Objectif Comparer l'efficacité et la tolérance du liraglutide par rapport au lixisenatide en association à la metformine (MET) chez des patients diabétiques de type 2 (DT2) insuffisamment contrôlés ...sous MET seule. Matériels et Méthodes Essai randomisé contrôlé, en ouvert de 26 semaines. Des patients DT2 (âge ≥ 18 ans, 7,5 % ≥ HbA1c ≤ 10,5 %, IMC ≥ 20 kg/m2 ) ont été randomisés selon un ratio 1 : 1 pour recevoir soit le liraglutide 1,8 mg/j, soit le lixisenatide 20 μg/j en association à la la MET. Le liraglutide était administré à n'importe quel moment de la journée, le lixisenatide était administré une heure avant le repas du matin ou du soir. Résultats 404 patients DT2 (60 % d'hommes, âge moyen 56 ans, IMC 35 kg/m2 , HbA1c 8,4 %, durée du diabète 6,4 ans) ont été randomisés. Après 26 semaines de traitement, la réduction de l'HbA1c sous liraglutide a été supérieure par rapport au lixisenatide (1,83 vs 1,21 %, p < 0,001), avec davantage de patients atteignant l'objectif d'HbA1c < 7 % (74,2 vs 45,5 %, p < 0,001). La baisse de la glycémie à jeun a été plus importante sous liraglutide (2,85 vs 1,70 mmol/l, P < 0,001). Le profil glycémique global en 9 points était significativement amélioré sous liraglutide, cependant l'excursion glycémique post prandiale était significativement plus basse pour le repas suivant l'administration du lixisenatide. La perte pondérale a été similaire dans les 2 groupes (− 4,3 kg pour lira, − 3,7 kg pour lixi, p = ns). Les profils de tolérance ont été globalement comparables. Les événements indésirables les plus fréquents étaient digestifs (nausées : 21,8 % pour lira et lixi ; diarrhées : 12,4 % pour lira, 9,9 % pour lixi). Les épisodes d'hypoglycémies confirmées ont été rares (hypoglycémie sévère ou glycémie < 3,1 mmol/l), sans aucun épisode sévère. Conclusions Le liraglutide en association à la metformine a été plus efficace que le lixisenatide en termes de contrôle glycémique. Une perte pondérale significative a été observée avec les deux traitements. Les profils de tolérance ont été similaires avec essentiellement des troubles digestifs et un risque hypoglycémique faible.
Sudden unexpected death in epilepsy (SUDEP) poses a poorly understood but considerable risk to people with uncontrolled epilepsy. There is controversy regarding the significance of postictal ...generalized EEG suppression as a biomarker for SUDEP risk, and it remains unknown whether postictal EEG suppression has a neurologic correlate. Here, we examined the profile of autonomic alterations accompanying seizures with a wrist-worn biosensor and explored the relationship between autonomic dysregulation and postictal EEG suppression.
We used custom-built wrist-worn sensors to continuously record the sympathetically mediated electrodermal activity (EDA) of patients with refractory epilepsy admitted to the long-term video-EEG monitoring unit. Parasympathetic-modulated high-frequency (HF) power of heart rate variability was measured from concurrent EKG recordings.
A total of 34 seizures comprising 22 complex partial and 12 tonic-clonic seizures from 11 patients were analyzed. The postictal period was characterized by a surge in EDA and heightened heart rate coinciding with persistent suppression of HF power. An increase in the EDA response amplitude correlated with an increase in the duration of EEG suppression (r = 0.81, p = 0.003). Decreased HF power correlated with an increase in the duration of EEG suppression (r = -0.87, p = 0.002).
The magnitude of both sympathetic activation and parasympathetic suppression increases with duration of EEG suppression after tonic-clonic seizures. These results provide autonomic correlates of postictal EEG suppression and highlight a critical window of postictal autonomic dysregulation that may be relevant in the pathogenesis of SUDEP.
To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB).
Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor ...weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender.
Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY3-36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite.
Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test (P=0.006). In addition, the good responders had a larger release of GLP-1 (P=0.009) and a greater suppression of ghrelin (P=0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders (P=0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 (P<0.001), PYY (P=0.008), CCK (P=0.010) and neurotensin (P<0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition.
Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.
Background:
Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management.
Objective:
To estimate the incidence of acute ON and the ...rates of conversion to MS and antibody-mediated ON.
Method:
Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly.
Results:
In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16–66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44–4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients.
Conclusion:
The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.
Chronic allograft vasculopathy (CAV) in murine heart allografts can be elicited by adoptive transfer of donor specific antibody (DSA) to class I MHC antigens and is independent of complement. Here we ...address the mechanism by which DSA causes CAV. B6.RAG1−/− or B6.RAG1−/−C3−/− (H‐2b) mice received B10.BR (H‐2k) heart allografts and repeated doses of IgG2a, IgG1 or F(ab’)2 fragments of IgG2a DSA (anti‐H‐2k). Intact DSA regularly elicited markedly stenotic CAV in recipients over 28 days. In contrast, depletion of NK cells with anti‐NK1.1 reduced significantly DSA‐induced CAV, as judged morphometrically. Recipients genetically deficient in mature NK cells (γ‐chain knock out) also showed decreased severity of DSA‐induced CAV. Direct NK reactivity to the graft was not necessary. F(ab’)2 DSA fragments, even at doses twofold higher than intact DSA, were inactive. Graft microvascular endothelial cells responded to DSA in vivo by increased expression of phospho‐extracellular signal‐regulated kinase (pERK), a response not elicited by F(ab’)2 DSA. We conclude that antibody mediates CAV through NK cells, by an Fc dependent manner. This new pathway adds to the possible mechanisms of chronic rejection and may relate to the recently described C4d‐negative chronic antibody‐mediated rejection in humans.
Chronic cardiac allograft vasculopathy in the mouse mediated by donor‐specific antibody is shown to require NK cells and the Fc portion of antibody but is independent of complement fixation. See editorial by Li and Baldwin on page 275.
The recent detection of fast radio bursts has generated strong interest in identifying the origin of these bright, non-repeating, highly dispersed pulses. The principal limitation in understanding ...the origin of these bursts is the lack of reliable distance estimates; their high dispersion measures imply that they may be at cosmological distances (0.1 < z < 1.0). Here, we discuss new distance constraints to the FRB010621 (a.k.a J1852−08) first reported by Keane. We use velocity resolved Hα and Hβ observations of diffuse ionized gas towards the burst to calculate an extinction-corrected emission measure along the line of sight. We combine this emission measure with models of Galactic rotation and of electron distribution to derive a 90 per cent probability of the pulse residing in the Galaxy. However, we cannot differentiate between the two Galactic interpretations of Keane: a neutron star with unusual pulse amplitude distribution or Galactic black hole annihilation.
Astrocytomas are the most common type of brain tumors in children. Activated BRAF protein kinase mutations are characteristic of pediatric astrocytomas with KIAA1549-BRAF fusion genes typifying ...low-grade astrocytomas and ⱽ⁶⁰⁰ᴱBRAF alterations characterizing distinct or higher-grade tumors. Recently, BRAF-targeted therapies, such as vemurafenib, have shown great promise in treating V600E-dependent melanomas. Like ⱽ⁶⁰⁰ᴱBRAF, BRAF fusion kinases activate MAPK signaling and are sufficient for malignant transformation; however, here we characterized the distinct mechanisms of action of KIAA1549-BRAF and its differential responsiveness to PLX4720, a first-generation BRAF inhibitor and research analog of vemurafenib. We found that in cells expressing KIAA1549-BRAF, the fusion kinase functions as a homodimer that is resistant to PLX4720 and accordingly is associated with CRAF-independent paradoxical activation of MAPK signaling. Mutagenesis studies demonstrated that KIAA1549-BRAF fusion-mediated signaling is diminished with disruption of the BRAF kinase dimer interface. In addition, the KIAA1549-BRAF fusion displays increased binding affinity to kinase suppressor of RAS (KSR), an RAF relative recently demonstrated to facilitate MEK phosphorylation by BRAF. Despite its resistance to PLX4720, the KIAA1549-BRAF fusion is responsive to a second-generation selective BRAF inhibitor that, unlike vemurafenib, does not induce activation of wild-type BRAF. Our data support the development of targeted treatment paradigms for BRAF-altered pediatric astrocytomas and also demonstrate that therapies must be tailored to the specific mutational context and distinct mechanisms of action of the mutant kinase.
For improved wound healing, antimicrobial adhesives are one path forward. However, with the current challenge of bacterial resistance, it is essential to choose the included drug carefully. ...Octenidine is an obvious choice due to its broad antimicrobial efficacy and no reported bacterial resistance. In its pure form, octenidine complexes efficiently with the platinum catalyst in the silicone composition, inhibiting the targeted hydrosilylation reaction and hindering curing. This obstacle is overcome by screening octenidine with cyclodextrins in homogeneously dispersed glycerol droplets, suppressing Pt inhibition in the silicone phase. Curing efficiency is demonstrated using rheology, which shows that it is possible to incorporate one wt% of octenidine into glycerol-silicone adhesives in the presence of (2-hydroxypropyl)-β-cyclodextrin without affecting the adhesives' mechanical properties. The interaction between octenidine and (2-hydroxypropyl)-β-cyclodextrin through an inclusion complex is confirmed by ROESY spectroscopy. Despite this screening, octenidine is still released efficiently from the glycerol-silicone adhesives upon contact with water, and the resulting antimicrobial action is subsequently demonstrated. This new technology constitutes a simple and efficient method for preparing wound care adhesives that actively inhibit the growth of four bacteria strains and one fungus.
Epilepsy-the propensity toward recurrent, unprovoked seizures-is a devastating disease affecting 65 million people worldwide. Understanding and treating this disease remains a challenge, as seizures ...manifest through mechanisms and features that span spatial and temporal scales. Here we address this challenge through the analysis and modelling of human brain voltage activity recorded simultaneously across microscopic and macroscopic spatial scales. We show that during seizure large-scale neural populations spanning centimetres of cortex coordinate with small neural groups spanning cortical columns, and provide evidence that rapidly propagating waves of activity underlie this increased inter-scale coupling. We develop a corresponding computational model to propose specific mechanisms-namely, the effects of an increased extracellular potassium concentration diffusing in space-that support the observed spatiotemporal dynamics. Understanding the multi-scale, spatiotemporal dynamics of human seizures-and connecting these dynamics to specific biological mechanisms-promises new insights to treat this devastating disease.
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