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Thyroid hormone (TH) is a critical regulator of cellular function and cell fate. The circulating TH level is relatively stable, while tissue TH action fluctuates according to cell type-specific mechanisms. Here, we focused on identifying mechanisms that regulate TH action through the type 2 deiodinase (D2) in glial cells. Dio2 mRNA has an unusually long 3'UTR where we identified multiple putative MSI1 binding sites for Musashi-1 (MSI1), a highly conserved RNA-binding cell cycle regulator. Binding to these sites was confirmed through electrophoretic mobility shift assay. In H4 glioma cells, shRNA-mediated MSI1 knockdown increased endogenous D2 activity, whereas MSI1 overexpression in HEK293T cells decreased D2 expression. This latter effect could be prevented by the deletion of a 3.6 kb region of the 3'UTR of Dio2 mRNA containing MSI1 binding sites. MSI1 immunoreactivity was observed in 2 mouse Dio2-expressing cell types, that is, cortical astrocytes and hypothalamic tanycytes, establishing the anatomical basis for a potential in vivo interaction of Dio2 mRNA and MSl1. Indeed, increased D2 expression was observed in the cortex of mice lacking MSI1 protein. Furthermore, MSI1 knockdown-induced D2 expression slowed down cell proliferation by 56% in primary cultures of mouse cortical astrocytes, establishing the functionality of the MSI1-D2-T3 pathway. In summary, Dio2 mRNA is a target of MSI1 and the MSI1-D2-T3 pathway is a novel regulatory mechanism of astrocyte proliferation with the potential to regulate the pathogenesis of human glioblastoma.
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Astrócitos , Proliferação de Células , Iodotironina Desiodinase Tipo II , Proteínas do Tecido Nervoso , Proteínas de Ligação a RNA , Animais , Humanos , Camundongos , Regiões 3' não Traduzidas , Astrócitos/metabolismo , Astrócitos/citologia , Linhagem Celular Tumoral , Células HEK293 , Iodeto Peroxidase/metabolismo , Iodeto Peroxidase/genética , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/genéticaRESUMO
BACKGROUND AND AIMS: Vitamin D deficiency is a common cause of secondary hyperparathyroidism, particularly in elderly people. The aim of this study was to evaluate the associations of serum vitamin D and parathormone (PTH) concentrations with blood pressure values and hypertension-mediated target organ damage (HMOD), including left ventricular (LV) hypertrophy and carotid plaque (CP). METHODS AND RESULTS: We enrolled consecutive patients admitted to the Hypertension Center of Federico II University Hospital in Naples, Italy. All patients underwent carotid doppler ultrasound and echocardiography, measurement of vitamin D and PTH levels and main clinical and laboratory parameters. A total of 126 patients (mean age 54 years, 68% males) were enrolled. Pearson's correlation analysis indicated that PTH levels directly correlated with age, diabetes, dyslipidemia, hypertension, fasting glucose, and LV mass, and inversely with glomerular filtration rate, LDL cholesterol, and vitamin D. Vitamin D levels correlated inversely with PTH, diabetes and CP. Multivariate regression models indicated that an increased LV mass was associated with the presence of obesity (ß = 0.342; P = 0.001). Maximal intima-media thickness was significantly associated with older age (ß = 0.303; P = 0.033). Combined presence of low vitamin D/high PTH levels were associated with more than 4-fold increased risk of having CP in both univariate (OR = 4.77, p = 0.0001) and multivariate regression analysis (OR = 4.52, p = 0.014). CONCLUSION: In a population at high cardiovascular risk, vitamin D and PTH levels were not directly associated with blood pressure values and HMOD. Secondary hyperparathyroidism due to vitamin D deficiency is associated with carotid atherosclerosis independently of other common cardiovascular risk factors.
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Background: The National Institutes of Health (NIH) is the major funding agency for biomedical research in the United States. To initiate a scholarly dialog about research and career development in the thyroid field, here we reviewed recent trends in NIH funding for this area. We used the Research Portfolio Online Reporting Tool database to estimate the level of NIH extramural support during 2013-2022 (number of active grants/year and $amount/year weighed by the total number of active grants/year and $amount/year), provided by the NIH to the thyroid field. We determined that in 2013, the NIH supported â¼140 grants/year, totaling almost $50 million/year, the majority in the form of R01 grants. Within the thyroid field, support was evenly split between thyroid cancer and thyroid hormone metabolism and action subareas. In the subsequent years (2014-2022), the total number of active grants peaked at 150/year ($55 million) in 2014 but progressively decreased to about 100 active grants/year ($30 million) in 2022. This trend occurred while the NIH budget increased from $29 to $46 billion/year. Globally, the number of thyroid-related publications increased by â¼70% during the study period, and the fractional contribution of several countries remained relatively stable, except for China which increased by â¼600%. Remarkably, the fraction of thyroid-related publications in the United States sponsored by the NIH decreased from 5.5% to 3.1% of the global number. Conclusion: These results constitute a very concerning scenario for research and education in the thyroid field. We appeal to the NIH, the professional societies in endocrinology and thyroidology, and all other relevant stakeholders such as thyroid-related professionals and thyroid patients to engage in further discussions to identify the root causes of this trend and implement an action plan to stabilize and eventually reverse this situation.
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CONTEXT: The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. OBJECTIVE: To assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. METHODS: The ELSA-Brasil study follows 15,105 adult Brazilians (aged 35 to 74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. RESULTS: Initiation of therapy with LT4 resulted in a 11-19% decrease in TSH, a â¼19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in â¼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and anti-diabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and, a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least one serum FT4 levels above the control reference range (>1.52â ng/dL), 38 participants (15.6%) had at least one serum FT3 below the reference range (<0.23â ng/dL). CONCLUSION: The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.
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Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 (MCT8) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3',5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.
Assuntos
Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual Ligada ao Cromossomo X , Atrofia Muscular , Animais , Humanos , Camundongos , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hipotonia Muscular/genética , Hormônios TireóideosRESUMO
CONTEXT: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time. OBJECTIVE: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period. METHODS: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. RESULTS: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7â µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes. CONCLUSION: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.
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Fabry disease (FD) is caused by mutations in the galactosidase alpha (GLA) gene which lead to the accumulation of globotriaosylceramide (Gb-3). Enzyme replacement therapy (ERT) and oral chaperone therapy are the current pharmacological treatments for this condition. However, in the literature, there is a growing emphasis on exploring non-pharmacological therapeutic strategies to improve the quality of life of patients with FD. In particular, the nutritional approach to FD has been marginally addressed in the scientific literature, although specific dietary interventions may be useful for the management of nephropathy and gastrointestinal complications, which are often present in patients with FD. Especially in cases of confirmed diagnosis of irritable bowel syndrome (IBS), a low-FODMAP diet can represent an effective approach to improving intestinal manifestations. Furthermore, it is known that some food components, such as polyphenols, may be able to modulate some pathogenetic mechanisms underlying the disease, such as inflammation and oxidative stress. Therefore, the use of healthy dietary patterns should be encouraged in this patient group. Sports practice can be useful for patients with multi-organ involvement, particularly in cardiovascular, renal, and neurological aspects. Therefore, the aim of this review is to summarize current knowledge on the role of nutrition and physical activity in FD patients.
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Doença de Fabry , Humanos , Doença de Fabry/terapia , Qualidade de Vida , Dieta , Exercício Físico , Estado NutricionalRESUMO
About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.
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Iodeto Peroxidase , Iodotironina Desiodinase Tipo II , Camundongos Endogâmicos C57BL , Animais , Masculino , Iodeto Peroxidase/genética , Camundongos , Dieta Hiperlipídica , Patrimônio Genético , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Marrom/metabolismo , Polimorfismo Genético , Resistência à Insulina/genética , Fígado Gorduroso/genéticaRESUMO
Fabry disease (FD), also known as Anderson-Fabry disease, is a hereditary disorder of glycosphingolipid metabolism, caused by a deficiency of the lysosomal alpha-galactosidase A enzyme. This causes a progressive accumulation of glycosphingolipids in tissues and organs which represents the main pathogenetic mechanism of FD. The disease is progressive and multisystemic and is characterized by early symptoms and late complications (renal, cardiac and neurological dysfunction). Fatigue and exercise intolerance are early common symptoms in FD patients but the specific causes are still to be defined. In this narrative review, we deal with the contribution of cardiac and pulmonary dysfunctions in determining fatigue and exercise intolerance in FD patients.
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Fabry disease (FD) is a lysosomal storage disorder due to the impaired activity of the α-galactosidase A (GLA) enzyme which induces Gb3 deposition and multiorgan dysfunction. Exercise intolerance and fatigue are frequent and early findings in FD patients, representing a self-standing clinical phenotype with a significant impact on the patient's quality of life. Several determinants can trigger fatigability in Fabry patients, including psychological factors, cardiopulmonary dysfunctions, and primary alterations of skeletal muscle. The "metabolic hypothesis" to explain skeletal muscle symptoms and fatigability in Fabry patients is growing acknowledged. In this report, we will focus on the primary alterations of the motor system emphasizing the role of skeletal muscle metabolic disarrangement in determining the altered exercise tolerance in Fabry patients. We will discuss the most recent findings about the metabolic profile associated with Fabry disease offering new insights for diagnosis, management, and therapy.
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Introduction: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and coronavirus disease 2019 (COVID-19). Objective: The objective was to identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. Methods: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. Results: In total, 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5%. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (P = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥92 cm² exhibited the best survival rate. Conclusion: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.
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COVID-19 , Músculo Esquelético , SARS-CoV-2 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Composição Corporal/genética , COVID-19/genética , COVID-19/diagnóstico por imagem , Genótipo , Heterozigoto , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Estudos Prospectivos , Tomografia Computadorizada por Raios XAssuntos
Arginina , Cardiomiopatias Diabéticas , Suplementos Nutricionais , Mitocôndrias Cardíacas , Humanos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/tratamento farmacológico , Arginina/administração & dosagem , Arginina/uso terapêutico , Animais , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologiaAssuntos
Modelos Animais de Doenças , Doença de Fabry , Mitocôndrias Cardíacas , Fenótipo , Animais , Doença de Fabry/fisiopatologia , Doença de Fabry/genética , Doença de Fabry/patologia , Doença de Fabry/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/metabolismo , Camundongos , Masculino , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismo , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismoRESUMO
FUNDAMENTO: Há grande controvérsia quanto ao diagnóstico de Insuficiência Renal Aguda (IRA), existindo mais de 30 diferentes definições. OBJETIVO: Avaliar a incidência e os fatores de risco para desenvolvimento de IRA no pós-operatório de cirurgia cardíaca de acordo com os critérios RIFLE, AKIN e KDIGO, e comparar o poder prognóstico desses critérios. MÉTODOS: Estudo de corte transversal que incluiu 321 pacientes (62 [53 - 71] anos, 140 homens) consecutivamente submetidos a cirurgia cardíaca entre junho de 2011 e janeiro de 2012. Os pacientes foram acompanhados por 30 dias, com vistas ao desenvolvimento de um desfecho composto (mortalidade, necessidade de diálise e internação prolongada). RESULTADOS: A incidência de IRA variou de 15% - 51%, conforme o critério diagnóstico adotado. Enquanto a idade se associou ao risco de IRA nos três critérios, houve variação nos demais determinantes. Durante o acompanhamento, 89 pacientes apresentaram o desfecho e todos os critérios se associaram ao risco aumentado na análise Cox univariada e após o ajuste para idade, sexo, diabetes e tipo de cirurgia. Contudo, após novo ajuste para tempo de circulação extracorpórea e presença de baixo débito cardíaco, apenas o diagnóstico de IRA pelo critério KDIGO manteve esta associação significativa (HR= 1,89 [95% IC: 1,18 - 3,06]). CONCLUSÕES: A incidência e os fatores de risco para IRA pós-cirurgia cardíaca têm grande variação de acordo com os critérios diagnósticos utilizados. Em nossa análise, o critério KDIGO se mostrou superior ao AKIN e ao RIFLE quanto ao seu poder prognóstico.
BACKGROUND: There is considerable controversy regarding the diagnosis of Acute Kidney Injury (AKI), and there are over 30 different definitions. OBJECTIVE: To evaluate the incidence and risk factors for the development of AKI following cardiac surgery according to the RIFLE, AKIN and KDIGO criteria, and compare the prognostic power of these criteria. METHODS: Cross-sectional study that included 321 consecutively patients (median age 62 [53-71] years; 140 men) undergoing cardiac surgery between June 2011 and January 2012. The patients were followed for up to 30 days, for a composite outcome (mortality, need for dialysis and extended hospitalization). RESULTS: The incidence of AKI ranged from 15% - 51%, accordingly to the diagnostic criterion adopted. While age was associated with risk of AKI in the three criteria, there were variations in the remaining risk factors. During follow-up, 89 patients developed the outcome and all criteria were associated with increased risk in the univariate Cox analysis and after adjustment for age, gender, diabetes, and type of surgery. However, after further adjustment for extracorporeal circulation and the presence of low cardiac output, only AKI diagnosed by the KDIGO criterion maintained this significant association (HR= 1.89 [95% CI: 1.18 - 3.06]). CONCLUSION: The incidence and risk factors for AKI after cardiac surgery vary significantly according to the diagnostic criteria used. In our analysis, AKI the KDIGO criterion was superior to AKIN and RIFLE with regard its prognostic power.
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Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Injúria Renal Aguda/diagnóstico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Injúria Renal Aguda/etiologia , Fatores Etários , Creatinina/sangue , Complicações Pós-Operatórias/diagnóstico , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de TempoRESUMO
Eventos tromboembólicos são complicações comuns em pacientes críticos. Podem apresentar sinais e sintomas pouco específicos e estão associados a um substancial aumento na morbimortalidade dos pacientes internados em unidades de terapia intensiva. Os agentes antitrombóticos são o pilar no tratamento e prevenção do tromboembolismo. Esta classe é também utilizada na prevenção do acidente vascular encefálico, na fibrilação atrial, na prevenção de eventos embólicos da insuficiência cardíaca, em pacientes com próteses valvares e têm sido associados a antiplaquetários na prevenção secundária da síndrome coronária aguda. Agentes antitrombóticos, como aspirina, clopidogrel, antagonistas da vitamina K e foundaparinux (inibidor indireto do fator Xa) já foram incorporados na prática clínica rotineira dos serviços de terapia intensiva. Recentemente, tem-se demonstrado grande interesse nos agentes que inibem seletivamente o fator Xa e a trombina. Estes apresentam estrutura molecular pequena e inibem simultaneamente o fator da coagulação livre no plasma e ligado ao trombo. Entre os novos anticoagulantes orais, dabigatran, rivaroxaban e apixaban são os que apresentam estudos clínicos em fases mais avançadas e uso na prática clínica já licenciado em alguns países. O objetivo desta revisão é salientar os principais estudos da literatura sobre novos anticoagulantes no cenário das unidades de terapia intensiva.
Thromboembolic events commonly occur in critically ill patients, and although they do not consistently present with specific signs and symptoms, they are associated with high morbity and mortality. Antithrombotic agents are the mainstay of the prevention and treatment of venous thromboembolism, and they are also used for stroke prevention in atrial fibrillation, embolism prevention in heart failure, and anticoagulation of prosthetic valves. These drugs have been combined with antiplatelet therapy for the prevention of secondary acute coronary syndrome. Antithrombotic agents such as Aspirin, clopidogrel, vitamin K antagonists and fondaparinux, an indirect Factor Xa inhibitor, are already incorporated into our clinical practice. New small-molecule, selective Factor Xa and thrombin inhibitors that simultaneously inhibit free plasma and clot-associated factor activities have received considerable attention recently. These new oral anticoagulants are in various phases of clinical development. dabigatran, rivaroxaban and apixaban are in more advanced phases of clinical development and are already available in a number of countries. This review article highlights the studies describing the use of these three anticoagulants in an intensive care setting.
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A funcão do eixo hipotálamo-hipófise-tireóide em animais portadores da "síndrome do T3 baixo", foi estudada em ratos implantados com o tumor de Walker-256. Ratos machos adultos foram injetados com 1 x 106 células tumorais viáveis, por via SC, e sacrificados após 10 dias. A intensidade da síndrome guardou relacão positiva com o tamanho do tumor desenvolvido. Houve diminuicão da atividade tireoideana documentada pela diminuicão da área nuclear das células foliculares, das concentracões plasmáticas do T4, da rTg e da captacão do 131I. Mesmo o implante SC de um pellet de TSH de liberacão lenta causou menor estimulacão tireoideana, avaliada após 2 e 24h nos ratos com tumor. A secrecão do rTSH avaliada através da administracão IV de TRH mostrou-se significativamente diminuída nestas condicões, indicando aumento do tônus inibidor hipotalâmico sobre a secrecão deste hormônio. A participacão de outros neuro-mediadores hipotalâmicos foi verificada através da administracão prévia de metoclopramida e/ou fisostigmina, com ou sem estímulo subseqüente pelo TRH. Nos animais tratados com metoclopramida, os valores do rTSH aumentaram significativamente, assim como a resposta ao estímulo de secrecão pelo TRH. A fisostigmina mostrou-se mais eficiente na mediacão da resposta de secrecão do rTSH, bem como na resposta ao estímulo de secrecão pelo TRH. A administracão concomitante dos dois fármacos, seguida do estímulo pelo TRH, normalizou a secrecão do rTSH. Conclui-se que, além das alteracões conhecidas do metabolismo das iodotironinas, a secrecão de TSH encontra-se diminuída nos animais portadores de tumor de Walker-256, sugerindo diminuicão global do tônus tireoideano.
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Ratos , Animais , Humanos , Masculino , /metabolismo , Síndromes do Eutireóideo Doente/etiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Neoplasias Mamárias Experimentais/metabolismo , Hormônios Tireóideos/sangue , Tireotropina/sangue , Dopamina/farmacologia , Síndromes do Eutireóideo Doente/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Metoclopramida/farmacologia , Fisostigmina/farmacologia , Hormônio Liberador de Tireotropina/sangue , Ratos Sprague-Dawley , Somatostatina/farmacologia , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismo , TireotropinaRESUMO
OBJETIVO: Análise estratificada de risco em Cirurgia de Revascularização Miocárdica (CRVM). MÉTODOS: Estudou-se, de forma prospectiva, 814 pacientes, aplicando-se dois índices prognósticos (IP): Parsonnet e Higgins Modificado. O IP Higgins foi Modificado por substituição da variável "valor do índice cardíaco" por "síndrome de baixo débito cardíaco", na admissão à Unidade de Terapia Intensiva (UTI). A capacidade discriminatória para morbimortalidade de ambos foi analisada através de curva ROC (receiver operating characteristic). Identificou-se, através de regressão logística, os fatores associados, de forma independente aos eventos. RESULTADOS: A taxa de mortalidade foi de 5,9 por cento e a de morbidade, 35,5 por cento. O IP Higgins Modificado, que analisa variáveis pré, intra-operatórias e variáveis fisiológicas na admissão à UTI, demonstrou áreas sob a curva ROC de 77 por cento para mortalidade e de 67 por cento, para morbidade. Por sua vez, o IP Parsonnet, que analisa somente variáveis pré-operatórias, demonstrou áreas de 62,2 por cento e 62,4 por cento, respectivamente. Doze variáveis caracterizaram-se como fatores prognósticos independentes: idade, diabete melito, baixa superfície corpórea, creatinina (>1,5 mg/dl), hipoalbuminemia, cirurgia não-eletiva, tempo prolongado de circulação extracorpórea (CEC), necessidade de balão intra-aórtico pós-CEC, síndrome de baixo débito cardíaco na admissão do paciente à UTI, freqüência cardíaca elevada, queda do bicarbonato sérico e alargamento do gradiente alvéolo-arterial de oxigênio nesse período. CONCLUSÃO: O IP Higgins Modificado mostrou-se superior ao IP Parsonnet na estratificação de risco cirúrgico, salientando a importância da análise de eventos intra-operatórios e variáveis fisiológicas na admissão do paciente à UTI, quando da definição prognóstica.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Revascularização Miocárdica/mortalidade , Brasil/epidemiologia , Métodos EpidemiológicosRESUMO
Impacto da Clonagem, Ruptura e Super-Expressäo do Gene das Desiodinases da lodotironina Sobre a Homeostase dos Hormônios Tiroidianos. A tiroxina (T4) é o principal produto de secreçäo da tiróide, um pró-hormônio que deve ser obrigatoriamente ativado a T3 para que possa iniciar a açäo do hormônio tiroideano. Esta reaçäo de desiodaçäo ocorre no anel fenólico da molécula de T4 e é catalisada por duas enzimas contendo selenocisteína, i.e. D1 e D2. Em contrapartida a esta via ativadora, tanto T4 quanto T3 säo irreversivelmente inativados por desiodaçäo do anel tirosil, uma reaçäo catalisada pela D3, a terceira enzima constituinte do grupo das selenodesiodases. Devido à sua pronunciada plasticidade fisiológica, a D2 é considerada a principal desiodase produtora de T3 em seres humanos. Recentemente, as observações feitas no camundongo com deficiência da D1, C3H, foram expandidas com a criaçäo dos camundongos D2 knockout ou com super-expressäo cardíaca do gene da D2. Os resultados obtidos indicam que as selenoenzimas constituem um sistema fisiológico que contribui com a homeostase do hormônio tiroideano durante adaptaçäo a mudanças no suprimento alimentar de iodo, exposiçäo ao frio, em pacientes com disfunçäo tiroideana e talvez durante jejum e doença sistêmica.