Normal Values of Circulating IGF-I Bioactivity in the Healthy Population: Comparison with five widely used IGF-I immunoassays

Background: IGF-I immunoassays are primarily used to estimate IGF-I bioactivity. Recently, an IGFI specific Kinase Receptor Activation Assay (KIRA) has been developed as an alternative method. However, no normative values have been established for the IGF-I KIRA. Objective: To establish normative values for the IGF-I KIRA in healthy adults. Design: Cross-sectional study in healthy non-fasting blood donors. Study participants: 426 healthy individuals (310 M, 116 F; age range: 18 – 79 yrs) Main outcome Measures: IGF-I bioactivity determined by the KIRA. Results were compared with total IGF-I, measured by five different IGF-I immunoassays. Results: Mean (± SD) IGF-I bioactivity was 423 (± 131) pmol/L and decreased with age (β = -3.4 pmol/L/yr, p < 0.001). In subjects younger than 55 yrs mean IGF-I bioactivity was significantly higher in women than in men. Above this age this relationship was inverse, suggesting a drop in IGF-I bioactivity after menopause. This drop was not reflected in total IGF-I levels. IGF-I bioactivity was significantly related to total IGF-I (rs varied between 0.46 – 0.52; P-values < 0.001). Conclusions: We established age-specific normative values for the IGF-I KIRA. We observed a significant drop in IGF-I bioactivity in women between 50 and 60 years, which was not perceived by IGF-I immunoassays. The IGF-I KIRA, when compared to IGF-I immunoassays, theoretically has the advantage that it measures net effects of IGF-binding proteins on IGF-I receptor activation. However, it has to be proven whether information obtained by the IGF-I KIRA is clinically more relevant than measurements obtained by IGF-I immunoassays

Low Circulating IGF-I Bioactivity in Elderly Men is associated with Increased Mortality

Context: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay (IGF-I KIRA) is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGFI. Objective: To study IGF-I bioactivity in relation to human survival. Design: Prospective observational study. Setting: A clinical research center at a university hospital. Study participants: 376 healthy elderly men (aged 73 to 94 years). Main outcome Measures: IGF-I bioactivity was determined by the IGF-I KIRA. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). Results: During the follow-up period of 8.6 years 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group (HR = 1.8, (95% CI: 1.2 − 2.8, p = 0.01) as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4 (95% CI: 1.3 − 4.3, p = 0.003) or a high inflammatory risk profile (HR = 2.3 (95% CI: 1.2 − 4.5, p = 0.01). Significant relationships were not observed for total or free IGF-I. Conclusion: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk

Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease

Early Pregnancy-Associated Plasma Protein A Concentrations are Associated with Third Trimester Insulin Sensitivity

Context: First or early second trimester pregnancy-associated plasma protein-A (PAPP-A) concentrations have previously been shown to be lower in women who subsequently develop gestational diabetes (GDM) and gestational hypertension. Objective: We therefore sought to investigate why circulating PAPP-A concentrations are related to the subsequent risk of GDM and gestational hypertension. Patients, Design and Setting: We measured serum PAPP-A concentrations around week 15 of pregnancy and related these to indices derived from week 28 oral glucose tolerance tests (OGTT) and blood pressures across pregnancy in the Cambridge Baby Growth Study cohort. Results: Increased PAPP-A concentrations were associated with reduced GDM risk (odds ratio 0.623 (0.453, 0.856), P=3.5 x 10$^{-3}$, n=777) and reduced mean arterial blood pressures (β=-0.202– -0.177, P=1.7–6.9 x 10$^{-3}$, n=347–355). They were also negatively associated with week 28 fasting (β=-0.149, P=6.6 x 10$^{-4}$, n=777) and 60 minute (β=-0.188, P=1.5 x 10-5, n=777) OGTT glucose concentrations. These associations were underpinned by the strong associations between increased week 15 PAPP-A concentrations and decreased week 28 insulin resistance (HOMA IR: β=-0.319, P=1.7 x 10$^{-13}$, n=768), and increased insulin secretion relative to insulin sensitivity (insulin disposition index: β=0.202, P=6.5 x 10$^{-6}$, n=731). Conclusions: These results suggest that links between PAPP-A concentrations in early pregnancy and subsequent glucose concentrations and blood pressures may be mediated by changes in insulin sensitivity (and secretion).Most of the endocrine measurements described in this study were funded by the Wellbeing of Women (the Royal College of Obstetricians and Gynaecologists, U.K.) (RG1644). Core funding for the Cambridge Baby Growth Study has come from the Medical Research Council (7500001180); European Union Framework 5 (QLK4-1999-01422); the Mothercare Charitable Foundation (RG54608); Newlife Foundation for Disabled Children (07/20) and the World Cancer Research Fund International (2004/03). In addition, there has been support from National Institute for Health Research Cambridge Biomedical Research Centre

Differential impact of glucose administered intravenously and orally on circulating mir-375 levels in human subjects

Background: To date, numerous nucleic acid species have been detected in the systemic circulation including microRNAs (miRNAs); however their functional role in this compartment remains unclear. Objective: The aim of this study was to determine whether systemic levels of miRNAs abundant in blood, including the neuroendocrine tissue-enriched miR-375, are altered in response to a glucose challenge. Design: Twelve healthy males were recruited for an acute cross-over study which consisted of two tests each following an eight-hour fasting period. An oral glucose tolerance test (OGTT) was performed and blood samples were collected over a 3-hour period. Following a period of at least one week, the same participants were administered an isoglycemic intravenous glucose infusion (IIGI) with the same blood collection protocol. Results: The glucose response curve following the IIGI mimicked that obtained after the OGTT, but as expected systemic insulin levels were lower during the IIGI compared to the OGTT (P<0.05). MiR-375 levels in circulation were increased only in response to an OGTT and not during an IIGI. In addition, the response to the OGTT also coincided with the transient increase of circulating glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and glucose-dependent insulinotropic polypeptide (GIP). Conclusions: The present findings show levels of miR-375 increase following administration of an OGTT and in light of its enrichment in cells of the gut, suggest that the gastrointestinal tract may play a significant role to the abundance and function of this microRNA in the blood

Soluble Klotho: a possible predictor of quality of life in acromegaly patients

Purpose: Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-

Formação do professor para uso da internet : o que querem os professores

Orientadora: Profª. Drª. Gláucia da Silva BritoDissertação (mestrado) - Universidade Federal do Paraná, Setor de Educação, Programa de Pós-Graduação em Educação. Defesa: Curitiba, 13/12/2016Inclui referências : f. 76-78Resumo: Esta pesquisa está inserida na linha de pesquisa Cultura, Escola e Ensino, do Setor de Educação da Universidade Federal do Paraná - UFPR, tendo como Área de Concentração em Educação, Cultura e Tecnologia. O fato de a tecnologia adentrar no espaço escolar vem provocando mudanças no cotidiano da sala de aula. Os professores percebem que disputam a atenção dos alunos com um elemento "invisível", mas presente - A internet. Muitos professores, ou quase todos já são usuários do ciberespaço, porém poucos fazem uso deste meio em suas aulas. Alegação de senso comum é de não estar preparado para tal utilização. A partir deste entendimento, definiu-se como problema de pesquisa: o que os professores do ensino médio, de uma escola pública, estadual, precisam em sua formação continuada para utilizar a internet em sala de aula? Como objetivo da pesquisa queremos identificar o que é necessário ser trabalhado numa formação continuada dos professores para uso da internet em sala de aula. O contexto para o desenvolvimento desta investigação dividiu-se em duas etapas, tendo como instrumento de coleta de dados um questionário, na primeira etapa da pesquisa e uma entrevista semiestruturada, realizada na segunda etapa. Participaram da pesquisa 12 professores de uma escola estadual de Curitiba/PR, que responderam de forma espontânea os questionários e destes foram selecionados 4 para participar da entrevista. A estruturação metodológica da pesquisa seguiu os princípios da pesquisa qualitativa, tomando por base os estudos de Alves-Mazzotti e Gewandsznadjer (1998), Laville e Dionne (1999), Lessard-Hébert, Goyette e Boutin (1990) e Günther (2006). O referencial teórico utilizado para a construção das reflexões sobre os envolvidos na formação do professor para uso da internet em sala de aula foram Marcelo-Garcia (1999), Lévy (1999), Moran (1997, 2001, 2011), Chantraine-Demailly (1995), Brito e Purificação (2011) e Abreu (2009) entre outros. Para a análise dos dados obtidos, utilizou-se a proposta de análise de conteúdo de Bardin (1977). Os resultados indicaram que a formação técnica é ainda a principal necessidade dos professores para ser trabalhada em cursos de formação para uso da internet em sala de aula. Dentre outros pontos que a análise apresentou, verificamos também que o grupo, embora sem ter em sua formação inicial preparação para uso da internet, já vivenciou uma prática com seus alunos. Palavras-chave: Internet. Formação continuada. Sala de aula.Abstract: The present research is inserted in the Culture, School and Education research line of the Education Sector from the Federal University of Paraná - UFPR, focusing on Education, Culture and Technology. The fact that technology entered into the school environment has been provoking changes in the daily classroom routine. Teachers noticed they vie for the attention of the students with an "invisible", but present element: the internet. Many teachers, or almost all of them are already cyberspace users, but few use it in class. Not being prepared for such usage is a common sense argument. From this understanding, it was defined the following research problem: what do high school teachers from state schools need in their lifelong learning for to use the internet in the classroom? As a research goal, we look forward to identifying what it needs to be addressed in lifelong learning courses for teachers regarding the internet use in the classroom. The context of this research development was divided into two stages, having a questionnaire as a data collection instrument in the first stage and a semi-structured interview, conducted during the second phase. 12 participants from a public school from Curitiba/PR answered the questionnaires spontaneously. From those, 4 were selected to participate in the interview. This study is a qualitative approach based on Alves-Mazzotti and Gewandsznadjer (1998), Laville and Dionne (1999), Lessard-Hébert, Goyette and Boutin (1990) and Günther (2006)'s methodology. The methodological structure of the research followed the principles of qualitative research, based on the studies of Alves-Mazzotti and Gewandsznadjer (1998), Laville and Dionne (1999), Lessard-Hébert, Goyette and Boutin (1990), and Günther (2006). The theoretical framework used for setting up teacher's reflection about the internet use in the classroom was Marcelo-Garcia (1999), Lévy (1999), Moran (1997, 2001, 2011), Chantraine-Demailly (1995), Brito and Purificação (2011), Abreu (2009) and others. For data analysis, we used content analysis according to Bardin's perspective (1977). The results indicated technical training is still the main necessity to be worked out in lifelong learnig courses for teachers. We also verifyed that the group has already experienced such practice while teaching although not having an initial internet use training. Keywords: Internet. Lifelong learning. Classroom

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice