14,470 research outputs found

    Intoxica√ß√Ķes por ferro e alum√≠nio: abordagem terap√™utica

    No full text
    Trabalho Final de Mestrado Integrado, Ci√™ncias Farmac√™uticas, 2021, Universidade de Lisboa, Faculdade de Farm√°cia.O ferro √© um elemento essencial para a maioria dos organismos, j√° que participa em diversos processos metab√≥licos. Contudo, a desregula√ß√£o da sua homeostasia est√° associada a diversas condi√ß√Ķes patol√≥gicas. A sobrecarga de ferro pode ter origem gen√©tica, quando est√£o associados a defeitos heredit√°rios na regula√ß√£o do metabolismo do ferro, ou adquirida, quando resulta de anemias associadas a sobrecarga de ferro, como a talass√©mia, administra√ß√£o parent√©rica de ferro ou doen√ßas hep√°ticas. A hemocromatose heredit√°ria √© uma das condi√ß√Ķes gen√©ticas mais comuns, sendo caracterizada por uma excessiva absor√ß√£o de ferro, devido a uma defici√™ncia na principal hormona reguladora do metabolismo do ferro, a hepcidina. O alum√≠nio √© um dos metais mais abundantes da Terra, embora n√£o apresente quaisquer fun√ß√Ķes fisiol√≥gicas no organismo humano, sendo considerado um perigo sem qualquer benef√≠cio. A baixa absor√ß√£o e eficiente excre√ß√£o renal diminuem o risco de toxicidade. No entanto, a fun√ß√£o renal comprometida e a hemodi√°lise tornam estes doentes particularmente suscet√≠veis ao desenvolvimento de intoxica√ß√£o por este metal. A flebotomia √© uma das principais formas de tratamento da hemocromatose heredit√°ria, uma vez que √© altamente eficaz e relativamente livre de efeitos adversos. Contudo, o seu uso √© limitado, principalmente em doentes com anemia ou doen√ßas card√≠acas graves. Para estes doentes a eritrocitaferese pode ser uma op√ß√£o vi√°vel, estando associada a uma maior efic√°cia na remo√ß√£o do ferro em excesso e a uma diminui√ß√£o dos eventos hemodin√Ęmicos associados √† flebotomia. O objetivo da terap√™utica por quela√ß√£o √© a remo√ß√£o de i√Ķes met√°licos t√≥xicos atrav√©s da forma√ß√£o de um complexo inerte e hidrossol√ļvel, pass√≠vel de ser excretado. A desferroxamina, a deferriprona e o deferasirox s√£o atualmente os agentes utilizados na pr√°tica cl√≠nica no tratamento da sobrecarga de ferro. As semelhan√ßas qu√≠micas entre o ferro e o alum√≠nio justificam a utiliza√ß√£o da desferroxamina no tratamento das intoxica√ß√Ķes por alum√≠nio. Os problemas associados √† utiliza√ß√£o destes agentes quelantes juntamente com a elevada preval√™ncia e as manifesta√ß√Ķes cl√≠nicas associadas √†s intoxica√ß√Ķes por ferro e alum√≠nio justificam a constante procura de novos agentes quelantes e de novas abordagens terap√™uticas cada vez mais eficazes e seguras, por forma a melhor a qualidade de vida destes doentes.Iron is an essential element for most organisms, as it participates in various metabolic processes. However, homeostasis dysregulation is associated with several pathological conditions. Iron overload can have genetic, when associated with hereditary defects in the regulation of iron metabolism, or acquired origin, when it results from anemia associated with iron overload, such as thalassemia, parenteral administration of iron or liver diseases. Hereditary hemochromatosis is one of the most common genetic conditions, characterized by excessive iron absorption, due to a deficiency in the principal hormone that regulates iron metabolism, hepcidin. Aluminum is one of the most abundant metals on Earth, although it doesn‚Äôt have any physiological functions in the human body, being considerated a potential danger without any benefit. Low absorption and efficient renal excretion decrease the risk of toxicity. However, compromised renal function and hemodialysis make these patients particularly susceptible to the development of poisoning by this metal. Phlebotomy is one of the main forms of treatment in patients with hereditary hemochromatosis, as it is highly effective and relatively free of adverse effects. However, its use is limited, mainly in patients with anemia or severe hearth disease. In the patients, erythrocytapheresis may be the viable option, which is associated with a greater efficacy in removing excess iron and a reduction in hemodynamic events associated with phlebotomy. The goal of chelation therapy is the removal of toxic metal ions through the formation of an inert and water-soluble complex that can be excreted. Desferrioxamine, deferiprone and deferasirox are currenty the agents used in clinical practice for treatment of iron overload. The chemical similarities between iron and aluminum justify the use of desferrioxamine for treatment of aluminum overload. The problems associated with the use of these chelating agents together with the high prevalence and clinical manifestations associated with iron and aluminum overload justify the constant search for new chelating agents and new therapeutic approaches that are increasingly effective and safe, in order to improve quality of life of these patients

    Associations of serum concentrations of metal nutrients with postpartum anemia among pregnant Chinese women: A large retrospective cohort study

    Get PDF
    Background and AimsThe association between serum concentrations of metal nutrients in pregnancy and postpartum anemia has not been widely studied. This study aimed to determine this association in a large retrospective cohort study.MethodsWe included 14,829 Chinese women with singleton pregnancies. Serum concentrations of metals before 28‚ÄČweeks of gestation, the occurrence of postpartum anemia and other potential covariates were obtained from their laboratory or medical records. Cox regression and restricted cubic spline regression models were used to explore the relationship between serum concentrations of metal nutrients in pregnancy and postpartum anemia.ResultsAfter adjustment for covariates, higher concentrations of iron (Fe), magnesium (Mg) and zinc (Zn) and lower concentrations of copper (Cu) were associated with a lower risk of postpartum anemia. Compared with those whose serum concentrations of metal nutrients were in the bottom quintile (Q1), the hazard ratios (HRs) of those whose serum concentrations of metal nutrients were in the top quintile (Q5) were 0.57 (95% confidence interval (CI): 0.50, 0.64) for Fe, 0.67 (95% CI: 0.60, 0.76) for Mg, 0.82 (95% CI: 0.73, 0.93) for Zn, and 1.44 (95% CI: 1.28, 1.63) for Cu. L-shaped curve relationships were found between increasing concentrations of Fe, Mg, and Zn and incidence of postpartum anemia. Higher serum concentrations of Cu were associated with an increased risk of postpartum anemia. Serum concentrations of Fe in Q5 were associated with a lower risk of postpartum anemia when they coincided with serum concentrations of Mg in Q5, Zn in Q5, or Cu in Q1.ConclusionHigher serum concentrations of Fe, Mg, and Zn, and lower serum concentrations of Cu were associated with a lower risk of postpartum anemia among pregnant women

    Nanosized metal‚Äďorganic frameworks as unique platforms for bioapplications

    Get PDF
    Metal‚Äďorganic frameworks (MOFs) are extremely versatile materials, which serve to create platforms with exceptional porosity and specific reactivities. The production of MOFs at the nanoscale (NMOFs) offers the possibility of creating innovative materials for bioapplications as long as they maintain the properties of their larger counterparts. Due to their inherent chemical versatility, synthetic methods to produce them at the nanoscale can be combined with inorganic nanoparticles (NPs) to create nanocomposites (NCs) with one-of-a-kind features. These systems can be remotely controlled and can catalyze abiotic reactions in living cells, which have the potential to stimulate further research on these nanocomposites as tools for advanced therapiesS

    Liver-dependent lung remodeling during systemic inflammation alters responses to secondary infection

    Full text link
    Systemic duress, like that elicited by sepsis, burns or trauma, predisposes patients to secondary pneumonia, demanding better understanding of host pathways influencing this deleterious connection. These pre-existing circumstances are capable of triggering the hepatic acute phase response (APR), which is essential for limiting susceptibility to secondary lung infections. To identify potential mechanisms underlying protection afforded by the lung-liver axis, our studies aimed to evaluate liver-dependent lung reprogramming when a systemic inflammatory challenge precedes pneumonia. WT mice and APR-deficient littermates lacking hepatocyte STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged intraperitoneally with LPS to induce endotoxemia. After 18h, pneumonia was induced by intratracheal E. coli instillation. Endotoxemia alone elicited significant transcriptional alterations in the lungs of WT and hepSTAT3-/- mice as determined by bulk RNAseq, with nearly 2,000 differentially expressed genes between genotypes. The gene signatures revealed exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. A separate study performed with single-cell RNASeq revealed a wide range of affected lung cells in hepSTAT3-/- mice, with macrophages/monocytes, neutrophils, fibroblasts, epithelial cells, and endothelial cells all exhibiting remodeled transcriptomes in the absence of an intact liver response. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. Coagulation proteins, including several acute phase proteins, were prevalent among these mediators, implying a dysregulation of this immune pathway despite no detectable change in blood clotting capacity in our initial studies. These results indicate that following systemic inflammation, liver acute phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the established vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs

    Ferroptosis in hematological malignant tumors

    Get PDF
    Ferroptosis is a kind of iron-dependent programmed cell death discovered in recent years. Its main feature is the accumulation of lipid reactive oxygen species in cells, eventually leading to oxidative stress and cell death. It plays a pivotal role in normal physical conditions and the occurrence and development of various diseases. Studies have shown that tumor cells of the blood system, such as leukemia cells and lymphoma cells, are sensitive to the response to ferroptosis. Regulators that modulate the Ferroptosis pathway can accelerate or inhibit tumor disease progression. This article reviews the mechanism of ferroptosis and its research status in hematological malignancies. Understanding the mechanisms of ferroptosis could provide practical guidance for treating and preventing these dreaded diseases

    Mitochondria: It is all about energy

    Get PDF
    Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases

    Nutrition and cognitive health: A life course approach

    Get PDF
    Multiple factors affect cognitive health, such as age-related changes in the brain, injuries, mood disorders, substance abuse, and diseases. While some cannot be changed, evidence exists of many potentially possibly modifiable lifestyle factors: diet, physical activity, cognitive and social engagement, smoking and alcohol consumption which may stabilize or improve declining cognitive function. In nutrition, the focus has been mainly on its role in brain development in the early years. There is a strong emerging need to identify the role of diet and nutrition factors on age-related cognitive decline, which will open up the use of new approaches for prevention, treatment or management of age-related disorders and maintaining a good quality of life among older adults. While data on effect of high protein diets is not consistent, low-fat diets are protective against cognitive decline. Several micronutrients like B group vitamins and iron, as well as many polyphenols play a crucial role in cognitive health. Mediterranean, Nordic, DASH, and MIND diets are linked to a lower risk of cognitive decline and dementia. The relationship between the gut microbiome and brain function through the gut-brain axis has led to the emergence of data on the beneficial effects of dietary fibers and probiotics through the management of gut microbes. A ‚Äúwhole diet‚ÄĚ approach as well as macro- and micro-nutrient intake levels that have protective effects against cardiovascular diseases are most likely to be effective against neurodegenerative disorders too. Young adulthood and middle age are crucial periods for determining cognitive health in old age. The importance of cardio metabolic risk factors such as obesity and hypertension, smoking and physical inactivity that develop in middle age suggest that preventive approaches are required for target populations in their 40s and 50s, much before they develop dementia. The commonality of dementia risk with cardiovascular and diabetes risk suggests that dementia could be added to present non-communicable disease management programs in primary healthcare and broader public health programs

    Annual SHOT Report 2018

    Get PDF
    SHOT is affiliated to the Royal College of PathologistsAll NHS organisations must move away from a blame culture towards a just and learning culture. All clinical and laboratory staff should be encouraged to become familiar with human factors and ergonomics concepts. All transfusion decisions must be made after carefully assessing the risks and benefits of transfusion therapy. Collaboration and co-ordination among staff is vital

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

    Get PDF
    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 ő≤ chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IőļB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substitui√ß√£o da v√°lvula a√≥rtica continua a ser a op√ß√£o terap√™utica de refer√™ncia para doentes com estenose a√≥rtica e visa a elimina√ß√£o da sobrecarga de press√£o, desencadeando a remodelagem reversa mioc√°rdica. Contudo, apesar do benef√≠cio hemodin√Ęmico imediato, nem todos os pacientes apresentam regress√£o completa da hipertrofia do mioc√°rdio, ficando com maior risco de eventos adversos, como a insufici√™ncia card√≠aca. Atualmente, os mecanismos biol√≥gicos subjacentes a uma remodelagem reversa incompleta ainda n√£o s√£o claros. Al√©m disso, n√£o dispomos de ferramentas de progn√≥stico definitivos nem de terapias auxiliares para melhorar a condi√ß√£o dos pacientes indicados para substitui√ß√£o da v√°lvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)prote√≥mica e prote√≥mica para a caracteriza√ß√£o, respetivamente, do mioc√°rdio e do l√≠quido peric√°rdico foi seguida, tomando partido de bi√≥psias e l√≠quidos peric√°rdicos recolhidos em ambiente cir√ļrgico. Das mais de 1800 e 750 prote√≠nas identificadas, respetivamente, no mioc√°rdio e no l√≠quido peric√°rdico dos pacientes com estenose a√≥rtica, um total de 90 prote√≠nas desreguladas foram detetadas. As an√°lises de anota√ß√£o de genes, de enriquecimento de vias celulares e discriminativa corroboram um cen√°rio de aumento da express√£o de genes pro-hipertr√≥ficos e de s√≠ntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tend√™ncia para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extr√≠nsecos que ativam death receptors), com ativa√ß√£o da resposta de fase aguda e do sistema imune, assim como da fibrose. A valida√ß√£o de alguns alvos espec√≠ficos atrav√©s de immunoblot e correla√ß√£o com dados cl√≠nicos apontou para a cadeia ő≤ do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predi√ß√£o de cinases a partir do fosfoproteoma, sugere que a modula√ß√£o da case√≠na cinase 2, a fam√≠lia de cinases do IőļB, a glicog√©nio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condi√ß√£o dos pacientes indicados para interven√ß√£o. Em particular, a avalia√ß√£o funcional de cardiomi√≥citos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfun√ß√£o card√≠aca, uma vez que os mi√≥citos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver for√ßa (tens√£o ativa). Este estudo levanta v√°rias hip√≥teses na investiga√ß√£o da remodelagem reversa. No futuro, estudos de ganho e/ou perda de fun√ß√£o realizados em cardiomi√≥citos isolados ou em modelos animais de banding-debanding da aorta ajudar√£o a testar a efic√°cia de modular os potenciais alvos terap√™uticos encontrados. Al√©m disso, estudos cl√≠nicos em coortes de maior dimens√£o trar√£o conclus√Ķes definitivas quanto ao valor de progn√≥stico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin

    A systematic literature review on information systems for disaster management and proposals for its future research agenda

    Get PDF
    Emergency management information systems (EMIS) are fundamental for responding to disasters effectively since they provide and process emergency-related information. A literature stream has emerged that corresponds with the increased relevance of the wide array of different information systems that have been used in response to disasters. In addition, the discussion around systems used primarily within responder organizations broadened to systems such as social media that are open to the general public. However, a systematic review of the EMIS literature stream is still missing. This literature review presents a timeline of EMIS research from 1990 up to 2021. It shows the types of information system scholars focused on, and what disaster response functions they supported. It furthermore identifies challenges in EMIS research and proposes future research directions
    • ‚Ķ
    corecore