S100A9-Driven AmyloidNeuroinfammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer’s Disease

Pro-infammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer’s disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinfammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to Aβand contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidifcation and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without Aβ. S100A9 and Aβplaque pathology was signifcantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new fndings highlight the detrimental consequences of prolonged post-TBI neuroinfammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specifc mechanism leading to AD development

Learning from Conect4children: A Collaborative Approach towards Standardization of Disease-Specific Paediatric Research Data

The conect4children (c4c) initiative was established to facilitate the development of new drugs and other therapies for paediatric patients. It is widely recognized that there are not enough medicines tested in all relevant ages of the paediatric population. To overcome this, it is imperative that clinical data from different sources are interoperable and can be pooled for larger post-hoc studies. c4c has collaborated with the Clinical Data Interchange Standards Consortium (CDISC) to develop the cross-cutting data resources that build on existing CDISC standards, in an effort to standardize paediatric data. The natural next step was an extension to disease-specific data items. c4c brought together several existing initiatives and resources relevant to disease-specific data and to analyse their use for standardizing disease-specific data in clinical trials. Several case studies that combined disease-specific data from multiple trials have demonstrated the need for disease-specific data standardization. We identified three relevant initiatives. These include European Reference Networks, European Joint Programme on Rare Diseases, and Pistoia Alliance. Other resources reviewed were: National Cancer Institute Enterprise Vocabulary Services, CDISC standards, pharmaceutical company-specific data dictionaries, Human Phenotype Ontology, Phenopackets, Unified Registry for Inherited Metabolic Disorders, Orphacodes, Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) and Observational Medical Outcomes Partnership. The collaborative partners associated with these resources were also reviewed briefly. A plan of action focussed on collaboration was generated for standardizing disease-specific paediatric clinical trial data. A paediatric data standards multistakeholder and multi-project user group was established to guide the remaining actions– FAIRification of metadata, a Phenopackets pilot with RDCA-DAP, applying Orphacodes to case report forms of clinical trials, introducing CDISC standards into European Reference Networks, testing of the CDISC Pediatric User Guide using data from the mentioned resources and organization of further workshops and educational materials

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957

European survey evaluating the use of azithromycin in neonates

Background: The role of Ureaplasma Urealyticum (UU) colonisation of the lungs remains controversial in the occurrence of bronchopulmonarydysplasia (BPD) of prematurity. The present European survey was conducted between April and July 2012, as part of the FP7-TINN2-project (Treat Infections in Neonates 2, www.tinn2-project.org). Aims and methods: It aimed to evaluate the position of neonatologists regarding the role of UU as a risk factor for BPD, use of azithromycin (AZY) for the prevention of BPD and factors that influence this practice in European neonatal intensive care units (NICUs). It was conducted using an online questionnaire of 64 questions. Results: 167 questionnaires from twenty-eight European countries were analyzed. All responders confirmed that the two major risk factors for BPD were prematurity ≤28weeks and high oxygen requirements. Various macrolides are used in Europe to treat or prevent Ureaplasma colonisation. Among them, AZY has antibacterial, anti-inflammatory and immuno-modulating properties, is employed throughout Europe (27% NICUs in 12countries), usually administered at a starting dose of 10mg/kg (60% of NICUs), followed by a maintenance dose of 5mg/kg/day (43% of NICUs). For 10 days. 78% of the NICUs were interested in the TINN2-project to evaluate the efficacy and safety of AZY versus placebo in reducing the risk of BPD in premature babies. For most neonatologists, newborns between 23 and 28weeks gestational age would be the best group of premature babies to be included in the trial

Gd-nanoparticles functionalization with specific peptides for ß-amyloid plaques targeting.

AmylDi

Collagen functionalisation by plasma coupled to chemical grafting

The promising trends in biotechnology and tissue engineering are based on the development of advanced materials with biomimetic features in order to recreate the native environment promoting the appropriate cell behavior for tissue regeneration. Cell therapy together with novel functionalized biomaterials represent a very promising approach in regenerative medicine for cartilage regeneration. Articular cartilage exhibits a well-ordered organization with an extracellular matrix arranged as a network of collagen fibers and proteoglycans that allow for cell adhesion, mechanical support, transduction of chemical and mechanical signals from the surrounding tissue to the cells. Electrospun materials are considered highly promising scaffolds for cartilage tissue engineering given their specific fibrous morphology that resembles the fibrous component of tissue extracellular matrix. Many synthetic and natural polymers have been successfully electrospun to obtain scaffolds. Among natural polymers, collagen is universally applied as biomaterial in regenerative medicine because of its unique biocompatibility, and structural property. Robust techniques for surface \u201cbiodecoration\u201d are currently required and the appropriate surface functionalization still remains a critical variable for the optimal performance of a wide range of biomaterials. Covalent bonding of bioactive molecules to material surface is a valid strategy in order to allow a sufficiently strong and specific affinity of biomolecules with the surface itself; in addition covalent bonding may permit site-directed immobilization and preservation of specific conformation and exposition to control biological responses. Plasma processes allow to tune surface properties of materials with negligible effect on their bulk. The need of improving cell/surface interaction has decisively introduced plasma techniques in the field of biomaterials; In addition, a wide range of compounds can be chosen as a monomer for plasma polymerization, providing a great diversity of possible surface modifications with different functional groups, including amine, anhydride, epoxide, carboxylic acid, cyano, halide, hydroxyl, furfuryl, and perfluoroalkyl