Different clinical outcomes between cerebral amyloid angiopathy-related inflammation and non-inflammatory form.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of CAA-ri and non-inflammatory CAA. MATERIALS AND METHODS: We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and APOE genotype when available. Outcomes were compared using Kaplan-Meier curves and log-rank tests. RESULTS: Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%, p < 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (p < 0.001 and p = 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml, p = 0.05). CAA-ri patients more likely carried at least one APOE ε4 allele (76% vs 37.5%, adjusted p = 0.05) particularly as homozygous status (56% vs 6.2%, p < 0.001). INTERPRETATION: CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.

Hybridization of automation practical courses.

Since 2020, the Covid-19 pandemic has led universities around the world to hybridize courses (i.e., replacement of classroom time by online activities), most often as a matter of urgency. The difficulty of hybridization depends on the kind of course (lectures, tutorials, practical works) and the type of course (mathematics, chemistry, engineering, informatics…). ET-LIOS is a 2 year project started in November 2020, led by the GIS S.mart (scientific interest French grouping for Industry 4.0) and 14 French universities. The objective is to propose solutions and resources to hybridize higher education courses dedicated to the Industry of the Future. In this paper, firstly, we present the problems to be solved to hybridize practical works. One of the challenges is to carry out solutions which can be used easily and adapted by all partners of the ET-LIOS. Secondly, for combinatorial logic practical work, we propose to use simulation softwares (HOME I/O and CONNECT I/O) installed on the students' computer, conjointly with customizable SCORM (Sharable Content Object Reference Model) packages which can be integrated in existing learning platforms of course management (LMS) like Moodle. This SCORM package enables students to test and to get feedback of their proposed solutions. The approach has been tested with Bachelor students in a combinatorial logic practical work. First results are very encouraging.

Correction to: Features of intracranial hemorrhage in cerebral venous thrombosis.

The original version of this article unfortunately contained mistakes. The correct information is given below.

Features of intracranial hemorrhage in cerebral venous thrombosis.

BACKGROUND: Cerebral venous thrombosis (CVT) is associated with intracranial hemorrhage. AIM: To identify clinical and imaging features of CVT-associated intracranial hemorrhage. We hypothesized that higher clot burden would be associated with a higher risk of intracranial hemorrhage. METHODS: We performed a retrospective analysis of an international, multicenter cohort of patients with confirmed cerebral venous thrombosis who underwent computed tomography within 2 weeks of symptom onset. Clinical and imaging features were compared between patients with and without intracranial hemorrhage. Clot burden was assessed by counting the number of thrombosed venous sinuses and veins on confirmatory imaging. RESULTS: We enrolled 260 patients from 10 institutions in Europe and Mexico. The mean age was 42 years and 74% were female. Intracranial hemorrhage was found in 102 (39%). Among them parenchymal hemorrhage occurred in 64 (63%), in addition, small juxta-cortical hemorrhage was found in 30 (29%), subarachnoid hemorrhage in 24 (24%) and subdural hemorrhage in 11 (11%). Multiple concomitant types of hemorrhage occurred in 23 (23%). Older age and superior sagittal thrombosis involvement were associated with presence of hemorrhage. The number of thrombosed venous sinuses was not associated with intracranial hemorrhage (median number IQRInterquartile ratio] of sinuses/veins involved with hemorrhage 2 (1-3) vs. 2 (1-3) without hemorrhage, p = 0.4). CONCLUSION: The high rate of intracranial hemorrhage in cerebral venous thrombosis is not explained by widespread involvement of the venous sinuses. Superior sagittal sinus involvement is associated with higher bleeding risk.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Cerebral microbleeds: a magnetic resonance imaging review of common and less common causes.

Cerebral microbleeds (CMBs) are small foci of (acute, subacute or chronic) blood products, best seen using magnetic resonance imaging (MRI) techniques sensitive to iron deposits (i.e. gradient-echo T2*-weighted and susceptibility-weighted imaging), frequently encountered in small vessel disease (SVD) (with hypertensive vasculopathy and cerebral amyloid angiopathy as the most frequent conditions) and also in other disorders. In this review, the MRI characteristics of CMBs and the associated MRI abnormalities encountered in common and less common SVD and non-SVD conditions are the main focus. Identification of the origin of CMBs depends on their localization, the presence of other associated MRI abnormalities, and the patient's history and clinical state.

Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Assessing the QT prolongation potential of a drug is typically done based on pivotal safety studies called thorough QT studies. Model-based estimation of the drug-induced QT prolongation at the estimated mean maximum drug concentration could increase efficiency over the currently used intersection-union test. However, robustness against model misspecification needs to be guaranteed in pivotal settings. The objective of this work was to develop an efficient, fully prespecified model-based inference method for thorough QT studies, which controls the type I error and provides satisfactory test power. This is achieved by model averaging: The proposed estimator of the concentration-response relationship is a weighted average of a parametric (linear) and a nonparametric (monotonic I-splines) estimator, with weights based on mean integrated square error. The desired properties of the method were confirmed in an extensive simulation study, which demonstrated that the proposed method controlled the type I error adequately, and that its power was higher than the power of the nonparametric method alone. The method can be extended from thorough QT studies to the analysis of QT data from pooled phase I studies.

Drug-induced hemolytic anemia: Pharmacological aspects.

Drug-induced hemolytic anemia is a very rare but potentially lethal adverse drug reaction, which can take the form of oxidative damage to vulnerable erythrocytes (as in glucose-6-phosphate dehydrogenase deficiency), drug-induced thrombotic microangiopathy, or immune-mediated hemolytic anemia. For each form, distinctive drugs are documented as potential triggers. When a formal diagnosis of hemolytic anemia is made following drug administration, a structured approach is recommended to assess the plausibility of an adverse drug reaction based on chronological sequence, epidemiological data, objective evidence (when available), and ruling out of non-drug causes. For suspicions of immune-mediated hemolytic anemia, investigations by a laboratory with specific expertise are crucial given the complexity of the field. If there is good reason to believe hemolytic anemia is drug-induced, immediate drug discontinuation is necessary and corticosteroid administration can be considered. The clinical pharmacology specialist can support evaluation of drug imputability and report the case to the pharmacovigilance system, an important last step in managing such events.

123I-FP-CIT SPECT imaging in blepharospasm.

INTRODUCTION: Blepharospasm is a focal dystonia characterized by involuntary cocontraction of the eyelid protractors, causing spasmodic closure of the eyelids. Apraxia of eyelid opening is caused by an inability to initiate lid opening without paralytic abnormality. Some studies suggest that patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening are more prone to developing Parkinson's disease. METHODS: In our study, 123I-FP-CIT (DAT) SPECT was performed in 24 patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening and no signs of parkinsonism to identify dopaminergic dysfunction. RESULTS: DAT-SPECT was abnormal in 11 (46%) cases (five patients with isolated blepharospasm and six patients with blepharospasm associated with apraxia of eyelid opening) whose mean disease duration was 11 years. CONCLUSION: Our study revealed presynaptic dopaminergic dysfunction, as determined by 123I-FP-CIT or DAT-SPECT, in nearly half of our blepharospasm patients (with or without apraxia of eyelid opening). Thus, the presence of blepharospasm might be an early sign of a parkinsonian syndrome.

Density heterogeneity and fluid-blood levels in patients aged over 55 with lobar hematoma.

BACKGROUND: Density heterogeneity and fluid-blood levels (FBLs) are frequently seen on acute CT scans of deep brain hemorrhage. Our aim was to analyze the density heterogeneity and FBLs seen on acute/subacute CT in patients aged>55 with lobar haemorrhage (LH), and to study the relationship of these brain abnormalities with other parameters, including cerebral amyloid angiopathy (CAA)-related abnormalities. METHODS: This was an observational study and retrospective analysis of early CT scans (<7 days) in patients aged>55 years with acute lobar hemorrhage who, between 2012 and 2015, were entered into our stroke database. A total of 37 LH episodes (without trauma, abnormal coagulation/platelet counts, vascular malformation, tumor or vasculitis) in 35 patients were analyzed. Other studied parameters were gender, age, history of hypertension, blood pressure on admission, prior antiplatelet treatment, aPTT, PTT, platelet count, hematocrit, timing of first CT, LH volume, involved lobe, cortical superficial siderosis, microbleeds, chronic LH and CAA (classic and modified Boston) criteria. CAA-related abnormalities seen on MRI were also scored. RESULTS: Overall, in 26 LH episodes (70%), CT was performed within 24h. Density heterogeneity and FBLs were seen in 19 (51%) and 9 (24%) LH episodes, respectively. Also, according to classic and modified Boston criteria, 18 (51%) and 24 (69%) patients, respectively, fulfilled criteria for probable/definite CAA. As for the presence of FBLs, a statistically significant association was found with both the presence of probable/definite CAA according to modified Boston criteria (P=0.033) and the presence of superficial siderosis (P=0.019). CONCLUSION: Density heterogeneity and, to a lesser degree, FBLs are frequently seen in patients aged>55 with LH. FBLs may also be associated with CAA-related hemorrhage.

Microfluidics-assisted generation of stimuli-responsive hydrogels based on alginates incorporated with thermo-responsive and amphiphilic polymers as novel biomaterials.

We used a droplet-based microfluidics technique to produce monodisperse responsive alginate-block-polyetheramine copolymer microgels. The polyetheramine group (PEA), corresponding to a propylene oxide /ethylene oxide ratio (PO/EO) of 29/6 (Jeffamine(®) M2005), was condensed, via the amine link, to alginates with various mannuronic/guluronic acids ratios and using two alginate:jeffamine mass ratios. The size of the grafted-alginate microgels varied from 60 to 80 µm depending on the type of alginate used and the degree of substitution. The droplet-based microfluidics technique offered exquisite control of both the dimension and physical chemical properties of the grafted-alginate microgels. These microgels were therefore comparable to isolated grafted-alginate chains in retaining both their amphiphilic and thermo-sensitive properties. Amphiphilicity was demonstrated at the oil-water interface where grafted-alginate microgels were found to decrease interfacial tension by ∼ 50%. The thermo-sensitivity of microgels was clearly demonstrated and a 10 to 20% reduction in size between was evidenced on increasing the temperature above the lower critical solution temperature (TLCST) of Jeffamine. In addition, the reversibility of thermo-sensitivity was demonstrated by studying the oil-water affinity of microgels with temperature after Congo red labeling. Finally, droplet-based microfluidics was found to be a good and promising tool for generating responsive biobased hydrogels for drug delivery applications and potential new colloidal stabilizers for dispersed systems such as Pickering emulsions.

Microfluidics assisted generation of innovative polysaccharide hydrogel microparticles.

Capillary flow-based approach such as microfluidic devices offer a number of advantages over conventional flow control technology because they ensure highly versatile geometry and can be used to produce monodisperse spherical and non-spherical polymeric microparticles. Based on the principle of a flow-focusing device to emulsify the coflow of aqueous solutions in an organic phase, we were able to produce the following innovative polysaccharide hydrogel microparticles: - Janus hydrogel microparticles made of pectin­pectin (homo Janus) and pectin­alginate (hetero Janus) were produced. The efficiency of separation of the two hemispheres was investigated by confocal scanning laser microscopy (CSLM) of previously labelled biopolymers. The Janus structure was confirmed by subjecting each microparticle hemisphere to specific enzymatic degradation. As a proof of concept, free BSA or BSA grafted with dextran, were encapsulated in each hemisphere of the hetero Janus hydrogel microparticles. While BSA, free or grafted with dextran, was always confined in the alginate hemisphere, a fraction of BSA diffused from the pectin to the alginate hemisphere. Methoxy groups along the pectin chain will be responsible of the decrease of the number of attractive electrostatic interactions occurring between amino groups of BSA and carboxylic groups of pectin. - Pectin hydrogel microparticles of complex shapes were successfully produced by combining on-chip the phenomenon of gelation and water diffusion induced self-assembly, using dimethyl carbonate as continuous phase, or by deformation of the pre-gelled droplets off-chip at a fluid­fluid interface. Sphere, oblate ellipsoid, torus or mushroom-type morphologies were thus obtained. Moreover, it was established that after crossing the interface during their collect, mushroom-type microparticles did not migrate in the calcium or DMC phase but stayed at the liquid­liquid interface. These new and original hydrogel microparticles will open up opportunities for studying relationships between combined enzymatic hydrolysis and active release for Janus particles and relationships between shape and swelling behaviour for anisotropic pectin microparticles.

Enzymatic hydrolysis studies of arabinogalactan-protein structure from Acacia gum: the self-similarity hypothesis of assembly from a common building block.

Arabinogalactan (AG) and arabinogalactan-protein (AGP) fractions were treated enzymatically using several proteases in acidic (pH 4) and alkaline (pH 7) conditions in order to go deeper insight into the structure and conformations of the two main fractions of Acacia senegal gum. Endoproteinase Glu-C, pepsin and phosphatase acid were thus used in acidic conditions while subtilisin A, pronase, trypsin, papain and proteinase K were used in alkaline conditions to cleave protein moieties of the two fractions. Structures of AG and AGP were probed using HPSEC-MALLS, small angle neutron scattering and far-UV circular dichroism. Enzymes did not affect AG fraction structure whatever the pH conditions used, highlighting the inaccessibility of the peptide backbone and the remarkable stability of this fraction in acidic and alkaline conditions. This result was in agreement with the thin oblate ellipsoid model we previously identified for the AG fraction where the 43 amino-acid residues peptide sequence was supposed, based on spectroscopic methods, to be totally buried. Contrary to AG fraction, AGP protein component was therefore cleaved using enzymes in alkaline conditions, the absence of enzymatic efficiency in acidic conditions being probably ascribed to long range electrostatic repulsions occurring between negatively charged AGP and enzymes at pH 4. The decrease of AGP molecular weight after hydrolysis in alkaline conditions went from 1.79 × 10(6) g mol(-1) for control AGP to as low as 1.68 × 10(5) g mol(-1) for papain-treated AGP. The overall structure of the enzyme-treated AGPs was found to be surprisingly quite similar whatever the enzyme used and close, with however some subtle differences, to AG unit. A tri-axial ellipsoid conformation was found in enzyme-treated AGPs and the two main preferential distances identified in the pair distance distribution function would claim in favor of rod-like or elongated particles or alternatively would indicate the presence of two particles differing in dimensions. The secondary structures content of control and enzyme-treated AGPs were similar, highlighting both the high rigidity of the protein backbone and the overall symmetry of AGP. This conclusion was reinforced by the more compact structures found when AGP was intact compare to the more elongated structures found when AGP was enzymatically cleaved. Finally, the structural similarities found in enzyme-treated AGP together with the theoretical calculations to analytically probe the type of branching would suggest that AGP would be made of a self-similar assembly of two types of building blocks, the second being a five-fold repetition of the first one, for which palindromic amino acid sequence would ensure a self-ordering of carbohydrate moieties along the polypeptide chains. The cleavage would therefore lead to hydrolysed building blocks with similar secondary structures and conformations whatever the enzyme used.

Bedside tested ocular motor disorders in multiple sclerosis patients.

Background/Aims. Ocular motor disorders (OMDs) are a common feature of multiple sclerosis (MS). In clinical practice, if not reported by patients, OMDs are often underdiagnosed and their prevalence is underestimated. Methods. We studied 163 patients (125 women, 76.7%, 38 men, 23.3%; median age 45.0 years; median disease duration 10 years; median EDSS 3.5) with definite MS (n = 150, 92%) or clinically isolated syndrome (n = 13, 8%) who underwent a thorough clinical examination of eye movements. Data on localization of previous relapses, MS subtype, and MRI findings were collected and analyzed. Results. Overall, 111/163 (68.1%) patients showed at least one abnormality of eye movement. Most frequent OMDs were impaired smooth pursuit (42.3%), saccadic dysmetria (41.7%), unilateral internuclear ophthalmoplegia (14.7%), slowing of saccades (14.7%), skew deviation (13.5%), and gaze evoked nystagmus (13.5%). Patients with OMDs had more severe disability (P = 0.0005) and showed more frequently infratentorial MRI lesions (P = 0.004). Localization of previous relapses was not associated with presence of OMDs. Conclusion. OMDs are frequent in patients with stable (no relapses) MS. A precise bedside examination of eye motility can disclose abnormalities that imply the presence of subclinical MS lesions and may have a substantial impact on definition of the diagnosis and on management of MS patients.