Detection of amyloid beta aggregates in the brain of BALB/c mice after Chlamydia pneumoniae infection

Neuroinflammation, initiated by cerebral infection, is increasingly postulated as an aetiological factor in neurodegenerative diseases such as Alzheimer’s disease (AD). We investigated whether Chlamydia pneumoniae (Cpn) infection results in extracellular aggregation of amyloid beta (Aβ) in BALB/c mice. At 1 week post intranasal infection (p.i.), Cpn DNA was detected predominantly in the olfactory bulbs by PCR, whereas brains at 1 and 3 months p.i. were Cpn negative. At 1 and 3 months p.i., extracellular Aβ immunoreactivity was detected in the brain of Cpn-infected mice but also in the brain of mock-infected mice and mice that were neither Cpn infected nor mock infected. However, these extracellular Aβ aggregates showed morphological differences compared to extracellular Aβ aggregates detected in the brain of transgenic APP751SL/PS1M146L mice. These data do not unequivocally support the hypothesis that Cpn infection induces the formation of AD-like Aβ plaques in the brain of BALB/c mice, as suggested before. However, future studies are required to resolve these differences and to investigate whether Cpn is indeed an etiological factor in AD pathogenesis

Polygenic burden in focal and generalized epilepsies

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japaneseancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64 710-15; Cleveland: P = 2.85 710-4; Finnish-ancestry Epi25: P = 1.80 710-4) or population controls (Epi25: P = 2.35 710-70; Cleveland: P = 1.43 710-7; Finnish-ancestry Epi25: P = 3.11 710-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 710-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74 710-19; Cleveland: P = 1.69 710-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60 710-15; Cleveland: P = 1.39 710-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

The Synthesis, Self-Assembly and Self-Organisation of Polysilane Block Copolymers

Block copolymers containing polysilane blocks are unique in that the polysilane components possess electro-active properties and are readily photodegradable. This review will discuss and assess the two major approaches to the synthesis of polysilane block copolymers via pre-formed polymer chain coupling and living polymerisation techniques. The self-organisation of polysilane block copolymers and the morphologies adopted in thin films are reviewed. Amphiphilic polysilane-containing block copolymers self-assemble in solvents selective for one block and a number of examples are highlighted. The versatility of these materials is highlighted by recent significant applications including the preparation of hollow crosslinked micellar aggregates in aqueous solutions and in patterned thin film generation subsequently employed as templates for the growth of cell cultures and CaCO (3.

Multi-location transshipment problem with capacitated production

We consider coordination among stocking locations through replenishment strategies that explicitly take into account lateral transshipments, i.e.; transfer of a product among locations at the same echelon level. Our basic contribution is the incorporationYaşar University, Department of Industrial Engineering, Bornova, Izmir 35100, Turkey; INSEAD, Technology and Operations Management Area, Boulevard de Constance, 77305 Fontainebleau, France; Technion, Faculty of Industrial Engineering and Management, Haif

SAT0273 PROGNOSTIC FACTORS FOR POOR OUTCOME IN BEHÇET’S SYNDROME WITH NEUROLOGICAL INVOLVEMENT: RESULTS FROM A CLINICAL LONG-TERM FOLLOW-UP OF A SINGLE CENTRE

Background:Behçet’s Syndrome (BS) is a vasculitis of unknown cause. Neurological disease is a type of its serious involvement and causes morbidity and mortality.Objectives:In this study, we aimed to describe the clinical characteristics of neuro-Behçet Syndrome (NBS) and to define prognostic factors that were associated with poor outcome.Methods:Among 2033 patients with BS, we performed a retrospective analysis of 94 patients (52.1% male; mean age 36.1 (11.9) years), who fulfilled the ISG-1990 for BS. We divided patients into two subgroups, either parenchymal (p-NBS) or non-parenchymal (np-NBS). Clinical, laboratory, and imaging characteristics of the patients were defined. We described the poor outcome as a modified Rankin score (mRS) &gt;= 3 at last follow-up and/or death, and assessed the predictor factors associated such kind of outcome.Results:In total, 52 (55.3%) patients presented with p-NBS, of whom 15 (28.8%) had progressive course, and 42 (44.7%) presented with np-NBS (Table.1). Ocular involvement was more common in p-NBS than np-NBS (59.6% vs. 39.1% respectively, p=0.04), whereas vascular involvement excluding sinus vein thrombosis was more frequent in patients with np-NBS (15.4% vs. 50.0%, respectively, p=0.001). Headache and papilledema were frequently observed in np-NBS (p&lt;0.001), whereas paresis, sensory symptoms, pyramidal and cerebellar signs were significantly common in p-NB (&lt;0.001). Twenty-five patients (26.6%) experienced at least one relapse. After a median of 54 (IQR 79.4) months, 11 patients (11.7%) had disabling sequela and a total of 5 (5.3%) deaths occurred. Characteristics of patients with and without poor outcome are presented in table 2. In multivariable logistic regression analysis, factors associated with poor outcome were initial mRS (OR 24.2 (95% CI 3.16 – 108.67)) and age &gt;= 40 at NBS diagnosis (OR 4.59 (95% CI 1.02 – 20.69)), meanwhile, headache at presentation was associated with a lower risk for poor outcome. (OR 0.22 (95% CI 0.05 – 0.91)).Conclusion:Neurologic involvement is a detrimental manifestation of BS and causes disability, even death. Patients who have an initial disabling presentation in advanced age are more likely to have poor prognosis. Treatment intensification in this subpopulation might be considered.References:NoneDisclosure of Interests:None declared</jats:sec

Improved dynamic cutting force model in ball-end milling. Part 1: theoretical modelling and experimental calibration

An accurate cutting force model of ball-end milling is essential for precision prediction and compensation of tool deflection that dominantly determines the dimensional accuracy of the machined surface. This paper presents an improved theoretical dynamic cutting force model for ball-end milling. The three-dimensional instantaneous cutting forces acting on a single flute of a helical ball-end mill are integrated from the differential cutting force components on sliced elements of the flute along the cutter-axis direction. The size effect of undeformed chip thickness and the influence of the effective rake angle are considered in the formulation of the differential cutting forces based on the theory of oblique cutting. A set of half immersion slot milling tests is performed with a one-tooth solid carbide helical ball-end mill for the calibration of the cutting force coefficients. The recorded dynamic cutting forces are averaged to fit the theoretical model and yield the cutting force coefficients. The measured and simulated dynamic cutting forces are compared using the experimental calibrated cutting force coefficients, and there is a reasonable agreement. A further experimental verification of the dynamic cutting force model will be presented in a follow-up paper