2,503 research outputs found
Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction
Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the alpha(2A)/alpha(2C)-drenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. alpha(2A)/alpha(2C)-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease
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Tremor in Patients with Inflammatory Bowel Disease
The spectrum of neurological manifestations of Crohnâs disease (CD) and ulcerative colitis (UC) is diverse and not fully understood. In addition to peripheral neuropathy, mild autonomic impairment has been reported. These problems themselves could also result in secondary neurological consequences, such as the exacerbation of enhanced physiological tremor. Indeed, some patients in our cohort complained of tremor. Hence, we hypothesized that enhanced physiological tremor would be more severe in patients with inflammatory bowel disease (IBD) than controls
Three-Dimensional and Biomimetic Technology in Cardiac Injury After Myocardial Infarction: Effect of Acellular Devices on Ventricular Function and Cardiac Remodelling
Dilated cardiomyopathy (DMC) of ischemic or non-ischemic aetiology remains a lethal condition nowadays. Despite early percutaneous or medical revascularization after an acute myocardial infarct (AMI), many patients still develop DMC and severe heart failure due to cardiac remodelling. Possibility of regenerating myocardium already damaged or at least inducing a more positive cardiac remodelling with use of biodegradable scaffolds has been attempted in many experimental studies, which can be cellular or acellular. In the cellular scaffolds, the cells are incorporated in the structure prior to implantation of the same into the injured tissue. Acellular scaffolds, in turn, are composites that use one or more biomaterials present in the extracellular matrix (ECM), such as proteoglycans non-proteoglycan polysaccharide, proteins and glycoproteins to stimulate the chemotaxis of cellular/molecular complexes as growth factors to initiate specific regeneration. For the development of scaffold, the choice of biomaterials to be used must meet specific biological, chemical and architectural requirements like ECM of the tissue of interest. In acute myocardial infarction, treating the root of the problem by repairing injured tissue is more beneficial to the patient. Inducing more constructive forms of endogenous repair. Thus, patches of acellular scaffolds capable of mimicking the epicardium and ECM should be able to attenuate both cardiac remodelling and adverse cardiac dysfunction
Bilayer mucoadhesive buccal film for mucosal ulcers treatment: development, characterization, and single study case
The formation of mucosal ulcers is an end result of epithelial damage, and it occurs due to some specific causes, such as trauma, aphthous stomatitis, lichen planus and lichenoid reactions, cytotoxic effects of chemotherapy and radiation, and drug-induced hypersensitivity reactions and malignant settings. This study focused on films for target drug delivery with respect to the treatment of the diseases of the oral mucosa, specifically mucositis. The results of a single clinical study as a pre-experimental design was performed and followed up to the outcome until 30 days. The polymeric film was prepared in a mucoadhesive bilayer structure: the basal layer with lidocaine HCl had a faster release than the apical layer with benzydamine HCl and N-acetyl-cysteine. Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and SEM characterized the physicalâchemical and morphological properties. The cell viability and cytotoxicity were evaluated in cell line MCF7. The transport mechanism of the solvent (swelling) and the drugs in the basal or apical layer (drug release) was explained with mathematical models. To evaluate the effect of movement inside the mouth, the folding endurance was determined. The mucoadhesive bilayer film is biologically safe and stimulates cellular proliferation. A single study in vivo demonstrated the therapeutic effect of the mucoadhesive bilayer film in buccal mucositis.The authors express their gratitude to financial support from CAPES/PROSUP-Brazil;
Sao Paulo Research Foundation 2011/21219-5; Sao Paulo Research Foundation. 2018/13432-0; Sao Paulo Research Foundation. 2018/11350-6; National Council for Scientific and Technological Development (CNPq) 425271/2016-1.info:eu-repo/semantics/publishedVersio
Phase I Safety and Immunogenicity Evaluation of MVA-CMDR, a Multigenic, Recombinant Modified Vaccinia Ankara-HIV-1 Vaccine Candidate
We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand.MVA-CMDR or placebo was administered intra-muscularly (IM; 10(7) or 10(8) pfu) or intradermally (ID; 10(6) or 10(7) pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10â¶2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFNÎł Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a (51)Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFNÎł Elispot of 78 SFC/10(6) PBMC at 10(8) pfu IM), but high in response rate (70% (51)Cr-release positive; 90% Elispot positive; 100% ICS positive, at 10(8) pfu IM); (ii) predominantly HIV Env-specific CD4(+) T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 10(8) pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 10(8) pfu IM).MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses.ClinicalTrials.gov NCT00376090
13-Series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis
This work was supported by funding from the European Research Council under the European Unionâs Horizon 2020 research and innovation program (Grant 677542), a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant 107613/Z/15/Z), and the Barts Charity (Grant MGU0343). This work was also funded, in part, by Medical Research Council Advance Course Masters (Grant MR/J015741/1). The authors declare no conflicts of interest
Developing a sustainability science approach for water systems
We convened a workshop to enable scientists who study water systems from both social science and physical science perspectives to develop a shared language. This shared language is necessary to bridge a divide between these disciplinesâ different conceptual frameworks. As a result of this workshop, we argue that we should view socio-hydrological systems as structurally co-constituted of social, engineered, and natural elements and study the âcharacteristic management challengesâ that emerge from this structure and reoccur across time, space, and socioeconomic contexts. This approach is in contrast to theories that view these systems as separately conceptualized natural and social domains connected by bi-directional feedbacks, as is prevalent in much of the water systems research arising from the physical sciences. A focus on emergent characteristic management challenges encourages us to go beyond searching for evidence of feedbacks and instead ask questions such as: What types of innovations have successfully been used to address these challenges? What structural components of the system affect its resilience to hydrological events and through what mechanisms? Are there differences between successful and unsuccessful strategies to solve one of the characteristic management challenges? If so, how are these differences affected by institutional structure and ecological and economic contexts? To answer these questions, social processes must now take center stage in the study and practice of water management. We also argue that water systems are an important class of coupled systems with relevance for sustainability science because they are particularly amenable to the kinds of systematic comparisons that allow knowledge to accumulate. Indeed, the characteristic management challenges we identify are few in number and recur over most of human history and in most geographical locations. This recurrence should allow us to accumulate knowledge to answer the above questions by studying the long historical record of institutional innovations to manage water systems
The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by zika virus
The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak took place in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water sup-plies of NE compared to other regions of Brazil. Experimentally, we described that STX dou-bled the quantity of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.Fil: Pedrosa, Carolina da S. G.. DâOr Institute for Research and Education; BrasilFil: Souza, Leticia R. Q.. DâOr Institute for Research and Education; BrasilFil: Gomes, Tiago A.. Universidade Federal do Rio de Janeiro; Brasil. Instituto Oswaldo Cruz; BrasilFil: de Lima, Caroline V. F.. DâOr Institute for Research and Education; BrasilFil: Ledur, Pitia F.. DâOr Institute for Research and Education; BrasilFil: Karmirian, Karina. DâOr Institute for Research and Education; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Barbeito AndrĂ©s, Jimena. Universidade Federal do Rio de Janeiro; Brasil. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. NĂ©stor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Costa, Marcelo do N.. Universidade Federal do Rio de Janeiro; BrasilFil: Higa, Luiza M.. Universidade Federal do Rio de Janeiro; BrasilFil: Rossi, Ătila D.. Universidade Federal do Rio de Janeiro; BrasilFil: Bellio, Maria. Universidade Federal do Rio de Janeiro; BrasilFil: Tanuri, Amilcar. Universidade Federal do Rio de Janeiro; BrasilFil: Prata Barbosa, Arnaldo. DâOr Institute for Research and Education; BrasilFil: Tovar Moll, Fernanda. DâOr Institute for Research and Education; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Garcez, Patricia P.. Universidade Federal do Rio de Janeiro; BrasilFil: Lara, Flavio A.. Instituto Oswaldo Cruz; BrasilFil: Molica, Renato J. R.. Universidad Federal Rural Pernambuco; BrasilFil: Rehen, Stevens K.. DâOr Institute for Research and Education; Brasil. Universidade Federal do Rio de Janeiro; Brasi
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