Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis.

BACKGROUND: Efficacy of statins has been extensively studied, with much less information reported on their unintended effects. Evidence from randomized controlled trials (RCTs) on unintended effects is often insufficient to support hypotheses generated from observational studies. We aimed to systematically assess unintended effects of statins from observational studies in general populations with comparison of the findings where possible with those derived from randomized trials. METHODS: Medline (1998 to January 2012, week 3) and Embase (1998 to 2012, week 6) were searched using the standard BMJ Cohort studies filter. The search was supplemented with reference lists of all identified studies and contact with experts in the field. We included prospective studies with a sample size larger than 1,000 participants, case control (of any size) and routine health service linkage studies of over at least one year duration. Studies in subgroups of patients or follow-up of patient case series were excluded, as well as hospital-based cohort studies. RESULTS: Ninety studies were identified, reporting on 48 different unintended effects. Statins were associated with lower risks of dementia and cognitive impairment, venous thrombo-embolism, fractures and pneumonia, but these findings were attenuated in analyses restricted to higher quality studies (respectively: OR 0.74 (95% CI 0.62 to 0.87); OR 0.92 (95% CI 0.81 to 1.03); OR 0.97 (95% CI 0.88 to 1.05); OR 0.92 (95% CI 0.83 to 1.02)); and marked heterogeneity of effects across studies remained. Statin use was not related to any increased risk of depression, common eye diseases, renal disorders or arthritis. There was evidence of an increased risk of myopathy, raised liver enzymes and diabetes (respectively: OR 2.63 (95% CI 1.50 to 4.61); OR 1.54 (95% CI 1.47 to 1.62); OR 1.31 (95% CI 0.99 to 1.73)). CONCLUSIONS: Our systematic review and meta-analyses indicate that high quality observational data can provide relevant evidence on unintended effects of statins to add to the evidence from RCTs. The absolute excess risk of the observed harmful unintended effects of statins is very small compared to the beneficial effects of statins on major cardiovascular events

Haemocompatibility of iron oxide nanoparticles synthesized for theranostic applications: a high-sensitivity microfluidic tool

The poor heating efficiency of the most reported magnetic nanoparticles (MNPs), allied to the lack of comprehensive biocompatibility and haemodynamic studies, hampers the spread of multifunctional nanoparticles as the next generation of therapeutic bio-agents in medicine. The present work reports the synthesis and characterization, with special focus on biological/toxicological compatibility, of superparamagnetic nanoparticles with diameter around 18 nm, suitable for theranostic applications (i.e. simultaneous diagnosis and therapy of cancer). Envisioning more insights into the complex nanoparticle-red blood cells (RBCs) membrane interaction, the deformability of the human RBCs in contact with magnetic nanoparticles (MNPs) was assessed for the first time with a microfluidic extensional approach, and used as an indicator of haematological disorders in comparison with a conventional haematological test, i.e. the haemolysis analysis. Microfluidic results highlight the potential of this microfluidic tool over traditional haemolysis analysis, by detecting small increments in the rigidity of the blood cells, when traditional haemotoxicology analysis showed no significant alteration (haemolysis rates lower than 2 %). The detected rigidity has been predicted to be due to the wrapping of small MNPs by the bilayer membrane of the RBCs, which is directly related to MNPs size, shape and composition. The proposed microfluidic tool adds a new dimension into the field of nanomedicine, allowing to be applied as a highsensitivity technique capable of bringing a better understanding of the biological impact of nanoparticles developed for clinical applications.This work was financially supported by: Project POCI-01-0145-FEDER-006984 – Associate Laboratory J Nanopart Res (2016) 18:194 Page 15 of 17 194 123 LSRE-LCM funded by FEDER funds through COMPETE2020 - Programa Operacional Competitividade e Internacionalizac¸a˜o (POCI) – and by national funds through FCT - Fundac¸a˜o para a Cieˆncia e a Tecnologia. R.O.R. acknowledges the Ph.D. scholarship SFRH/BD/97658/2013 Granted by FCT. A.M.T.S acknowledges the FCT Investigator 2013 Programme (IF/01501/ 2013), with financing from the European Social Fund and the Human Potential Operational Programme. M.B. would like to thank ERDF (European Regional Development Fund) under grant PO Norte CCDR-N/ON.2 Programme. J.G. also thanks the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 600375.info:eu-repo/semantics/publishedVersio

Ornithine uptake and the modulation of drug sensitivity in <i>Trypanosoma brucei</i>

Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO “essential medicine” eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these amino acid transporters (AATs). In a heterologous expression system, TbAAT10-1 is selective for ornithine, whereas TbAAT2-4 transports both ornithine and histidine. These AATs are also necessary to maintain intracellular ornithine and polyamine levels in T. brucei, thereby decreasing sensitivity to eflornithine and increasing sensitivity to suramin. Consistent with competition for histidine, high extracellular concentrations of this amino acid phenocopied a TbAAT2-4 genetic defect. Our findings established TbAAT10-1 and TbAAT2-4 as the parasite ornithine transporters, one of which can be modulated by histidine, but both of which affect sensitivity to important anti-HAT drugs.—Macedo, J. P., Currier, R. B., Wirdnam, C., Horn, D., Alsford, S., Rentsch, D. Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei

Disruption of the inositol phosphorylceramide synthase gene affects Trypanosoma cruzi differentiation and infection capacity

Sphingolipids (SLs) are essential components of all eukaryotic cellular membranes. In fungi, plants and many protozoa, the primary SL is inositol-phosphorylceramide (IPC). Trypanosoma cruzi is a protozoan parasite that causes Chagas disease (CD), a chronic illness for which no vaccines or effective treatments are available. IPC synthase (IPCS) has been considered an ideal target enzyme for drug development because phosphoinositol-containing SL is absent in mammalian cells and the enzyme activity has been described in all parasite forms of T. cruzi. Furthermore, IPCS is an integral membrane protein conserved amongst other kinetoplastids, including Leishmania major, for which specific inhibitors have been identified. Using a CRISPR-Cas9 protocol, we generated T. cruzi knockout (KO) mutants in which both alleles of the IPCS gene were disrupted. We demonstrated that the lack of IPCS activity does not affect epimastigote proliferation or its susceptibility to compounds that have been identified as inhibitors of the L. major IPCS. However, disruption of the T. cruzi IPCS gene negatively affected epimastigote differentiation into metacyclic trypomastigotes as well as proliferation of intracellular amastigotes and differentiation of amastigotes into tissue culture-derived trypomastigotes. In accordance with previous studies suggesting that IPC is a membrane component essential for parasite survival in the mammalian host, we showed that T. cruzi IPCS null mutants are unable to establish an infection in vivo, even in immune deficient mice

The ocean sampling day consortium

Ocean Sampling Day was initiated by the EU-funded Micro B3 (Marine Microbial Biodiversity, Bioinformatics, Biotechnology) project to obtain a snapshot of the marine microbial biodiversity and function of the world’s oceans. It is a simultaneous global mega-sequencing campaign aiming to generate the largest standardized microbial data set in a single day. This will be achievable only through the coordinated efforts of an Ocean Sampling Day Consortium, supportive partnerships and networks between sites. This commentary outlines the establishment, function and aims of the Consortium and describes our vision for a sustainable study of marine microbial communities and their embedded functional traits

Conjugating his-tagged proteins to magnetic nanoparticles: tips and challenges

Resumen del póster presentado al 5th Multistep Enzyme Catalyzed Processes Congress (MECPC), celebrado online del 13 al 16 de septiembre de 2021.The histidine tag (His-tag) is one of the most used affinity-tag for protein purification due to its small size and versatility. Agarose and sepharose beads containing nitriloacetic acid (NTA) transition metal derivatives are widely used for the purification of His-tagged proteins, thanks to their high affinity to the His-tag genetically fused to the protein of interest [1]. The same chemistry can be used to conjugate enzymes to magnetic nanoparticles (MNPs) with the aim of tuning their activity by magnetic heating [2, 3]. Within the frame of the FET-OPEN project HOTZYMES (https://www.hotzymes.eu), different MNPs have been synthetized and coated with polyacrylic acid and dimercaptosuccinic acid, and then were further functionalized with NTA-Cu2+ as His-tag chelating agent. Different proteins were expressed as His-tag variants and immobilized on the MNPs, including monomeric (superfolded GFP), dimeric (C. violaceum transaminase, CvTA; C. uda cellobiose phosphorylase, CuCbP), and tetrameric (B. stearothermophilus alcohol dehydrogenase, ADH) variants. While for the monomeric protein selected as model no difficulties in the bioconjugation processes were observed, when using dimeric or tetrameric enzymes the aggregation of the MNPs occurs very easily due to crosslinking between the nanoparticles. This colloidal destabilization of the MNPs is favored due to its high surface area and the presence of several tags per enzyme molecule. To avoid this situation, different strategies have been developed: saturation of the binding site of the nanoparticles, presence of a small percentage of imidazole in reaction, changes in the incubation conditions (pH, ionic strength, …). First positive results confirm that by playing with different factors it is possible to conjugate different His-tagged enzymes to very different MNPs in terms of size, shape, surface area, and colloidal stability. Actually, it is possible to avoid protein and MNPs aggregation while obtaining good activity yields for the conjugated enzymes and maintaining the magnetic heating capacity of the MNPs.The research for this work has received funding from the European Union (EU) project HOTZYMES (grant agreement n° 829162) under EU’s Horizon 2020 Programme Research and Innovation actions H2020-FETOPEN-2018-2019-2020-01. Authors also thank Spanish MINECO project BIO2017-84246-C2-1-R, DGA and Fondos Feder (Bionanosurf E15_17R).Peer reviewe

The relationships between biotic uniqueness and abiotic uniqueness are context dependent across drainage basins worldwide

[EN] Context: Global change, including land-use change and habitat degradation, has led to a decline in biodiversity, more so in freshwater than in terrestrial ecosystems. However, the research on freshwaters lags behind terrestrial and marine studies, highlighting the need for innovative approaches to comprehend freshwater biodiversity. Objectives: We investigated patterns in the relationships between biotic uniqueness and abiotic environmental uniqueness in drainage basins worldwide. Methods: We compiled high-quality data on aquatic insects (mayflies, stoneflies, and caddisflies at genus-level) from 42 drainage basins spanning four continents. Within each basin we calculated biotic uniqueness (local contribution to beta diversity, LCBD) of aquatic insect assemblages, and four types of abiotic uniqueness (local contribution to environmental heterogeneity, LCEH), categorized into upstream land cover, chemical soil properties, stream site landscape position, and climate. A mixed-effects meta-regression was performed across basins to examine variations in the strength of the LCBD-LCEH relationship in terms of latitude, human footprint, and major continental regions (the Americas versus Eurasia). Results: On average, relationships between LCBD and LCEH were weak. However, the strength and direction of the relationship varied among the drainage basins. Latitude, human footprint index, or continental location did not explain significant variation in the strength of the LCBD-LCEH relationship. Conclusions: We detected strong context dependence in the LCBD-LCEH relationship across the drainage basins. Varying environmental conditions and gradient lengths across drainage basins, land-use change, historical contingencies, and stochastic factors may explain these findings. This context dependence underscores the need for basin-specific management practices to protect the biodiversity of riverine systemsSIOpen Access funding provided by University of Oulu (including Oulu University Hospital). The work for this article was supported by the Academy of Finland’s grant to JHeino for the project GloBioTrends (Grant No. 331957). JGG was funded by the European Union Next Generation EU/PRTR (Grant No. AG325). Work by LMB has been continuously supported by the National Council for Scientifc & Technological Development (CNPq) and Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) (grants 308974/2020–4 and 465610/2014–5). PB and ZC were fnancially supported by the National Research Development and Innovation Ofce (NKFIH FK 135 136), and PB was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences BO-00106–21. LB thanks the National Council for Scientifc and Technological Development (CNPq) for the Scientifc Initiation Fellowship for JVASS and the productivity fellowship in research to LSB (process nº. 305929/2022–4). MC was awarded National Council for Scientifc & Technological Development (CNPq) research productivity grant 304060/2020–8 and received grants (PPM 00104–18, APQ-00261–22) from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais. SD and JRGM acknowledge funding by the Leibniz Competition (Grant No. J45/2018) and the German Federal Ministry of Education and Research (BMBF grant agreement number no. 033W034A). DRM was supported by National Council for Scientifc & Technological Development (CNPq) (Grant No. PQ-309763–2020-7). DMPC received a postdoctoral scholarship from P&D Aneel- Cemig GT-611. PH was partially funded by the eLTER PLUS project (Grant Agreement No. 871128). LJ is grateful to 33 Forest, CIKEL Ltd. and Instituto de Floresta Tropical (IFT), Biodiversity Research Consortium Brazil-Norway (BRC), and Norsk Hydro for the fnancial and logistical support for sampling. Brazilian National Council for Scientifc and Technological Development (CNPq) is acknowledged for fnancing the projects and for granting a research productivity fellowship to LJ (304710/2019–9). APJF was supported by Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq, Brazil, process no. 449315/2014–2 and 481015/2011–6). RL also received a research productivity fellowship from CNPq (grant # 312531/2021–4). MSL received a postdoctoral scholarship from ANEEL/CEMIG (Project GT-599). Part of feld sampling and aquatic insects processing were funded by Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq; 403758/2021–1); Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM; Programa Biodiversa) and INCT ADAPTA II – (CNPq: 465540/2014–7; FAPEAM: 062.1187/2017). NH (308970/2019–5) received productivity fellowships from CNPq. RTM received a fellowship from Biodiversa/FAPEAM (01.02.016301.03271/2021–93). KLM acknowledges fnancial support from the Swiss Federal Ofce for the Environment to undertake data collection. Funding for the Segura River basin project was provided by the Seneca Foundation and the European Fund of Regional Development (PLP10/FS/97). FOR was supported by CNPq research grant. TS was partially funded by grant 13/50424–1 and 21/00619–7 from the São Paulo Research Foundation (FAPESP), and by grant 309496/2021–7 from the Conselho Nacional de Desenvolvimento Científco e Tecnológico (CNPq). FVN was supported by grant #2021/13299–0, São Paulo Research Foundation (FAPESP). ALA acknowledges Brazilian National Council for Scientifc and Technological Development (CNPq, Brazil) for granting a postdoctoral scholarship to her (process number: 167873/2022–9