlated with their binding mode, and vice versa, integrating structural and functional knowledge from different GPCR classes.-Rovira, X., Malhaire, F., Scholler, P., Rodrigo, J., Gonzalez-Bulnes, P., Llebaria, A., Pin, J.-P., Giraldo, J., Goudet, C. Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors.
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Loss of Krox20 results in aortic valve regurgitation and impaired transcriptional activation of fibrillar collagen genes.
Cardiovasc. Res.
PUBLISHED: 10-24-2014
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Heart valve maturation is achieved by the organization of extracellular matrix (ECM) and the distribution of valvular interstitial cells. However, the factors that regulate matrix components required for valvular structure and function are unknown. Based on the discovery of its specific expression in cardiac valves, we aimed to uncover the role of Krox20 (Egr-2) during valve development and disease.
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Perceived articulatory precision in patients with Parkinson's disease after deep brain stimulation of subthalamic nucleus and caudal zona incerta.
Clin Linguist Phon
PUBLISHED: 10-22-2014
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Abstract The effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and caudal zona incerta (cZi) on speech articulation in patients with Parkinson's disease (PD) was investigated. Read speech samples were collected from nine patients with STN-DBS and 10 with cZi-DBS. The recordings were made pre-operatively and 12 months post-operatively with stimulator on and off (on medication). Blinded, randomised, repeated perceptual assessments were performed on words and isolated fricatives extracted from the recordings to assess (1) overall articulatory quality ratings, (2) frequency of occurrence of misarticulation patterns and (3) fricative production. Statistically significant worsening of articulatory measures on- compared with off-stimulation occurred in the cZi-DBS group, with deteriorated articulatory precision ratings, increased presence of misarticulations (predominately altered realisations of plosives and fricatives) and a reduced accuracy in fricative production. A similar, but not significant, trend was found for the STN-DBS group.
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Last generation triazoles for imported eumycetoma in eleven consecutive adults.
PLoS Negl Trop Dis
PUBLISHED: 10-01-2014
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Optimal management of eumycetoma, a severely debilitating chronic progressive fungal infection of skin, disseminating to bone and viscera, remains challenging. Especially, optimal antifungal treatment and duration are ill defined.
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The future of smoking-attributable mortality: the case of England & Wales, Denmark and the Netherlands.
Addiction
PUBLISHED: 09-30-2014
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We formally estimate future smoking-attributable mortality up to 2050 for the total national populations of England & Wales, Denmark and the Netherlands, providing an update and extension of the descriptive smoking-epidemic model.
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Isolation of Functionalized Phenolic Monomers through Selective Oxidation and C?O Bond Cleavage of the ?-O-4 Linkages in Lignin.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 09-23-2014
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Functionalized phenolic monomers have been generated and isolated from an organosolv lignin through a two-step depolymerization process. Chemoselective catalytic oxidation of ?-O-4 linkages promoted by the DDQ/tBuONO/O2 system was achieved in model compounds, including polymeric models and in real lignin. The oxidized ?-O-4 linkages were then cleaved on reaction with zinc. Compared to many existing methods, this protocol, which can be achieved in one pot, is highly selective, giving rise to a simple mixture of products that can be readily purified to give pure compounds. The functionality present in these products makes them potentially valuable building blocks.
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Imported african histoplasmosis in an immunocompetent patient 40 years after staying in a disease-endemic area.
Am. J. Trop. Med. Hyg.
PUBLISHED: 09-22-2014
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Histoplasmosis caused by Histoplasma capsulatum var. duboisii is a rare disease outside central and western Africa. In Europe, all cases are imported. We report a case of an African histoplasmosis with isolated pulmonary involvement in a non-immunocompromised patient that occurred 40 years after his stay in a disease-endemic area. The patient was given itraconazole. (18)F-fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography was used to assess evolution during treatment. The outcome for the patient was favorable.
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Noneruptive Fever Revealing Murine Typhus in a Traveler Returning From Tunisia.
J Travel Med
PUBLISHED: 08-27-2014
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Rickettsia species are increasingly being recognized as a cause of infection among returning travelers. Murine typhus (MT) was mistakenly thought to have disappeared in the 1970s in Tunisia, yet recent serological data show that Rickettsia typhi, the causative agent of MT, still circulates in the Tunisian population. We report here a case of MT in a woman returning from Tunisia and hospitalized in France. Her presentation was nonspecific, with acute noneruptive fever. Diagnosis was confirmed by cross-adsorption and immunoblotting. Clinicians taking care of returning travelers with fever should be aware of MT, and know how to diagnose and treat it.
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Quantitative Risk Assessment of Haemolytic and Uremic Syndrome Linked to O157:H7 and Non-O157:H7 Shiga-Toxin Producing Escherichia coli Strains in Raw Milk Soft Cheeses.
Risk Anal.
PUBLISHED: 08-25-2014
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Shiga-toxin producing Escherichia coli (STEC) strains may cause human infections ranging from simple diarrhea to Haemolytic Uremic Syndrome (HUS). The five main pathogenic serotypes of STEC (MPS-STEC) identified thus far in Europe are O157:H7, O26:H11, O103:H2, O111:H8, and O145:H28. Because STEC strains can survive or grow during cheese making, particularly in soft cheeses, a stochastic quantitative microbial risk assessment model was developed to assess the risk of HUS associated with the five MPS-STEC in raw milk soft cheeses. A baseline scenario represents a theoretical worst-case scenario where no intervention was considered throughout the farm-to-fork continuum. The risk level assessed with this baseline scenario is the risk-based level. The impact of seven preharvest scenarios (vaccines, probiotic, milk farm sorting) on the risk-based level was expressed in terms of risk reduction. Impact of the preharvest intervention ranges from 76% to 98% of risk reduction with highest values predicted with scenarios combining a decrease of the number of cow shedding STEC and of the STEC concentration in feces. The impact of postharvest interventions on the risk-based level was also tested by applying five microbiological criteria (MC) at the end of ripening. The five MCs differ in terms of sample size, the number of samples that may yield a value larger than the microbiological limit, and the analysis methods. The risk reduction predicted varies from 25% to 96% by applying MCs without preharvest interventions and from 1% to 96% with combination of pre- and postharvest interventions.
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Prevention of infections during primary immunodeficiency.
Clin. Infect. Dis.
PUBLISHED: 08-14-2014
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Because infectious diseases are a major source of morbidity and mortality in the majority of patients with primary immunodeficiencies (PIDs), the application of a prophylactic regimen is often necessary. However, because of the variety of PIDs and pathogens involved, and because evidence is scarce, practices are heterogeneous. To homogenize practices among centers, the French National Reference Center for PIDs aimed at elaborating recommendations for anti-infectious prophylaxis for the most common PIDs. We performed a literature review of infectious complications and prophylactic regimens associated with the most frequent PIDs. Then, a working group including different specialists systematically debated about chemoprophylaxis, immunotherapy, immunization, and recommendations for patients. Grading of prophylaxis was done using strength of recommendations (decreasing from A to D) and evidence level (decreasing from I to III). These might help infectious diseases specialists in the management of PIDs and improving the outcome of patients with PIDs.
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Old DAT and new data: Positive direct antiglobulin test identifies a subgroup with poor outcome among chronic lymphocytic leukemia stage A patients.
Am. J. Hematol.
PUBLISHED: 08-08-2014
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Only a minority of chronic lymphocytic leukemia (CLL) patients harboring a positive direct antiglobulin test (DAT) will develop autoimmune hemolytic anemia (AIHA). In a single institution cohort of 378 CLL patients, 56 patients (14.8%) had at least one positive DAT during the course of the disease, either at diagnosis or later. We found no relationship between the time of the first positive DAT and overall survival (OS). However, patients with a positive DAT who did not develop AIHA had the same adverse outcome as patients who developed AIHA. Of the patients who were in Binet stage A at diagnosis, those with a positive DAT had a significantly shorter OS, regardless of their IGHV mutational status, however, there was a strong association with VH1-69. By multivariate analysis, a positive DAT was found to be an independent adverse prognostic factor for OS. Thus, DAT represents a strong adverse prognostic factor and its determination should be repeated during follow-up. Am. J. Hematol., 2014. © 2014 Wiley Periodicals, Inc.
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An Augmented ABCA4 Screen Targeting Non-coding Regions Reveals a Deep Intronic Founder Variant in Belgian Stargardt Patients.
Hum. Mutat.
PUBLISHED: 07-30-2014
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Autosomal recessive Stargardt disease (STGD1) is hallmarked by a large proportion of patients with a single heterozygous causative variant in the disease gene ABCA4. Braun et al. (2013) reported deep intronic variants of ABCA4 in STGD1 patients with one coding variant, prompting us to perform an augmented screen in 131 Belgian STGD1 patients with one or no ABCA4 variant to uncover deep intronic causal ABCA4 variants. This revealed a second variant in 28.6% of cases. Twenty-six percent of these carry the same causal variant c.4539+2001G>A (V4). Haplotyping in V4 carriers showed a common region of 63 kb, suggestive of a founder mutation. Genotype-phenotype correlations suggest a moderate-to-severe impact of V4 on the STGD1 phenotype. In conclusion, V4 occurs in a high fraction of Belgian STGD1 patients and represents the first deep intronic founder mutation in ABCA4. This emphasizes the importance of augmented molecular genetic testing of ABCA4 in Belgian STGD1. This article is protected by copyright. All rights reserved.
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Clinical utility of chitotriosidase enzyme activity in nephropathic cystinosis.
Orphanet J Rare Dis
PUBLISHED: 07-29-2014
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BackgroundNephropathic cystinosis is an inherited autosomal recessive lysosomal storage disorder characterized by the pathological accumulation and crystallization of cystine inside different cell types. WBC cystine determination forms the basis for the diagnosis and therapeutic monitoring with the cystine depleting drug (cysteamine). The chitotriosidase enzyme is a human chitinase, produced by activated macrophages. Its elevation is documented in several lysosomal storage disorders. Although, about 6% of Caucasians have enzyme deficiency due to homozygosity of 24-bp duplication mutation in the chitotriosidase gene, it is currently established as a screening marker and therapeutic monitor for Gaucher¿s disease.MethodsPlasma chitotriosidase activity was measured in 45 cystinotic patients, and compared with 87 healthy controls and 54 renal disease patients with different degrees of renal failure (CKD1-5). Chitotriosidase levels were also correlated with WBC cystine in 32 treated patients. Furthermore, we incubated control human macrophages in-vitro with different concentrations of cystine crystals and monitored the response of tumor necrosis factor-alpha (TNF-¿) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n¿=¿10) versus wild-type mice (n¿=¿10).ResultsPlasma chitotriosidase activity in cystinotic patients (0¿3880, median 163 nmol/ml/h) was significantly elevated compared to healthy controls (0¿90, median 18 nmol/ml/h) and to CKD patients (0¿321, median 52 nmol/ml/h), P¿<¿0.001 for both groups. Controls with decreased renal function had mild to moderate chitotriosidase elevations; however, their levels were significantly lower than in cystinotic patients with comparable degree of renal insufficiency. Chitotriosidase activity positively correlated with WBC cystine content for patients on cysteamine therapy (r¿=¿0.8), P¿<¿0.001. In culture, human control macrophages engulfed cystine crystals and released TNF-¿ into culture supernatant in a crystal concentration dependent manner. Chitotriosidase activity was also significantly increased in macrophage supernatant and cell-lysate. Furthermore, chitotriosidase activity was significantly higher in cystinotic knocked-out than in the wild-type mice, P¿=¿0.003.ConclusionsThis study indicates that cystine crystals are potent activators of human macrophages and that chitotriosidase activity is a useful marker for this activation and a promising clinical biomarker and therapeutic monitor for nephropathic cystinosis.
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Exploring the Active Conformation of Cyclohexane Carboxylate Positive Allosteric Modulators of the Type?4 Metabotropic Glutamate Receptor.
ChemMedChem
PUBLISHED: 07-24-2014
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The active conformation of a family of metabotropic glutamate receptor subtype?4 (mGlu4 ) positive allosteric modulators (PAMs) with the cyclohexane 1,2-dicarboxylic scaffold present in cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041) was investigated by testing structurally similar six-membered ring compounds that have a locked conformation. The norbornane and cyclohexane molecules designed as mGlu4 conformational probes and the enantiomers of the trans diastereomer were computationally characterized and tested in mGlu4 pharmacological assays. The results support a VU0155041 active conformation, with the chair cyclohexane having the aromatic amide substituent in an axial position and the carboxylate in an equatorial position. Moreover, the receptor displays enantiomeric discrimination of the chiral PAMs. The constructed pharmacophore characterized a highly constrained mGlu4 allosteric binding site, thus providing a step forward in structure-based drug design for mGlu4 PAMs.
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Inherited CARD9 Deficiency in 2 Unrelated Patients With Invasive Exophiala Infection.
J. Infect. Dis.
PUBLISHED: 07-23-2014
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?Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa.
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Age-associated evolution of plasmatic amyloid in mouse lemur primates: relationship with intracellular amyloid deposition.
Neurobiol. Aging
PUBLISHED: 07-18-2014
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Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Amyloid-? peptide (A?) deposition in the brain is one of its hallmarks, and the measure of plasma A? is considered to be a biomarker for anti-amyloid drug efficacy in animal models of AD. However, age-associated plasmatic A? modulation in animal models is practically never addressed in the literature. Mouse lemur primates are used as a model of normal and AD-like cerebral aging. Here, we studied the effect of age on plasmatic A? in 58 mouse lemurs aged from 1 to 10 years. A subset of animals presented high plasmatic A?, and the proportion of animals with high plasmatic A? was higher in aged animals as compared with young ones. Histologic evaluation of the brain of some of these animals was carried out to assess extracellular and intracellular amyloid load. In aged lemurs, plasmatic A? was negatively correlated with the density of neurons accumulating deposits of A?.
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Role of smoking in regional variation in mortality in Poland.
Addiction
PUBLISHED: 06-13-2014
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We assess the effect of smoking on regional disparities in mortality in Poland and its contribution to the change in regional disparities during the last two decades.
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A Novel Time Series Approach to Bridge Coding Changes with a Consistent Solution Across Causes of Death.
Eur J Popul
PUBLISHED: 06-07-2014
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Revisions of the International Classification of Diseases (ICD) can lead to biases in cause-specific mortality levels and trends. We propose a novel time series approach to bridge ICD coding changes which provides a consistent solution across causes of death. Using a state space model with interventions, we performed time series analysis to cause-proportional mortality for ICD9 and ICD10 in the Netherlands (1979-2010), Canada (1979-2007) and Italy (1990-2007) on chapter level. A constraint was used to keep the sum of cause-specific interventions zero. Comparability ratios (CRs) were estimated and compared to existing bridge coding CRs for Italy and Canada. A significant ICD9 to ICD10 transition occurred among 13 cause of death groups in Italy, 7 in Canada and 3 in the Netherlands. Without the constraint, all-cause mortality after the classification change would be overestimated by 0.4 % (NL), 0.03 % (Canada) and 0.2 % (Italy). The time series CRs were in the same direction as the bridge coding CRs but deviated more from 1. A smooth corrected trend over the ICD-transition resulted from applying the time series approach. Comparing the time series CRs for Italy (2003), Canada (1999) and the Netherlands (1995) revealed interesting commonalities and differences. We demonstrated the importance of adding the constraint, the validity of our methodology and its advantages above earlier methods. Applying the method to more specific causes of death and integrating medical content to a larger extent is advocated.
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Functional correlates of the speech-in-noise perception impairment in dyslexia: an MRI study.
Neuropsychologia
PUBLISHED: 05-23-2014
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Dyslexia is a language-based neurodevelopmental disorder. It is characterized as a persistent deficit in reading and spelling. These difficulties have been shown to result from an underlying impairment of the phonological component of language, possibly also affecting speech perception. Although there is little evidence for such a deficit under optimal, quiet listening conditions, speech perception difficulties in adults with dyslexia are often reported under more challenging conditions, such as when speech is masked by noise. Previous studies have shown that these difficulties are more pronounced when the background noise is speech and when little spatial information is available to facilitate differentiation between target and background sound sources. In this study, we investigated the neuroimaging correlates of speech-in-speech perception in typical readers and participants with dyslexia, focusing on the effects of different listening configurations. Fourteen adults with dyslexia and 14 matched typical readers performed a subjective intelligibility rating test with single words presented against concurrent speech during functional magnetic resonance imaging (fMRI) scanning. Target words were always presented with a four-talker background in one of three listening configurations: Dichotic, Binaural or Monaural. The results showed that in the Monaural configuration, in which no spatial information was available and energetic masking was maximal, intelligibility was severely decreased in all participants, and this effect was particularly strong in participants with dyslexia. Functional imaging revealed that in this configuration, participants partially compensate for their poorer listening abilities by recruiting several areas in the cerebral networks engaged in speech perception. In the Binaural configuration, participants with dyslexia achieved the same performance level as typical readers, suggesting that they were able to use spatial information when available. This result was, however, associated with increased activation in the right superior temporal gyrus, suggesting the need to reallocate neural resources to overcome speech-in-speech difficulties. Taken together, these results provide further understanding of the speech-in-speech perception deficit observed in dyslexia.
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Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients.
Blood
PUBLISHED: 05-23-2014
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This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 ?g/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.
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Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma.
Int. J. Cancer
PUBLISHED: 05-05-2014
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Several studies provide evidences for Mantle Cell Lymphoma (MCL) cells survival relying on B-cell receptor (BCR)-mediated signalling pathways whereas the nature of this activation is unknown. Significant progress in MCL treatment is achieved through therapies targeting BCR associated kinases, i.e. Ibrutinib and Fostamatinib, inhibitors of BTK and SYK, respectively. Our study addresses survival signals emanating from the BCR or the tumour environment and how inhibiting BCR signalling effectors might impact these survival signals. We found that BTK was constitutively activated and that SYK phosphorylation was highly increased and sustained upon BCR activation of primary MCL cells. Moreover, MCL cells from leukemic patients secreted high amount of IL1?, IL6, IL8 and CCL5. Activation of the BCR induced (i) cell survival, (ii) STAT3 activation and (iii) increased autocrine secretion of IL1?, IL6, IL8, CCL5, IL10, TNF?, and VEGF. Specific inhibition of BTK by Ibrutinib or SYK by Fostamatinib (R406) reversed these protective effects and decreased both basal and BCR-induced autocrine cytokines secretions associated with STAT3 phosphorylation. Interestingly, targeting BTK and SYK prevented and inhibited BCR-induced MCL cells adhesion to human bone marrow stromal cells (HMSC) in short and long term co-culture. We demonstrated that BCR-induced survival relies on autocrine secretion of IL1?, TNF? and CCL5 that might facilitate adhesion of MCL cells to HMSC. Treatment with Ibrutinib or Fostamatinib blocked the chemotactic signal thus increasing apoptosis. © 2014 Wiley Periodicals, Inc.
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Retinal Ganglion Cell Distribution and Spatial Resolving Power in Deep-Sea Lanternfishes (Myctophidae).
Brain Behav. Evol.
PUBLISHED: 04-29-2014
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Topographic analyses of retinal ganglion cell density are very useful in providing information about the visual ecology of a species by identifying areas of acute vision within the visual field (i.e. areas of high cell density). In this study, we investigated the neural cell distribution in the ganglion cell layer of a range of lanternfish species belonging to 10 genera. Analyses were performed on wholemounted retinas using stereology. Topographic maps were constructed of the distribution of all neurons and both ganglion and amacrine cell populations in 5 different species from Nissl-stained retinas using cytological criteria. Amacrine cell distribution was also examined immunohistochemically in 2 of the 5 species using anti-parvalbumin antibody. The distributions of both the total neuron and the amacrine cell populations were aligned in all of the species examined, showing a general increase in cell density toward the retinal periphery. However, when the ganglion cell population was topographically isolated from the amacrine cell population, which comprised up to 80% of the total neurons within the ganglion cell layer, a different distribution was revealed. Topographic maps of the true ganglion cell distribution in 18 species of lanternfishes revealed well-defined specializations in different regions of the retina. Different species possessed distinct areas of high ganglion cell density with respect to both peak density and the location and/or shape of the specialized acute zone (i.e. elongated areae ventro-temporales, areae temporales and large areae centrales). The spatial resolving power was calculated to be relatively low (varying from 1.6 to 4.4 cycles per degree), indicating that myctophids may constitute one of the less visually acute groups of deep-sea teleosts. The diversity in retinal specializations and spatial resolving power within the family is assessed in terms of possible ecological functions and evolutionary history. © 2014 S. Karger AG, Basel.
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Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels.
Mol. Cell Proteomics
PUBLISHED: 04-09-2014
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Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. Although the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 min, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation, and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples and motivates reexamination of collection protocols for phosphoprotein analysis.
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The eyes of lanternfishes (Myctophidae, Teleostei): novel ocular specializations for vision in dim light.
J. Comp. Neurol.
PUBLISHED: 03-19-2014
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Lanternfishes are one of the most abundant groups of mesopelagic fishes in the world's oceans and play a critical role in biomass vertical turnover. Despite their importance, very little is known about their physiology or how they use their sensory systems to survive in the extreme conditions of the deep sea. In this study, we provide a comprehensive description of the general morphology of the myctophid eye, based on analysis of 53 different species, to understand better their visual capabilities. Results confirm that myctophids possess several visual adaptations for dim-light conditions, including enlarged eyes, an aphakic gap, a tapetum lucidum, and a pure rod retina with high densities of long photoreceptors. Two novel retinal specializations were also discovered. The first specialization is a fundal pigmentation in adult eyes, found within an isolated retinal region (typically central retina) composed of modified pigment epithelial cells, which we hypothesize to be the remnant of a more pronounced visual specialization important in larval stages. The second specialization is an aggregation of extracellular microtubular-like structures found within the sclerad region of the inner nuclear layer of the retina. We hypothesize that the marked interspecific differences in the hypertrophy of these microtubular-like structures may be related to inherent differences in visual function. A general interspecific variability in other parts of the eye is also revealed and examined in this study. The contribution of both ecology and phylogeny to the evolution of ocular specializations and vision in dim light are discussed.
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Congenital fixed dilated pupils due to ACTA2- multisystemic smooth muscle dysfunction syndrome.
J Neuroophthalmol
PUBLISHED: 03-14-2014
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Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders.
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Impaired brain energy metabolism in the BACHD mouse model of Huntington's disease: critical role of astrocyte-neuron interactions.
J. Cereb. Blood Flow Metab.
PUBLISHED: 02-19-2014
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Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.
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Recurrent SMARCA4 mutations in small cell carcinoma of the ovary.
Nat. Genet.
PUBLISHED: 02-18-2014
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Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, highly aggressive form of ovarian cancer primarily diagnosed in young women. We identified inactivating biallelic SMARCA4 mutations in 100% of the 12 SCCOHT tumors examined. Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT.
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The eosinophil surface receptor epidermal growth factor-like module containing mucin-like hormone receptor 1 (EMR1): a novel therapeutic target for eosinophilic disorders.
J. Allergy Clin. Immunol.
PUBLISHED: 02-13-2014
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Although several novel agents are currently in clinical trials for eosinophilic disorders, none has demonstrated efficacy in reducing blood and tissue eosinophilia in all subjects. Additional approaches are clearly needed.
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Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy.
Genet. Med.
PUBLISHED: 02-05-2014
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Autosomal recessive retinal dystrophies are clinically and genetically heterogeneous, which hampers molecular diagnosis. We evaluated identity-by-descent-guided Sanger sequencing or whole-exome sequencing in 26 families with nonsyndromic (19) or syndromic (7) autosomal recessive retinal dystrophies to identify disease-causing mutations.
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Selective ROCK2 Inhibition In Focal Cerebral Ischemia.
Ann Clin Transl Neurol
PUBLISHED: 01-28-2014
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Rho-associated kinase (ROCK) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology. ROCK inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant ROCK isoform (ROCK1 or ROCK2) in acute stroke is not known.
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Multi-talker background and semantic priming effect.
Front Hum Neurosci
PUBLISHED: 01-01-2014
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The reported studies have aimed to investigate whether informational masking in a multi-talker background relies on semantic interference between the background and target using an adapted semantic priming paradigm. In 3 experiments, participants were required to perform a lexical decision task on a target item embedded in backgrounds composed of 1-4 voices. These voices were Semantically Consistent (SC) voices (i.e., pronouncing words sharing semantic features with the target) or Semantically Inconsistent (SI) voices (i.e., pronouncing words semantically unrelated to each other and to the target). In the first experiment, backgrounds consisted of 1 or 2 SC voices. One and 2 SI voices were added in Experiments 2 and 3, respectively. The results showed a semantic priming effect only in the conditions where the number of SC voices was greater than the number of SI voices, suggesting that semantic priming depended on prime intelligibility and strategic processes. However, even if backgrounds were composed of 3 or 4 voices, reducing intelligibility, participants were able to recognize words from these backgrounds, although no semantic priming effect on the targets was observed. Overall this finding suggests that informational masking can occur at a semantic level if intelligibility is sufficient. Based on the Effortfulness Hypothesis, we also suggest that when there is an increased difficulty in extracting target signals (caused by a relatively high number of voices in the background), more cognitive resources were allocated to formal processes (i.e., acoustic and phonological), leading to a decrease in available resources for deeper semantic processing of background words, therefore preventing semantic priming from occurring.
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Role of the DHH1 Gene in the Regulation of Monocarboxylic Acids Transporters Expression in Saccharomyces cerevisiae.
PLoS ONE
PUBLISHED: 01-01-2014
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Previous experiments revealed that DHH1, a RNA helicase involved in the regulation of mRNA stability and translation, complemented the phenotype of a Saccharomyces cerevisiae mutant affected in the expression of genes coding for monocarboxylic-acids transporters, JEN1 and ADY2 (Paiva S, Althoff S, Casal M, Leao C. FEMS Microbiol Lett, 1999, 170?301-306). In wild type cells, JEN1 expression had been shown to be undetectable in the presence of glucose or formic acid, and induced in the presence of lactate. In this work, we show that JEN1 mRNA accumulates in a dhh1 mutant, when formic acid was used as sole carbon source. Dhh1 interacts with the decapping activator Dcp1 and with the deadenylase complex. This led to the hypothesis that JEN1 expression is post-transcriptionally regulated by Dhh1 in formic acid. Analyses of JEN1 mRNAs decay in wild-type and dhh1 mutant strains confirmed this hypothesis. In these conditions, the stabilized JEN1 mRNA was associated to polysomes but no Jen1 protein could be detected, either by measurable lactate carrier activity, Jen1-GFP fluorescence detection or western blots. These results revealed the complexity of the expression regulation of JEN1 in S. cerevisiae and evidenced the importance of DHH1 in this process. Additionally, microarray analyses of dhh1 mutant indicated that Dhh1 plays a large role in metabolic adaptation, suggesting that carbon source changes triggers a complex interplay between transcriptional and post-transcriptional effects.
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Efficient genome engineering of Toxoplasma gondii using CRISPR/Cas9.
PLoS ONE
PUBLISHED: 01-01-2014
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Toxoplasma gondii is a parasite of humans and animals, and a model for other apicomplexans including Plasmodium spp., the causative agents of malaria. Despite many advances, manipulating the T. gondii genome remains labor intensive, and is often restricted to lab-adapted strains or lines carrying mutations that enable selection. Here, we use the RNA-guided Cas9 nuclease to efficiently generate knockouts without selection, and to introduce point mutations and epitope tags into the T. gondii genome. These methods will streamline the functional analysis of parasite genes and enable high-throughput engineering of their genomes.
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The influence of photoreceptor size and distribution on optical sensitivity in the eyes of lanternfishes (Myctophidae).
PLoS ONE
PUBLISHED: 01-01-2014
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The mesopelagic zone of the deep-sea (200-1000 m) is characterised by exponentially diminishing levels of downwelling sunlight and by the predominance of bioluminescence emissions. The ability of mesopelagic organisms to detect and behaviourally react to downwelling sunlight and/or bioluminescence will depend on the visual task and ultimately on the eyes and their capacity for detecting low levels of illumination and intermittent point sources of bioluminescent light. In this study, we investigate the diversity of the visual system of the lanternfish (Myctophidae). We focus specifically on the photoreceptor cells by examining their size, arrangement, topographic distribution and contribution to optical sensitivity in 53 different species from 18 genera. We also examine the influence(s) of both phylogeny and ecology on these photoreceptor variables using phylogenetic comparative analyses in order to understand the constraints placed on the visual systems of this large group of mesopelagic fishes at the first stage of retinal processing. We report great diversity in the visual system of the Myctophidae at the level of the photoreceptors. Photoreceptor distribution reveals clear interspecific differences in visual specialisations (areas of high rod photoreceptor density), indicating potential interspecific differences in interactions with prey, predators and/or mates. A great diversity in photoreceptor design (length and diameter) and density is also present. Overall, the myctophid eye is very sensitive compared to other teleosts and each species seems to be specialised for the detection of a specific signal (downwelling light or bioluminescence), potentially reflecting different visual demands for survival. Phylogenetic comparative analyses highlight several relationships between photoreceptor characteristics and the ecological variables tested (depth distribution and luminous tissue patterns). Depth distribution at night was a significant factor in most of the models tested, indicating that vision at night is of great importance for lanternfishes and may drive the evolution of their photoreceptor design.
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Identification of T. gondii myosin light chain-1 as a direct target of TachypleginA-2, a small-molecule inhibitor of parasite motility and invasion.
PLoS ONE
PUBLISHED: 01-01-2014
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Motility of the protozoan parasite Toxoplasma gondii plays an important role in the parasite's life cycle and virulence within animal and human hosts. Motility is driven by a myosin motor complex that is highly conserved across the Phylum Apicomplexa. Two key components of this complex are the class XIV unconventional myosin, TgMyoA, and its associated light chain, TgMLC1. We previously showed that treatment of parasites with a small-molecule inhibitor of T. gondii invasion and motility, tachypleginA, induces an electrophoretic mobility shift of TgMLC1 that is associated with decreased myosin motor activity. However, the direct target(s) of tachypleginA and the molecular basis of the compound-induced TgMLC1 modification were unknown. We show here by "click" chemistry labelling that TgMLC1 is a direct and covalent target of an alkyne-derivatized analogue of tachypleginA. We also show that this analogue can covalently bind to model thiol substrates. The electrophoretic mobility shift induced by another structural analogue, tachypleginA-2, was associated with the formation of a 225.118 Da adduct on S57 and/or C58, and treatment with deuterated tachypleginA-2 confirmed that the adduct was derived from the compound itself. Recombinant TgMLC1 containing a C58S mutation (but not S57A) was refractory to click labelling and no longer exhibited a mobility shift in response to compound treatment, identifying C58 as the site of compound binding on TgMLC1. Finally, a knock-in parasite line expressing the C58S mutation showed decreased sensitivity to compound treatment in a quantitative 3D motility assay. These data strongly support a model in which tachypleginA and its analogues inhibit the motility of T. gondii by binding directly and covalently to C58 of TgMLC1, thereby causing a decrease in the activity of the parasite's myosin motor.
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Three weeks of murine hindlimb unloading induces shifts from B to T and from th to tc splenic lymphocytes in absence of stress and differentially reduces cell-specific mitogenic responses.
PLoS ONE
PUBLISHED: 01-01-2014
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Extended space missions are known to induce stress and immune dysregulation. Hindlimb unloading is a ground-based model used to reproduce most spaceflight conditions. The aim of this study was to better characterize the consequences of prolonged exposure to hindlimb unloading on murine splenic lymphocyte sub-populations. To ensure that the observed changes were not due to tail restraint but to the antiorthostatic position, three groups of mice were used: control (C), orthostatic restrained (R) and hindlimb unloaded (HU). After 21 days of exposure, no difference in serum corticosterone levels nor in thymus and spleen weights were observed between HU mice and their counterparts, revealing a low state of stress. Interestingly, flow cytometric analyses showed that B cells were drastically reduced in HU mouse spleens by 59% and, while the T cells number did not change, the Th/Tc ratio was decreased. Finally, the use of a fluorescent dye monitoring lymphoproliferation demonstrated that lymphocyte response to mitogen was reduced in Th and Tc populations and to a greater extent in B cells. Thus, we showed for the first time that, even if restraint has its own effects on the animals and their splenic lymphocytes, the prolonged antiorthostatic position leads, despite the absence of stress, to an inversion of the B/T ratio in the spleen. Furthermore, the lymphoproliferative response was impaired with a strong impact on B cells. Altogether, these results suggest that B cells are more affected by hindlimb unloading than T cells which may explain the high susceptibility to pathogens, such as gram-negative bacteria, described in animal models and astronauts.
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Alleviating Pain Hypersensitivity through Activation of Type 4 Metabotropic Glutamate Receptor.
J. Neurosci.
PUBLISHED: 11-29-2013
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Hyperactivity of the glutamatergic system is involved in the development of central sensitization in the pain neuraxis, associated with allodynia and hyperalgesia observed in patients with chronic pain. Herein we study the ability of type 4 metabotropic glutamate receptors (mGlu4) to regulate spinal glutamate signaling and alleviate chronic pain. We show that mGlu4 are located both on unmyelinated C-fibers and spinal neurons terminals in the inner lamina II of the spinal cord where they inhibit glutamatergic transmission through coupling to Cav2.2 channels. Genetic deletion of mGlu4 in mice alters sensitivity to strong noxious mechanical compression and accelerates the onset of the nociceptive behavior in the inflammatory phase of the formalin test. However, responses to punctate mechanical stimulation and nocifensive responses to thermal noxious stimuli are not modified. Accordingly, pharmacological activation of mGlu4 inhibits mechanical hypersensitivity in animal models of inflammatory or neuropathic pain while leaving acute mechanical perception unchanged in naive animals. Together, these results reveal that mGlu4 is a promising new target for the treatment of chronic pain.
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Primary immunodeficiencies underlying fungal infections.
Curr. Opin. Pediatr.
PUBLISHED: 11-19-2013
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We review the primary immunodeficiencies (PIDs) underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors.
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Self-Intoxication with Baclofen in Alcohol-Dependent Patients with Co-existing Psychiatric Illness: An Emergency Department Case Series.
Alcohol Alcohol.
PUBLISHED: 11-12-2013
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The aim of the study was to describe the characteristics and management of alcohol-dependent patients with co-existing psychiatric illness seen after self-intoxication with oral baclofen in an emergency department (ED).
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Clinical outcome of isolated serous tubal intraepithelial carcinomas (STIC).
Int. J. Gynecol. Cancer
PUBLISHED: 11-01-2013
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Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC.
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Sensitivity Analysis for Critical Control Points Determination and Uncertainty Analysis to Link FSO and Process Criteria: Application to Listeria monocytogenes in Soft Cheese Made from Pasteurized Milk.
Risk Anal.
PUBLISHED: 10-29-2013
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Microbiological food safety is an important economic and health issue in the context of globalization and presents food business operators with new challenges in providing safe foods. The hazard analysis and critical control point approach involve identifying the main steps in food processing and the physical and chemical parameters that have an impact on the safety of foods. In the risk-based approach, as defined in the Codex Alimentarius, controlling these parameters in such a way that the final products meet a food safety objective (FSO), fixed by the competent authorities, is a big challenge and of great interest to the food business operators. Process risk models, issued from the quantitative microbiological risk assessment framework, provide useful tools in this respect. We propose a methodology, called multivariate factor mapping (MFM), for establishing a link between process parameters and compliance with a FSO. For a stochastic and dynamic process risk model of Listeriamonocytogenes in soft cheese made from pasteurized milk with many uncertain inputs, multivariate sensitivity analysis and MFM are combined to (i) identify the critical control points (CCPs) for L.monocytogenes throughout the food chain and (ii) compute the critical limits of the most influential process parameters, located at the CCPs, with regard to the specific process implemented in the model. Due to certain forms of interaction among parameters, the results show some new possibilities for the management of microbiological hazards when a FSO is specified.
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Deep dermatophytosis and inherited CARD9 deficiency.
N. Engl. J. Med.
PUBLISHED: 10-16-2013
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Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause.
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Risk factors for urinary tract infection with multiple drug-resistant Escherichia coli in cats.
J. Feline Med. Surg.
PUBLISHED: 09-24-2013
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The emergence of multiple drug-resistant (MDR) bacteria is a growing public health problem. The objective of this retrospective study was to identify risk factors associated with MDR Escherichia coli infection of the urinary tract in cats. All cats presenting with an E coli urinary infection between March 2010 and December 2012 were included and divided into two groups: an MDR group and a non-MDR group. The effects of different variables on the occurrence of a MDR E coli infection were evaluated: age, sex, additional diseases, number of antibiotics and number of days of hospitalisation. Fifty-two cats were identified (10 MDR and 42 non-MDR). The number of antibiotic groups used within the last 3 months was associated with an increased risk of MDR E coli urinary infection (P = 0.007). The association of the number of days of hospitalisation within the last 3 months and the increased risk of MDR E coli urinary infection did not reach significance (P = 0.090). This study provides evidence that systematic urinary culture with antibiotic sensitivity testing should be recommended when treating urinary tract infections if antibiotics have been prescribed within the past 3 months. Moreover, the selection of MDR bacteria through antibiotic use should be considered as a potential risk associated with treatment.
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STAT3 inhibitors for cancer therapy: Have all roads been explored?
JAKSTAT
PUBLISHED: 09-24-2013
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The signal transducer and activator of transcription STAT3 is a transcription factor which plays a key role in normal cell growth and is constitutively activated in about 70% of solid and hematological cancers. Activated STAT3 is phosphorylated on tyrosine and forms a dimer through phosphotyrosine/src homology 2 (SH2) domain interaction. The dimer enters the nucleus via interaction with importins and binds target genes. Inhibition of STAT3 results in the death of tumor cells, this indicates that it is a valuable target for anticancer strategies; a view that is corroborated by recent findings of activating mutations within the gene. Yet, there is still only a small number of STAT3 direct inhibitors; in addition, the high similarity of STAT3 with STAT1, another STAT family member mostly oriented toward apoptosis, cell death and defense against pathogens, requires that STAT3-inhibitors have no effect on STAT1. Specific STAT3 direct inhibitors consist of SH2 ligands, including G quartet oligodeoxynucleotides (ODN) and small molecules, they induce cell death in tumor cells in which STAT3 is activated. STAT3 can also be inhibited by decoy ODNs (dODN), which bind STAT3 and induce cell death. A specific STAT3 dODN which does not interfere with STAT1-mediated interferon-induced cell death has been designed pointing to the STAT3 DBD as a target for specific inhibition. Comprehensive analysis of this region is in progress in the laboratory to design DBD-targeting STAT3 inhibitors with STAT3/STAT1 discriminating ability.
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The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases.
Medicine (Baltimore)
PUBLISHED: 08-29-2013
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Imatinib is the treatment of choice for FIP1L1/PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P CEL), but its optimal dosing, duration, and possibility of discontinuation are still a matter of debate. A retrospective multicenter study was conducted with 44 F/P CEL patients identified in the French Eosinophil Network and treated with imatinib. The most frequently involved systems were skin (57%), spleen (52%), and lung (45%), and eosinophilic heart disease was observed in 15 patients (34%). Complete hematologic response (CHR) was obtained in all patients, and complete molecular response (CMR) in 95% of patients (average initial imatinib dose, 165 mg/d). For 29 patients the imatinib dose was tapered with a maintenance dose of 58 mg/d (±34 mg/d), allowing sustained CHR and CMR. None of the patients developed resistance during a median follow-up of 52.3 months (range, 1.4-97.4 mo). Imatinib was stopped in 11 patients; 6 of the patients subsequently relapsed, but 5 remained in persistent CHR or CMR (range, 9-88 mo). These results confirm that an initial low-dose regimen of imatinib (100 mg/d) followed by a lower maintenance dose can be efficient for obtaining long-term CHR and CMR. Our data also suggest that imatinib can be stopped in some patients without molecular relapse.
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A modular approach to triazole-containing chemical inducers of dimerisation for yeast three-hybrid screening.
Molecules
PUBLISHED: 08-01-2013
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The yeast three-hybrid (Y3H) approach shows considerable promise for the unbiased identification of novel small molecule-protein interactions. In recent years, it has been successfully used to link a number of bioactive molecules to novel protein binding partners. However despite its potential importance as a protein target identification method, the Y3H technique has not yet been widely adopted, in part due to the challenges associated with the synthesis of the complex chemical inducers of dimerisation (CIDs). The development of a modular approach using potentially "off the shelf" synthetic components was achieved and allowed the synthesis of a family of four triazole-containing CIDs, MTX-Cmpd2.2-2.5. These CIDs were then compared using the Y3H approach with three of them giving a strong positive interaction with a known target of compound 2, TgCDPK1. These results showed that the modular nature of our synthetic strategy may help to overcome the challenges currently encountered with CID synthesis and should contribute to the Y3H approach reaching its full potential as an unbiased target identification strategy.
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Risk-Based Approach for Microbiological Food Safety Management in the Dairy Industry: The Case of Listeria monocytogenes in Soft Cheese Made from Pasteurized Milk.
Risk Anal.
PUBLISHED: 06-20-2013
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According to Codex Alimentarius Commission recommendations, management options applied at the process production level should be based on good hygiene practices, HACCP system, and new risk management metrics such as the food safety objective. To follow this last recommendation, the use of quantitative microbiological risk assessment is an appealing approach to link new risk-based metrics to management options that may be applied by food operators. Through a specific case study, Listeria monocytogenes in soft cheese made from pasteurized milk, the objective of the present article is to practically show how quantitative risk assessment could be used to direct potential intervention strategies at different food processing steps. Based on many assumptions, the model developed estimates the risk of listeriosis at the moment of consumption taking into account the entire manufacturing process and potential sources of contamination. From pasteurization to consumption, the amplification of a primo-contamination event of the milk, the fresh cheese or the process environment is simulated, over time, space, and between products, accounting for the impact of management options, such as hygienic operations and sampling plans. A sensitivity analysis of the model will help orientating data to be collected prioritarily for the improvement and the validation of the model. What-if scenarios were simulated and allowed for the identification of major parameters contributing to the risk of listeriosis and the optimization of preventive and corrective measures.
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