Outcome and prognosis of isolated carotid vasculitis.

OBJECTIVE: To assess the prognosis and outcome of patients with isolated carotid vasculitis. METHODS: We performed a retrospective multicenter study of 36 patients (median age at diagnosis was 37 [IQR 27-45] years and 11 [31 %] patients were men) with initial presentation as isolated carotid vasculitis. Study endpoints included vascular complications, relapses, and progression to large vessel vasculitis (i.e. Giant cell arteritis or Takayasu). RESULTS: The most frequent involvement was the left internal carotid artery (39 %), and 81 % had stenosis. After a median follow-up of 32 months [IQR 12-96], 21 (58 %) patients had a vascular event, including 31 % of new onset vascular lesions and 25 % of stroke/transient ischemic attack. Patients with stroke had less carotidynia at diagnosis (33 % vs 74 %, p = 0.046), higher significant carotid stenosis (i.e. > 50 %) (89 % vs. 30 %, p = 0.026) and higher severe carotid stenosis (i.e. >70 %) (67 % vs 19 %, p = 0.012), compared to those without stroke. Twenty (52 %) patients experienced relapses. High CRP at diagnosis was associated with relapses (p = 0.022). At the end of follow-up, 21 (58 %) patients were classified as having Takayasu arteritis, 13 (36 %) as isolated carotid vasculitis, and two (6 %) as giant cell arteritis. CONCLUSION: Carotid vasculitis may occur as a topographically limited lesion and is associated with significant rate of vascular complications.

Activation of innate immunity by 14-3-3 ε, a new potential alarmin in osteoarthritis.

OBJECTIVE: The innate immune system plays a central role in osteoarthritis (OA). We identified 14-3-3ε as a novel mediator that guides chondrocytes toward an inflammatory phenotype. 14-3-3ε shares common characteristics with alarmins. These endogenous molecules, released into extracellular media, are increasingly incriminated in sustaining OA inflammation. Alarmins bind mainly to toll-like receptor 2 (TLR2) and TLR4 receptors and polarize macrophages in the synovium. We investigated the effects of 14-3-3ε in joint cells and tissues and its interactions with TLRs to define it as a new alarmin involved in OA. DESIGN: Chondrocyte, synoviocyte and macrophage cultures from murine or OA human samples were treated with 14-3-3ε. To inhibit TLR2/4 in chondrocytes, blocking antibodies were used. Moreover, chondrocytes and bone marrow macrophage (BMM) cultures from knockout (KO) TLRs mice were stimulated with 14-3-3ε. Gene expression and release of inflammatory mediators [interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNFα)] were evaluated via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and ELISA. RESULTS: In vitro, 14-3-3ε induced gene expression and release of IL6 and MCP1 in the treated cells. The inflammatory effects of 14-3-3ε were significantly reduced following TLRs inhibition or in TLRs KO chondrocytes and BMM. CONCLUSIONS: 14-3-3ε is able to induce an inflammatory phenotype in synoviocytes, macrophages and chondrocytes in addition to polarizing macrophages. These effects seem to involve TLR2 or TLR4 to trigger innate immunity. Our results designate 14-3-3ε as a novel alarmin in OA and as a new target either for therapeutic and/or prognostic purposes.

CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

Cessation of oral anticoagulants in antiphospholipid syndrome.

Objective To study the outcome of patients with antiphospholipid syndrome (APS) after oral anticoagulant treatment cessation. Methods We performed a retrospective study of patients with APS experiencing cessation of oral anticoagulant and enrolled in a French multicentre observational cohort between January 2014 and January 2016. The main outcome was the occurrence of recurrent thrombotic event after oral anticoagulation cessation. Results Forty four APS patients interrupted oral anticoagulation. The median age was 43 (27-56) years. The median duration of anticoagulation was 21 (9-118) months. Main causes of oral anticoagulant treatment cessation were switch from vitamin K antagonists to aspirin in 15 patients, prolonged disappearance of antiphospholipid antibodies in ten, bleeding complications in nine and a poor therapeutic adherence in six. Eleven (25%) patients developed a recurrent thrombotic event after oral anticoagulation cessation, including three catastrophic APS and one death due to lower limb ischemia. Antihypertensive treatment required at time of oral anticoagulants cessation seems to be an important factor associated with recurrent thrombosis after oral anticoagulant cessation (15.2% in patients with no relapse versus 45.5% in patients with recurrent thrombosis, p = 0.038). Oral anticoagulant treatment was re-started in 18 (40.9%) patients. Conclusion The risk of a new thrombotic event in APS patients who stopped their anticoagulation is high, even in those who showed a long lasting disappearance of antiphospholipid antibodies. Except for the presence of treated hypertension, this study did not find a particular clinical or biological phenotype for APS patients who relapsed after anticoagulation cessation. Any stopping of anticoagulant in such patients should be done with caution.

BIL&GIN: A neuroimaging, cognitive, behavioral, and genetic database for the study of human brain lateralization.

We report on a database, named BIL&GIN, designed for investigating the cognitive, behavioral, genetic, and brain morphological/functional correlates of hemispheric specialization. The database contains records from a sample of 453 adult participants enriched in left-handers (45%, N=205) as compared to the general population. For each subject, socio-demographic data, hand and eye laterality, family handedness, and cognitive abilities in the language, motor, visuo-spatial, and numerical domains have been recorded. T1-MRI and DTI data were also acquired, as well as resting-state functional MRI. Task-evoked functional MRI was performed in a sub-sample of 303 subjects (157 left-handers) using a customized functional battery of 16 cognitive tasks exploring the same three cognitive domains. Performances at the tasks executed in the magnet as well as post-acquisition debriefing were recorded. A saliva sample was obtained from the subjects of this sub-sample from which DNA was extracted. The BIL&GIN contains results of imaging data processing for each subject, namely maps of tissue (GM, WM, CSF) probability, cortical thickness, cortical surface, and diffusion parameters as well as regional values of these phenotypes for regions of both AAL and FreeSurfer parcellations. For the subjects who underwent FMRI, individual SPM contrast maps for each of the 8 runs were also calculated and included in the database, as well as corresponding BOLD variations in ROIs of the AAL and AICHA atlases, and Wilke's hemispheric functional lateralization index. The BIL&GIN data sharing is based on a collaborative model.

Quality of life in systemic lupus erythematosus: description in a cohort of French patients and association with blood hydroxychloroquine levels.

OBJECTIVES: Benefits of hydroxychloroquine (HCQ) use on physician reported outcomes are well documented in systemic lupus erythematosus (SLE). We assess for the first time the association and predictive value of blood HCQ levels towards health-related quality of life (HRQOL) in SLE. METHODS: Data from the PLUS study (a randomized, double-blind, placebo-controlled, multicentre study) were utilized. Blood HCQ levels were quantified by high-performance liquid chromatography along with HRQOL assessments (Medical Outcomes Study-SF-36) at baseline (V1) and month 7 (V2). RESULTS: 166 SLE patients' data were analysed. Mean (SD) age and disease duration were 44.4 (10.7) and 9.3 (6.8) years. Eighty-seven per cent were women. Mean (SD, median, IQR) HCQ concentrations in the blood at V1 were 660 (314, 615, 424) ng/ml and increased to 1020 (632, 906, 781) ng/ml at V2 (mean difference 366 units, 95% confidence interval -472 to -260, p < 0.001). No significant correlations between HCQ concentrations with HRQOL domains at V1 or V2 were noted. There were no differences in HRQOL stratified by HCQ concentrations. HCQ concentrations at V1 or changes in HCQ concentration (V2-V1) were not predictive of HRQOL at V2 or changes in HRQOL (V2-V1). CONCLUSIONS: No association of HCQ concentrations with current or longitudinal HRQOL were found in SLE.

Endopolygalacturonases reveal molecular features for processivity pattern and tolerance towards acetylated pectin.

Endopolygalacturonases (EndoPGs) hydrolyse the 1-4 linkages between two alpha-d-galacturonic acids (GalA) of the smooth homogalacturonan regions of pectin. GalA may be methyl-esterified on the carboxylic group and acetyl-esterified on the hydroxylic groups. EndoPG activity most often decreases with such increasing degree of substitution. In this paper, we used bioinformatics and molecular modelling technics to explain the tolerance profile at the molecular scale and processivity scheme of three endoPGs with respect to acetylated pectin substrate; the first two enzymes originate from Aspergillus niger (AnPGI and AnPGII) and the third from Fusarium moniliforme (FmPG). Partly acetylated and methylated homogalacturonan fragments in complex with the three PGs were successively modelled in silico. The amino acid residues involved in substrate binding were identified for each enzyme. Similarly, the docking pattern of the differently decorated oligomers in the catalytic groove was individually characterized for each enzyme. This work shows full agreement with our previous extensive mass spectrometry analysis of the hydrolytic products that established distinct tolerance profiles for the three endoPGs and earlier work that ascertained processivity, specifically for AnPGI. In our previous work, AnPGI was shown to be the most powerful enzyme among the three enzymes with an enhanced tolerance towards O2- and O3-acetylated substrates. We report here amino acids of AnPGI that are unique in binding the pectin backbone and that are identified as possibly crucial for its specificity, namely S191(An)(PGI)/D240(An)(PGI). Similarly, topologically equivalent residues in AnPGII and FmPG were identified that could impede such binding; S234(An)(PGII)/S91(An)(PGII) and S245(Fm)(PG)/V89(Fm)(PG). In addition, we report here, from normal mode analysis computed on AnPG1, a shear bending motion of 15 A of amplitude that fully accredits the processive action pattern for this enzyme, with D240(An)(PGI) and R96(An)(PGI) working as crampons to favour the sliding of the substrate. Conversely, the same method clearly evidences a hinge binding motion for AnPGII and FmPG that should only authorize one hydrolytic event per enzyme/substrate encounter.

Exposures associated with making or playing with viscoelastic polymer toys known as Slime: a retrospective case series from French Poison Control Centres.

Context: Slime is a slow-flowing material with viscoelastic properties which is attractive to children. Its preparation is based on the crosslinking of polyvinyl alcohol, polyvinyl acetate or starch with boric acid.Objectives: The goal of this study was to describe the adverse effects of Slime.Materials and methods: This is a descriptive retrospective study of cases of exposure reported to French Poison Control Centres between January 2014 and May 2018. The following parameters were used: age and sex, date and circumstances of exposure, symptoms and severity.Results: Two hundred and eight (208) cases of exposure were recorded, 93 cases happened in 2017, and 88 cases in the first four and a half months of 2018. The average age was of 8 years old; 190 patients were younger than 15. Fifty-seven percent (57%) were female. Regarding routes of exposure, 168 were oral, 30 cutaneous, eight ocular, one inhalation and one ear exposure. Eighty-two (82) patients were symptomatic, including 81 cases of low severity and one of average severity (keratitis). All cases lead to recovery.Conclusion: No significant adverse health effects are expected to develop if only small amounts are swallowed; making Slime with home ingredients is a potential cause of boric acid exposure that must be supervised by adults.

[Liver disease and pregnancy]. / Pathologies hépatiques et grossesse.

Liver dysfunction during pregnancy can be related or not to pregnancy itself. The purpose of this review is to summarize the possible causes of liver dysfunction during pregnancy and their management. Liver dysfunction during pregnancy can be chronic or acute, independent or specific to pregnancy. Management of liver disease can be different during pregnancy. The knowledge of liver dysfunction during pregnancy is of help for a better management of the mother in order to avoid maternal and fetal mortality and morbidity.

Treatment of myelodysplastic syndromes with 5q deletion before the lenalidomide era; the GFM experience with EPO and thalidomide.

Anemia in MDS with 5q deletion was generally considered, until the advent of lenalidomide, unresponsive to available treatments. We analyzed erythroid response to erythropoetin (EPO) or darbepoetin (DAR) and thalidomide in MDS with 5q deletion treated by French centers (GFM) and in whom karyotype was successfully performed. Of 345 patients treated with EPO or DAR+/-G-CSF, 48 had 5q deletion. The response rate was 46% (31% major, 15% minor) according to International Working Group (IWG) 2000 criteria versus 64% in patients without 5q deletion (p=0.03). According to IWG 2006 criteria, the response rate in patients with 5q deletion was 39% versus 52% in patients without 5q deletion (p=0.10). Mean duration of response was 14 months versus 25 months (IWG 2000) and 13 months versus 27 months (IWG 2006) in 5q deletion and non-5q deletion patients (p=0.019 and 0.003, respectively). Of 120 MDS treated with thalidomide, all of whom had successful cytogenetic analysis, 37% of the 24 patients with 5q deletion responded (IWG 2000 criteria, 20% major, 17% minor) with a mean duration of 9.5 months, versus 32% (18% major, 14% minor) in MDS without 5q deletion and a mean response duration of 9 months (p=NS). Our results confirm that response rates to EPO or DAR and thalidomide are clearly inferior to those obtained with lenalidomide.

[Hydroxychloroquine and systemic lupus: a reappraisal]. / Hydroxychloroquine dans le traitement du lupus: le renouveau.

PURPOSE: Hydroxychloroquine (HCQ) is still too often considered as a second-line treatment in systemic lupus erythematosus (SLE) patients. KEY POINTS: Recently, interest for this drug has grown as a consequence of its favorable efficacy/toxicity ratio, its low cost and the availability of a blood measurement assay. Its efficiency has been demonstrated in the reduction of the risk of SLE flares and of overall damage accrual. The properties of HCQ also include a beneficial effect on lipid profile, and a protective effect against the occurrence of thrombotic events and of low bone mineral density related to corticosteroids. As a consequence, HCQ appears to have a protective effect on survival in people with SLE. Side-effects and contraindications are rare. Even if the incidence of retinopathy in clinical practice is very low, regular screening of this complication is required, but its modalities are not consensual. CONCLUSION: These data are strong evidence for a wide prescription of HCQ. This should easily improve the management of our SLE patients.

[Relapsing polychondritis: What's new in 2017?] / Polychondrite atrophiante : actualités en 2017.

Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on pathophysiology are scarce and suggest an autoimmune mechanism. Recently, the possibility of dividing patients with RP into three distinct clinical phenotypes has been suggested: the hematological form representing less than 10% of patients, essentially older men with associated myelodysplasia and poor prognosis, the respiratory form representing about 25% of patients with predominant tracheobronchial involvement, and the mild and most frequent form, representing 65% of patients, with a good prognosis. Recent data on survival shows an improvement of overall prognosis compared to historical series. Reported poor prognosis factors are male gender, associated haemopathies and cardiac involvement. Few recent series suggest an interest for positron emission tomography for the diagnosis and the follow-up of treatment. Due to the lack of randomized therapeutic trial, treatment remains empirical and is mainly based on oral corticosteroids sometimes associated with immunosuppressive agents. The use of biologic agents has recently been reported in small retrospective series with different outcome. Finally, some selected patients with mild and occasional peripheral chondritis might justify a treatment with colchicine or a therapeutic abstention with occasional short-term corticosteroids therapy.

Action pattern of Fusarium moniliforme endopolygalacturonase towards pectin fragments: Comprehension and prediction.

The structures of complexes of Fusarium moniliforme endopolygalacturonase (endoPG) with non-methylated or partly methylated homogalacturonan fragments were modeled to identify the residues involved in substrate binding and to correlate the cleavage pattern with the experimental productive modes. The conformational space of the complex was extensively explored and malto- to hexo-oligogalacturonates were modeled in the active cleft. To select the most highly probable productive complex for each oligomer between DP2 and 6, four energetic criteria were defined. Noteworthingly, the results were in accordance with the experimental results showing the mode of action of this enzyme towards un-methyl-esterified oligogalacturonates. Furthermore, the amino-acid residues involved in the binding were confirmed by similar studies performed on other endoPGs. Then, the oligomers were gradually methyl-esterified at one or more positions and similar docking experiments were carried out. Markedly, the docking energies were not significantly modified by the methyl-esterification of the substrate and it is likely that the methyl-esterification of the substrate does not alter the mode of action of the enzyme. Finally, 1D sequence and 3D structure of the endopolygalacturonase of Aspergillus niger II, known to be strictly non-tolerant to methylesters, were compared with the sequence and structure of the tolerant F. moniliforme endopolygalacturonase to get to a structural comprehension of the tolerant-or not-behaviour of endoPGs with methyl-esterified pectins.

Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).

Sixteen adult patients with relapsed (7 patients) or refractory (9 patients) acute leukemia received mitoxantrone (10 mg/m2 per day for 3 days) and etoposide (200 mg/m2 per day for 3 days) with escalating dose of cyclosporin A (CsA) from a loading dose of 2 mg to 6.5 mg/kg per 2 h followed by 3 days continuous infusion of 5-15 mg/kg per day. The major toxicities were stomatitis and prolonged aplasia, occurring for 15 mg/kg per day of CsA. Transient conjugated hyperbilirubinemia occurred in all patients, and was CsA dose-dependent (r = 0.7). Adequate serum levels of CsA (> 1 microgram/ml) were obtained in 3/6 patients treated with 10 mg/kg per day and 4/4 patients with 15 mg/kg per day. The pharmacokinetic of mitoxantrone showed an unusual increase of carboxylic metabolites, parallel to CsA levels. We observed six responses (two complete and four partial remissions), and eight resistances. Two patients died at days 3 and 8 from sepsis. Before treatment, 7/16 patients tested for P-gp with C219 were positive (> 10% positive cells). 3/6 responders were P-gp-positive. At time of leukemic regrowth, cells expressing P-gp before therapy reverted to P-gp-negative cells.

[Liver diseases and pregnancy]. / Pathologies hépatiques et grossesse.

Liver disease can be observed in pregnant women whether or not related to pregnancy. Liver disorders can be revealed by pruritus, vomiting, jaundice or abnormal liver blood tests during pregnancy. These liver manifestations can lead to the diagnosis of liver disease specifically associated to pregnancy as intrahepatic pregnancy, intrahepatic cholestasis of pregnancy, Hyperemesis gravidarum, acute fatty liver of pregnancy and preeclampsia-induced liver injury. Pregnancy may also be a risk factor for other liver diseases coincident with pregnancy as viral hepatitis, thrombosis, drug toxicity or gallstone. Finally, pre-existing liver disease must be taken into account given the risk of fœto-maternal transmission risk as well as the risk of decompensation of underlying cirrhosis secondary to the hemodynamic changes caused by pregnancy. The aim of this revue is to perform an update on the various situations that can be observed, the principles of management of these liver diseases, in order to reduce the risk of complications and to ensure the best maternal and fetal prognosis.

Heschl's gyrification pattern is related to speech-listening hemispheric lateralization: FMRI investigation in 281 healthy volunteers.

This study investigates the structure-function relationships between the anatomy of Heschl's gyri (HG) and speech hemispheric lateralization in 281 healthy volunteers (135 left-handers). Hemispheric lateralization indices (HFLIs) were calculated with Wilke's method from the activations obtained via functional magnetic resonance imaging while listening to lists of words (LIST). The mean HFLI during LIST was rightward asymmetrical, and left-handers displayed a trend toward decreased rightward asymmetry. The correlations between LIST BOLD contrast maps and individual HFLIs demonstrated that among the cortical areas showing significant asymmetry during LIST, only phonological regions explained HFLI variability. Significant positive correlations were present among the left HG, supramarginal gyri, and the anterior insula. Significant negative correlations occurred in the mid-part of the right superior temporal sulcus. Left HG had the largest functional activity during LIST and explained 10% of the HFLI variance. There was a strong anatomo-functional link in the HG: duplication was associated with a decrease in both the surface area of the anterior HG and HG functional activity. Participants with a single left HG exhibited leftward anatomical and functional asymmetry of HG, but participants with a left duplication lost either anatomical and/or functional leftward asymmetries. Finally, manual preference was related to HG anatomy, but not to HG functional asymmetries measured during LIST. The anatomical characteristics of left-handers (lower occurrence of right HG duplication and a smaller surface area of the right first HG) thus appeared to be unrelated to variations in speech lateralization with handedness.

Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus.

OBJECTIVE: Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. METHODS: We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded. RESULTS: To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug-drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23-58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504-2,229 ng/ml] versus 917 ng/ml [range 208-3316 ng/ml]) (P < 0.001). CONCLUSION: We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.

Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging.

Both the amygdala and the hippocampus are involved in the pathogenesis of a number of neurologic conditions, including temporal lobe epilepsy, postanoxic amnesia, and Alzheimer's disease. To enhance the investigation and management of patients with these disorders, we developed a protocol to measure the volumes of the amygdala and as much of the hippocampus as possible (approximately 90 to 95%) using high-resolution MRI. We present the anatomic basis of these two protocols and our results in normal control subjects. These volumetric studies of the amygdala may clarify the role of this structure in the pathogenesis of temporal lobe epilepsy.