Macrocalcitonin Is a Novel Pitfall in the Routine of Serum Calcitonin Immunoassay

Context: Calcitonin (CT) is a sensitive marker of medullary thyroid carcinoma (MTC) and is used for primary diagnosis and follow-up after thyroidectomy. However, persistently elevated CT is observed even after complete surgical removal without evidence of a recurrent or persistent tumor. Objective: To investigate the presence of assay interference in the serum CT of MTC patients who are apparently without a structural disease. Patients and Methods: We studied three index MTC cases for CT assay interference and 14 patients with metastatic MTC. The CT level was measured using an immunofluorometric assay. Screening for assay interference was performed by determination of CT levels before and after serum treatment with polyethylene glycol. Additionally, samples were analyzed by chromatography on ultra-performance liquid chromatography and protein A-Sepharose. Results: Patients with biochemical and structural disease showed CT mean recovery of 84.1% after polyethylene glycol treatment, whereas patients suspected of interference showed recovery from 2-7%. The elution profile on UPLC showed that the immunometric CT from these three patients behaved like a high molecular mass aggregate (>300 kDa). Additionally, when these samples were applied to the protein A-Sepharose, CT immunoreactivity was retained on the column and was only released after lowering the pH. Conclusions: For the first time, our results show the presence of a novel pitfall in the CT immunoassay: "macrocalcitonin." Its etiology, frequency, and meaning remain to be defined, but its recognition is of interest and can help clinicians avoid unnecessary diagnostic investigations and treatment during the follow-up of MTC.Sao Paulo State Research Foundation-FAPESPFAPESPFederal Agency of Support and Evaluation of Postgraduate Education (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)National Council for Scientific and Technological DevelopmentUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Thyroid Dis Ctr, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Biochem, Div Mol Biol, BR-04044020 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Thyroid Dis Ctr, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Div Endocrinol, Dept Med,Lab Mol & Translat Endocrinol, BR-04039032 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Biochem, Div Mol Biol, BR-04044020 Sao Paulo, SP, BrazilFAPESP: 2006/60402-1FAPESP: 2010/51547-1FAPESP: 2010/19478Web of Scienc

Branched-Chain Amino Acids, Alanine, and Thyroid Function:A Cross-Sectional, Nuclear Magnetic Resonance (NMR)-Based Approach from ELSA-Brasil

The association of thyroid function with essential and non-essential amino acids is understudied, despite their common metabolic roles. Thus, our aim was to evaluate the association of thyroid function with the levels of branched-chain amino acids (BCAAs—leucine, isoleucine, and valine) and of alanine in the general population. We utilized data from the São Paulo research center of ELSA-Brasil, a longitudinal population-based cohort study. Thyroid parameters included thyroid stimulating hormone (TSH), free T4 and free T3 levels, and the FT4:FT3 ratio. BCAAs and alanine were analyzed on a fully automated NMR platform. The current analysis included euthyroid participants and participants with subclinical hyperthyroidism and hypothyroidism. We used Pearson’s coefficient to quantify the correlation between thyroid-related parameters and amino acids. Linear regression models were performed to analyze whether thyroid parameters were associated with BCAAs and alanine levels. We included 4098 participants (51.3 ± 9.0 years old, 51.5% women) in this study. In the most adjusted model, higher levels of TSH were associated with higher levels of alanine, FT4 levels were inversely associated with isoleucine levels, FT3 levels were statistically significant and positively associated with valine and leucine, and the T3:T4 ratio was positively associated with all amino acids. We observed that subclinical hypothyroidism was positively associated with isoleucine and alanine levels in all models, even after full adjustment. Our findings highlight the association of subclinical hypothyroidism and thyroid-related parameters (including TSH, free T4, free T3, and FT4:FT3 ratio) with BCAAs and alanine. Further studies are needed to explore the mechanisms underlying this association. These insights contribute to our understanding of the influence of thyroid-related parameters on BCAA and alanine metabolism.</p

Cell-Free Antigens from Paracoccidioides brasiliensis Drive IL-4 Production and Increase the Severity of Paracoccidioidomycosis

The thermally dimorphic fungus Paracoccidioides brasiliensis (Pb) is the causative agent of paracoccidioidomycosis (PCM), one of the most frequent systemic mycosis that affects the rural population in Latin America. PCM is characterized by a chronic inflammatory granulomatous reaction, which is consequence of a Th1-mediated adaptive immune response. In the present study we investigated the mechanisms involved in the immunoregulation triggered after a prior contact with cell-free antigens (CFA) during a murine model of PCM. The results showed that the inoculation of CFA prior to the infection resulted in disorganized granulomatous lesions and increased fungal replication in the lungs, liver and spleen, that paralleled with the higher levels of IL-4 when compared with the control group. The role of IL-4 in facilitating the fungal growth was demonstrated in IL-4-deficient- and neutralizing anti-IL-4 mAb-treated mice. The injection of CFA did not affect the fungal growth in these mice, which, in fact, exhibited a significant diminished amount of fungus in the tissues and smaller granulomas. Considering that in vivo anti-IL-4-application started one week after the CFA-inoculum, it implicates that IL-4-CFA-induced is responsible by the mediation of the observed unresponsiveness. Further, the characterization of CFA indicated that a proteic fraction is required for triggering the immunosuppressive mechanisms, while glycosylation or glycosphingolipids moieties are not. Taken together, our data suggest that the prior contact with soluble Pb antigens leads to severe PCM in an IL-4 dependent manner

The burden of mental disorders, substance use disorders and self-harm among young people in Europe, 1990-2019 : Findings from the Global Burden of Disease Study 2019

Background Mental health is a public health issue for European young people, with great heterogeneity in resource allocation. Representative population-based studies are needed. The Global Burden of Disease (GBD) Study 2019 provides internationally comparable information on trends in the health status of populations and changes in the leading causes of disease burden over time. Methods Prevalence, incidence, Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) from mental disorders (MDs), substance use disorders (SUDs) and self-harm were estimated for young people aged 10-24 years in 31 European countries. Rates per 100,000 population, percentage changes in 1990-2019, 95% Uncertainty Intervals (UIs), and correlations with Sociodemographic Index (SDI), were estimated. Findings In 2019, rates per 100,000 population were 16,983 (95% UI 12,823 - 21,630) for MDs, 3,891 (3,020 4,905) for SUDs, and 89.1 (63.8 - 123.1) for self-harm. In terms of disability, anxiety contributed to 647.3 (432 -912.3) YLDs, while in terms of premature death, self-harm contributed to 319.6 (248.9-412.8) YLLs, per 100,000 population. Over the 30 years studied, YLDs increased in eating disorders (14.9%;9.4-20.1) and drug use disorders (16.9%;8.9-26.3), and decreased in idiopathic developmental intellectual disability (-29.1%;23.8-38.5). YLLs decreased in self-harm (-27.9%;38.3-18.7). Variations were found by sex, age-group and country. The burden of SUDs and self-harm was higher in countries with lower SDI, MDs were associated with SUDs. Interpretation Mental health conditions represent an important burden among young people living in Europe. National policies should strengthen mental health, with a specific focus on young people. Funding The Bill and Melinda Gates Foundation Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe

INDIGO-DataCloud: A data and computing platform to facilitate seamless access to e-infrastructures

This paper describes the achievements of the H2020 project INDIGO-DataCloud. The project has provided e-infrastructures with tools, applications and cloud framework enhancements to manage the demanding requirements of scientific communities, either locally or through enhanced interfaces. The middleware developed allows to federate hybrid resources, to easily write, port and run scientific applications to the cloud. In particular, we have extended existing PaaS (Platform as a Service) solutions, allowing public and private e-infrastructures, including those provided by EGI, EUDAT, and Helix Nebula, to integrate their existing services and make them available through AAI services compliant with GEANT interfederation policies, thus guaranteeing transparency and trust in the provisioning of such services. Our middleware facilitates the execution of applications using containers on Cloud and Grid based infrastructures, as well as on HPC clusters. Our developments are freely downloadable as open source components, and are already being integrated into many scientific applications

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

The state of health in the European Union (EU-27) in 2019: a systematic analysis for the Global Burden of Disease study 2019

Background: The European Union (EU) faces many health-related challenges. Burden of diseases information and the resulting trends over time are essential for health planning. This paper reports estimates of disease burden in the EU and individual 27 EU countries in 2019, and compares them with those in 2010.Methods: We used the Global Burden of Disease 2019 study estimates and 95% uncertainty intervals for the whole EU and each country to evaluate age-standardised death, years of life lost (YLLs), years lived with disability (YLDs) and disability-adjusted life years (DALYs) rates for Level 2 causes, as well as life expectancy and healthy life expectancy (HALE).Results:In 2019, the age-standardised death and DALY rates in the EU were 465.8 deaths and 20,251.0 DALYs per 100,000 inhabitants, respectively. Between 2010 and 2019, there were significant decreases in age-standardised death and YLL rates across EU countries. However, YLD rates remained mainly unchanged. The largest decreases in age-standardised DALY rates were observed for "HIV/AIDS and sexually transmitted diseases" and "transport injuries" (each -19%). "Diabetes and kidney diseases" showed a significant increase for age-standardised DALY rates across the EU (3.5%). In addition, "mental disorders" showed an increasing age-standardised YLL rate (14.5%).Conclusions: There was a clear trend towards improvement in the overall health status of the EU but with differences between countries. EU health policymakers need to address the burden of diseases, paying specific attention to causes such as mental disorders. There are many opportunities for mutual learning among otherwise similar countries with different patterns of disease