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INTRODUÇÃO: A anafilaxia é uma reação alérgica multissistêmica grave, de início agudo e potencialmente fatal. Poucos são os dados sobre sua epidemiologia no Brasil. O Registro Brasileiro de Anafilaxia da Associação Brasileira de Alergia e Imunologia (RBAASBAI) teve como objetivo ampliar o conhecimento sobre anafilaxia em indivíduos brasileiros. MÉTODOS: Estudo observacional transversal com questionário online sobre dados demográficos, desencadeantes suspeitos, manifestações clínicas, atendimento durante a reação, investigação diagnóstica e aconselhamento após a reação de pacientes que experimentaram uma reação anafilática. RESULTADOS: Entre junho/2021 e abril/2023, foram incluídos 237 pacientes (131 femininos): 99 crianças/adolescentes; 127 adultos e 11 idosos. Houve predomínio de meninos entre crianças/adolescentes (55,5%), e de mulheres entre os adultos (64,5%), e mediana de idade de 22 anos (< 1 a 77 anos). As manifestações cutâneas (92,8%) foram as mais frequentes, seguidas pelas respiratórias (70,1%), gastrointestinais (52,3%), neurológicas (36,3%) e cardiovasculares (35,3%). Os principais desencadeantes foram: alimentos (43,0%), medicamentos (26,2%), himenópteros (21,6%) e látex (2,5%); os alimentos entre crianças (leite, ovo, amendoim/castanhas), e os fármacos (anti-inflamatórios e antibióticos) entre os adultos. Quanto ao tratamento, 61,1% recebeu adrenalina (52,7% por profissional e 8,4% via autoinjetor de adrenalina -AIA). Uma adolescente (12 anos) faleceu após picada de abelha. A maioria recebeu plano escrito de emergência (78,1%) e foi ensinada a usar o AIA (70%). CONCLUSÃO: Os alimentos foram os desencadeantes mais comuns entre crianças/adolescentes, e os fármacos entre adultos brasileiros. A adrenalina continua sendo subutilizada, reforçando a necessidade de maior disseminação do tratamento adequado da anafilaxia.
INTRODUCTION: Anaphylaxis is a life-threatening, acute, severe multisystem allergic reaction.There is little data on its epidemiology in Brazil. The Brazilian Anaphylaxis Registry of the Brazilian Association of Allergy and Immunology (RBA-ASBAI) was devised to expand knowledge about anaphylaxis in Brazilian individuals. METHODS: Cross-sectional observational study using an online questionnaire to collect data on demographics, suspected triggers, clinical manifestations, treatment during the reaction, diagnostic workup, and post-reaction counseling in patients who have experienced an anaphylactic reaction. RESULTS: Between June 2021 and April 2023, 237 patients were included (131 female): 99 children/adolescents (<18yo), 127 adults (18-64yo), and 11 older adults (65-77yo). There was a male predominance in the pediatric group (55.5%), while females were predominant among adults (64.5%). The median age was 22 years (range, <1 to 77). The most frequent clinical manifestations were cutaneous (92.8%), followed by respiratory (70.1%), gastrointestinal (52.3%), neurological (36.3%), and cardiovascular (35.3%). The most common triggers were foods (43.0%), drugs (26.2%), venoms (21.6%), and latex (2.5%). Foods (milk, egg, peanuts/tree nuts) predominated among children, versus drugs (mostly nonsteroidal anti-inflammatory drugs and antibiotics) among adults. Regarding treatment, 61.1% received epinephrine (52.7% by a healthcare professional and 8.4% via epinephrine auto-injector [EAI]). One teenager (12yo) died due to a bee sting. Most patients received a written emergency plan (78.1%) and were taught how to use the EAI (70%). CONCLUSION: Foods were the most common triggers of anaphylaxis among Brazilian children and adolescents, while drugs predominated among adults. Epinephrine continues to be underused, highlighting the need for greater awareness of proper treatment of anaphylaxis.
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Humanos , Sociedades MédicasRESUMEN
The activity of two chlorinated isocyanurates (NaDCC and TCCA) and peroxymonosulphate (OXONE) was evaluated against biofilms of Stenotrophomonas maltophilia, an emerging pathogen isolated from drinking water (DW), and for the prevention of biofilm regrowth. After disinfection of pre-formed 48 h-old biofilms, the culturability was reduced up to 7 log, with OXONE, TCCA, and NaDCC showing more efficiency than free chlorine against biofilms formed on stainless steel. The regrowth of biofilms previously exposed to OXONE was reduced by 5 and 4 log CFU cm-2 in comparison to the unexposed biofilms and biofilms exposed to free chlorine, respectively. Rheometry analysis showed that biofilms presented properties of viscoelastic solid materials, regardless of the treatment. OXONE reduced the cohesiveness of the biofilm, given the significant decrease in the complex shear modulus (G*). AFM analysis revealed that biofilms had a fractured appearance and smaller bacterial aggregates dispersed throughout the surface after OXONE exposure than the control sample. In general, OXONE has been demonstrated to be a promising disinfectant to control DW biofilms, with a higher activity than chlorine. The results also show the impact of the biofilm mechanical properties on the efficacy of the disinfectants in biofilm control.
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Desinfectantes , Agua Potable , Stenotrophomonas maltophilia , Cloro/farmacología , Biopelículas , Desinfectantes/farmacología , Agua Potable/microbiologíaRESUMEN
Type 2 diabetes (T2D) is a highly concerning public health problem of the twenty-first century. Currently, it is estimated that T2D affects 422 million people worldwide with a rapidly increasing prevalence. During the past two decades, T2D has been widely shown to have a major impact in the brain. This, together with the cognitive decline and increased risk for dementia upon T2D, may arise from the complex interaction between normal brain aging and central insulin signaling dysfunction. Among the several features shared between T2D and some neurodegenerative disorders (e.g., Alzheimer disease (AD)), the impairment of insulin signaling may be a key link. However, these may also involve changes in sex hormones' function and metabolism, ultimately contributing to the different susceptibilities between females and males to some pathologies. For example, female sex has been pointed as a risk factor for AD, particularly after menopause. However, less is known on the underlying molecular mechanisms or even if these changes start during middle-age (perimenopause). From the above, we hypothesized that sex differentially affects hormone-mediated intracellular signaling pathways in T2D brain, ultimately modulating the risk for neurodegenerative conditions. We aimed to evaluate sex-associated alterations in estrogen/insulin-like growth factor-1 (IGF-1)/insulin-related signaling, oxidative stress markers, and AD-like hallmarks in middle-aged control and T2D rat brain cortices. We used brain cortices homogenates obtained from middle-aged (8-month-old) control Wistar and non-obese, spontaneously T2D Goto-Kakizaki (GK) male and female rats. Peripheral characterization of the animal models was done by standard biochemical analyses of blood, plasma, or serum. Steroid sex hormones, oxidative stress markers, and AD-like hallmarks were given by specific ELISA kits and colorimetric techniques, whereas the levels of intracellular signaling proteins were determined by Western blotting. Albeit the high levels of plasma estradiol and progesterone observed in middle-aged control females suggested that they were still under their reproductive phase, some gonadal dysfunction might be already occurring in T2D ones, hence, anticipating their menopause. Moreover, the higher blood and lower brain cholesterol levels in female rats suggested that its dysfunctional uptake into the brain cortex may also hamper peripheral estrogen uptake and/or its local brain steroidogenic metabolism. Despite the massive drop in IGF-1 levels in females' brains, particularly upon T2D, they might have developed some compensatory mechanisms towards the maintenance of estrogen, IGF-1, and insulin receptors function and of the subsequent Akt- and ERK1/2-mediated signaling. These may ultimately delay the deleterious AD-like brain changes (including oxidative damage to lipids and DNA, amyloidogenic processing of amyloid precursor protein and increased tau protein phosphorylation) associated with T2D and/or age (reproductive senescence) in female rats. By demonstrating that differential sex steroid hormone profiles/action may play a pivotal role in brain over T2D progression, the present study reinforces the need to establish sex-specific preventive and/or therapeutic approaches and an appropriate time window for the efficient treatment against T2D and AD.
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Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Diabetes Mellitus Tipo 2/patología , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Susceptibilidad a Enfermedades , Estradiol/sangre , Femenino , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lípidos/sangre , Masculino , Ratas , Ratas WistarRESUMEN
The endoplasmic reticulum (ER) is the principal organelle responsible for the proper folding/processing of nascent proteins and perturbed ER function leads to a state known as ER stress. Mammalian cells try to overcome ER stress through a set of protein signaling pathways and transcription factors termed the unfolded protein response (UPR). However, under unresolvable ER stress conditions, the UPR is hyperactivated inducing cell dysfunction and death. The accumulation of misfolded proteins in the brain of Alzheimer's disease (AD) patients suggests that alterations in ER homeostasis might be implicated in the neurodegenerative events that characterize this disorder. This review discusses the involvement of ER stress in the pathogenesis of AD, focusing the processing and trafficking of the AD-related amyloid precursor protein (APP) during disease development. The potential role of ER as a therapeutic target in AD will also be debated.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/metabolismo , Retículo Endoplásmico/metabolismo , Animales , Humanos , Transporte de ProteínasRESUMEN
According to World Health Organization estimates, type 2 diabetes (T2D) is an epidemic (particularly in under development countries) and a socio-economic challenge. This is even more relevant since increasing evidence points T2D as a risk factor for Alzheimer's disease (AD), supporting the hypothesis that AD is a "type 3 diabetes" or "brain insulin resistant state". Despite the limited knowledge on the molecular mechanisms and the etiological complexity of both pathologies, evidence suggests that neurodegeneration/death underlying cognitive dysfunction (and ultimately dementia) upon long-term T2D may arise from a complex interplay between T2D and brain aging. Additionally, decreased brain insulin levels/signaling and glucose metabolism in both pathologies further suggests that an effective treatment strategy for one disorder may be also beneficial in the other. In this regard, one such promising strategy is a novel successful anti-T2D class of drugs, the glucagon-like peptide-1 (GLP-1) mimetics (e.g. exendin-4 or liraglutide), whose potential neuroprotective effects have been increasingly shown in the last years. In fact, several studies showed that, besides improving peripheral (and probably brain) insulin signaling, GLP-1 analogs minimize cell loss and possibly rescue cognitive decline in models of AD, Parkinson's (PD) or Huntington's disease. Interestingly, exendin-4 is undergoing clinical trials to test its potential as an anti-PD therapy. Herewith, we aim to integrate the available data on the metabolic and neuroprotective effects of GLP-1 mimetics in the central nervous system (CNS) with the complex crosstalk between T2D-AD, as well as their potential therapeutic value against T2D-associated cognitive dysfunction.
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Enfermedad de Alzheimer , Biomimética , Diabetes Mellitus Tipo 2 , Péptido 1 Similar al Glucagón , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Exenatida , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/uso terapéutico , Glucosa/metabolismo , Humanos , Resistencia a la Insulina/genética , Liraglutida , Péptidos/uso terapéutico , Ponzoñas/uso terapéuticoRESUMEN
Diabetes mellitus is one of the most prevalent chronic diseases. Since glucose is the main fuel of the brain, its levels should be maintained within a narrow range to ensure normal brain function. Indeed, the literature shows that uncontrolled blood glucose levels, whether too high or too low, impact brain structure and function potentiating cognitive impairment. Uncoupling proteins (UCPs) are a family of mitochondrial anion carrier proteins located on the inner mitochondrial membrane, and their primary function is to leak protons from the intermembrane space into the mitochondrial matrix. The specific role of neuronal UCPs has been widely discussed and although there is no general agreement, there is a strong conviction that these proteins may be involved in the defense against mitochondrial reactive oxygen species (ROS) production and, consequently, protecting against oxidative damage. The generation of ROS is increasingly recognized as playing an important role in diabetes, neurodegenerative disorders and aging where mitochondria are both sources and targets of these reactive species. This review examines the neurodegenerative events associated with diabetes, highlighting the role of hyperglycemia and/or hypoglycemia on cognitive function. The role of mitochondria, neuronal UCPs and their impact in central nervous system will be elucidated. Finally, we will discuss neuronal UCPs as possible therapeutic targets for the treatment of diabetes-associated central complications and neurodegenerative diseases, namely Alzheimer's and Parkinson's diseases.
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Demencia/fisiopatología , Hiperglucemia/fisiopatología , Hipoglucemia/fisiopatología , Canales Iónicos/fisiología , Mitocondrias/fisiología , Proteínas Mitocondriales/fisiología , Demencia/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Hiperglucemia/complicaciones , Hipoglucemia/complicaciones , Proteína Desacopladora 1RESUMEN
Activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one the most frequent genetic events in human cancer. A cell-based imaging assay that monitored the translocation of the Akt effector protein, Forkhead box O (FOXO), from the cytoplasm to the nucleus was employed to screen a collection of 33,992 small molecules. The positive compounds were used to screen kinases known to be involved in FOXO translocation. Pyrazolopyrimidine derivatives were found to be potent FOXO relocators as well as biochemical inhibitors of PI3Kalpha. A combination of virtual screening and molecular modeling led to the development of a structure-activity relationship, which indicated the preferred substituents on the pyrazolopyrimidine scaffold. This leads to the synthesis of ETP-45658, which is a potent and selective inhibitor of phosphoinositide 3-kinases and demonstrates mechanism of action in tumor cell lines and in vivo in treated mice.
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Núcleo Celular/metabolismo , Inhibidores Enzimáticos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirazoles/metabolismo , Pirimidinas/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Animales , Línea Celular , Cromonas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Furanos/metabolismo , Humanos , Ratones , Ratones Transgénicos , Estructura Molecular , Morfolinas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/química , Pirazoles/farmacología , Piridinas/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Transcranial cerebral oximetry was developed for early detection of cerebral hypoxia and to avoid cerebral dysfunctions. However, near infrared spectroscopy (NIRS) data obtained during surgery are subject to intrinsic and extrinsic influences that have to be accounted for when interpreting the recordings. METHODS: We developed an NIRS matrix to provide brief information for specific intervention to correct changes of cerebral oxygen saturation (COS). Selected vital data and the descriptors of cerebrovascular and neurofunctional status were linked to logistic chains. RESULTS: The matrix is horizontally and vertically grouped and contains five descriptors: 1. change of COS; 2. key variable (parameter related to the change of COS); 3. associated parameters (vital data that do not cause COS alterations); 4. interpretation of values or preconditions most probably due to COS changes; and 5. the intervention most likely to normalize the COS or return it to baseline. The descriptors are grouped horizontally to a logistics chain. CONCLUSION: The modular expandable NIRS matrix we describe has promise for clinical use in surgical, neurointerventional, and anaesthesiological contexts.