Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Gold nanoparticles functionalized with Gd3+ chelates displaying fast water exchange, superb pH stability and inertness towards transmetalation with Zn2+ have been prepared and characterized as a new high relaxivity (29 mM-1s-1, 30 MHz, 25 ºC) Contrast Agent potentially safe for in vivo MRI applications. The Lipari-Szabo treatment for internal rotation was used to evaluate the effect of linker flexibility on the relaxivity of the gold nanoparticles. The relaxivity is limited by chelate flexibility. The effect of fast water exchange on the relaxivity of gold nanoparticles functionalized with Gd3+ chelates is also addressed in this communication.Fundação para a Ciência e TecnologiaProjecto PTDC/QUI/70063/2006PhD grant SFRH/BD/63994/2008 to Miguel FerreiraRede Nacional de RMN REDE/1517/RMN/2005 for the acquisition of the Varian VNMRS 600 NMR spectrometer in Coimbra and the Bruker Avance-3 400 Plus in BragaB. Mousavi and L. Helm acknowledge financial support by the Swiss National Science Foundation.COST D38 Actio

New dextrin nanomagnetogels: production, characterization and in vivo performance as dual modality imaging bioprobe

Dual modality contrast agents, such as radiolabelle d magnetic nanoparticles, are promising candidates for a number of diagnostic applications, since they combine two complementing imaging modalities, namely photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). The benefit of such combin ation lies on the ability to interpret more accurately abnormalities in vivo , by integrating the high sensitivity of SPECT with the superb spatial resolution and anatomical information provi ded by MRI [1]. Superparamagnetic iron oxide nanoparticles (SPION) have been extensively s tudied as MRI contrast agents [2]. SPIONs need to be coated in order to allow formulation in aqueous solutions and to increase in vivo stability [3]. Dextrin nanomagnetogels consists on superparamagnet ic iron oxide nanoparticles ( γ -Fe 2 O 3 ) stabilized within hydrophobized-dextrin nanogel (sc heme 1). The nanomagnetogel formulation, with about 4 mM of iron and a diameter of 100 nm, p resents relevant features such as superparamagnetic behaviour, high stability, narrow size distribution and potential for magnetic guidance to target areas by means of an external ma gnetic field [4]. The functionalization of the dextrin nanomagnetogel with a DOTA-monoamide ω -thiol metal chelator and radiolabelling with 111 In were used to ascertain its in vivo stability and behavior (blood clearance rate and o rgan distribution) after intravenous administration in m ice model. The surface modification of the nanomagnetogel with PEG 5,000 was accomplished in a n attempt to escape the phagocytic system. The unloaded radiolabeled dextrin nanogel ( around 30 nm) showed lower uptake in the liver, spleen and kidneys than the nanomagnetogel l oaded with SPIONs (around 110 nm). This difference in biodistribution profile can be ascrib ed to the differences in the particle size. Nanomagnetogel pegylation resulted in lower liver a nd spleen accumulation. The blood half-life obtained was approximately 4 hours for all formulat ions. A good correlation between the amount of polymer (quantified through radioactivity) and t he amount of iron (ICP measurement) in the spleen was observed, indicating that leakage of iro n from the nanomagnetogels after intravenous administration was negligible. The pilo t imaging study demonstrated good performance of dextrin nanomagnetogels as dual moda lity imaging (MRI and SPECT) bioprobes as expected by the high transverse relaxi vity (215-248 mM -1 s -1 ) obtained in vitro , higher than those of commercial available formulati ons (160-177 mM -1 s -1 ). The production of the nanomagnetogel is simple and easy to scale up, thus offering great technological potential

Dextrin-based nanomagnetogel: in vivo biodistribution and stability

The biodistribution profile of a new dextrin nanomagnetogel, which consists on -Fe2O3 superparamagnetic nanoparticles loaded within a polymeric matrix of modified dextrin, was studied in mice. The nanomagnetogel bear a monomodal size distribution profile (average diameter 110 nm) close to neutral surface charge and higher relaxivity (r2 = 215-248 mM-1s-1 and r2/r1 = 13-11) than those of commercial formulations (r2 = 160-177 mM-1s-1 and r2/r1 = 4-7). Also the observed blood half-life - approximately 4 hours - is superior to that of similar commercially available formulations, which remain few minutes in circulation. Pegylation resulted in 1.7 and 1.2-fold lower accumulation in the liver and spleen, respectively, within the first 24 h. Noteworthy, a good correlation was obtained between the amount of polymer (quantified by scintigraphy) in the spleen, 48 h after administration, and the amount of iron physically loaded through hydrophobic interactions (quantified by ICP) indicating the absence of iron leakage from the polymeric matrix. This study provides evidence on the in vivo stability of a self-assembled nanomagnetogel, a much relevant feature which is seldom reported in the literature.The authors thank the Project “strong>BioHealth - Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE-07-0124-FEDER-000027, co-funded by the Programa Operacional Regional do Norte (ON.2 O Novo Norte), QREN, FEDER. The authors thank the Magnisense Corporation for providing a MIAplex Reader and CFGCG the EU COST TD1004 Action “Theragnostics Imaging and Therapy”. The authors thank Professor Cidália Botelho for the iron analysis by Atomic Absorbance Spectroscopy at the Oporto University, Chemical Engineering Department. C. Gonçalves, J. P. Silva, J. A. Martins, and M. F. M. Ferreira acknowledge FCT Portugal, for postdoc grants SFRH/BPD/70524/2010 and SFRH/BPD/64958/2009, sabbatical grant SFRH/BSAB/ 1328/2013 and PhD grant SFRH/BD/63994/2009, respectively

CD20+ T cells in monoclonal B cell lymphocytosis and chronic lymphocytic leukemia: frequency, phenotype and association with disease progression

Introduction: In monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), the expansion of malignant B cells disrupts the normal homeostasis and interactions between B cells and T cells, leading to immune dysregulation. CD20+ T cells are a subpopulation of T cells that appear to be involved in autoimmune diseases and cancer. Methods: Here, we quantified and phenotypically characterized CD20+ T cells from MBL subjects and CLL patients using flow cytometry and correlated our findings with the B-cell receptor mutational status and other features of the disease. Results and discussion: CD20+ T cells were more represented within the CD8+T cell compartment and they showed a predominant memory Tc1 phenotype. CD20+ T cells were less represented in MBL and CLL patients vs healthy controls, particularly among those with unmutated IGVH gene. The expansion of malignant B cells was accompanied by phenotypic and functional changes in CD20+ T cells, including an increase in follicular helper CD4+ CD20+ T cells and CD20+ Tc1 cells, in addition to the expansion of the TCR Vb 5.1 in CD4+ CD20+T cells in CLL.info:eu-repo/semantics/publishedVersio

Stroke frequency, associated factors, and clinical features in primary systemic vasculitis: a multicentric observational study

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV. Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed. Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00–4.06): 102 (2.13% 95% CI 1.73–2.56) with stroke and 81 (1.68% 95% CI 1.33–2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet’s disease (9.5%, 95% CI 5.79–14.37), polyarteritis nodosa (6.2%, 95% CI 3.25–10.61), and Takayasu’s arteritis (6.0%, 95% CI 4.30–8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09–3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20–3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05–9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01–2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period. Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet’s. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence

Biochars in soils : towards the required level of scientific understanding

Key priorities in biochar research for future guidance of sustainable policy development have been identified by expert assessment within the COST Action TD1107. The current level of scientific understanding (LOSU) regarding the consequences of biochar application to soil were explored. Five broad thematic areas of biochar research were addressed: soil biodiversity and ecotoxicology, soil organic matter and greenhouse gas (GHG) emissions, soil physical properties, nutrient cycles and crop production, and soil remediation. The highest future research priorities regarding biochar's effects in soils were: functional redundancy within soil microbial communities, bioavailability of biochar's contaminants to soil biota, soil organic matter stability, GHG emissions, soil formation, soil hydrology, nutrient cycling due to microbial priming as well as altered rhizosphere ecology, and soil pH buffering capacity. Methodological and other constraints to achieve the required LOSU are discussed and options for efficient progress of biochar research and sustainable application to soil are presented.Peer reviewe

Insights on multiple myeloma treatment strategies

The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future

International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable

Histological inflammation in the endoscopically uninflamed mucosa is associated with worse outcomes in limited ulcerative colitis

Background: The Montreal classification categorizes patients with ulcerative colitis (UC) based on their macroscopic disease extent. Independent of endoscopic extent, biopsies through all colonic segments should be retrieved during index colonoscopy. However, the prognostic value of histological inflammation at diagnosis in the inflamed and uninflamed regions of the colon has never been assessed.Methods: This was a multicenter retrospective cohort study of newly diagnosed patients with treatment-naïve proctitis and left-sided UC. Biopsies from at least 2 colonic segments (endoscopically inflamed and uninflamed mucosa) were retrieved and reviewed by 2 pathologists. Histological features in the endoscopically inflamed and uninflamed mucosa were scored using the Nancy score. The primary outcomes were disease complications (proximal disease extension, need for hospitalization or colectomy) and higher therapeutic requirements (need for steroids or for therapy escalation).Results: Overall, 93 treatment-naïve patients were included, with a median follow-up of 44 months (range, 2-329). The prevalence of any histological inflammation above the endoscopic margin was 71%. Proximal disease extension was more frequent in patients with histological inflammation in the endoscopically uninflamed mucosa at diagnosis (21.5% vs 3.4%, P = 0.04). Histological involvement above the endoscopic margin was the only predictor associated with an earlier need for therapy escalation (adjusted hazard ratio, 3.69; 95% confidence interval, 1.05- 13.0); P = 0.04) and disease complications (adjusted hazard ratio, 4.79; 95% confidence interval, 1.10-20.9; P = 0.04).Conclusions: The presence of histological inflammation in the endoscopically uninflamed mucosa at the time of diagnosis was associated with worse outcomes in limited UC.peer-reviewe

Stroke frequency, associated factors, and clinical features in primary systemic vasculitis: A multicentric observational study

Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV. Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed. Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00–4.06): 102 (2.13% 95% CI 1.73–2.56) with stroke and 81 (1.68% 95% CI 1.33–2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet’s disease (9.5%, 95% CI 5.79–14.37), polyarteritis nodosa (6.2%, 95% CI 3.25–10.61), and Takayasu’s arteritis (6.0%, 95% CI 4.30–8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09–3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20–3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05–9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01–2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period. Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet’s. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence