ADAMTS13 gene variants and function in women with preeclampsia: a population- based nested case- control study from the HUNT Study.

INTRODUCTION Known genetic variants with reference to preeclampsia only explain a proportion of the heritable contribution to the development of this condition. The association between preeclampsia and the risk of cardiovascular disease later in life has encouraged the study of genetic variants important in thrombosis and vascular inflammation also in relation to preeclampsia. The von Willebrand factor-cleaving protease, ADAMTS13, plays an important role in micro vascular thrombosis, and partial deficiencies of this enzyme have been observed in association with cardiovascular disease and preeclampsia. However, it remains unknown whether decreased ADAMTS13 levels represent a cause or an effect of the event in placental and cardiovascular disease. METHODS We studied the distribution of three functional genetic variants of ADAMTS13, c.1852C>G (rs28647808), c.4143_4144dupA (rs387906343), and c.3178C>T (rs142572218) in women with preeclampsia and their controls in a nested case-control study from the second Nord-Trøndelag Health Study (HUNT2). We also studied the association between ADAMTS13 activity and preeclampsia, in serum samples procured unrelated in time of the preeclamptic pregnancy. RESULTS No differences were observed in genotype, allele or haplotype frequencies of the different ADAMTS13 variants when comparing cases and controls, and no association to preeclampsia was found with lower levels of ADAMTS13 activity. CONCLUSION Our findings indicate that ADAMTS13 variants and ADAMTS13 activity do not contribute to an increased risk of preeclampsia in the general population.

Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy.

The complex relation between thrombotic thrombocytopenic purpura (TTP) and pregnancy is concisely reviewed. Pregnancy is a very strong trigger for acute disease manifestation in patients with hereditary TTP caused by double heterozygous or homozygous mutations of ADAMTS13 (ADisintegrin And Metalloprotease with ThromboSpondin type 1 domains, no. 13). In several affected women disease onset during their first pregnancy leads to the diagnosis of hereditary TTP. Without plasma treatment mother and especially fetus are at high risk of dying. The relapse risk during a next pregnancy is almost 100% but regular plasma transfusion starting in early pregnancy will prevent acute TTP flare-up and may result in successful pregnancy outcome. Pregnancy may also constitute a mild risk factor for the onset of acute acquired TTP caused by autoantibody-mediated severe ADAMTS13 deficiency. Women having survived acute acquired TTP may not be at very high risk of TTP relapse during an ensuing next pregnancy but seem to have an elevated risk of preeclampsia. Monitoring of ADAMTS13 activity and inhibitor titre during pregnancy may help to guide management and to avoid disease recurrence. Finally, TTP needs to be distinguished from the much more frequent hypertensive pregnancy complications, preeclampsia and especially HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome.

Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency.

The congenital form of thrombotic thrombocytopenic purpura (TTP) is caused by genetic mutations in ADAMTS13. Some, but not all, congenital TTP patients manifest renal insufficiency in addition to microangiopathic hemolysis and thrombocytopenia. We included 32 congenital TTP patients in the present study, which was designed to assess whether congenital TTP patients with renal insufficiency have predisposing mutations in complement regulatory genes, as found in many patients with atypical hemolytic uremic syndrome (aHUS). In 13 patients with severe renal insufficiency, six candidate complement or complement regulatory genes were sequenced and 11 missense mutations were identified. One of these missense mutations, C3:p.K155Q mutation, is a rare mutation located in the macroglobulin-like 2 domain of C3, where other mutations predisposing for aHUS cluster. Several of the common missense mutations identified in our study have been reported to increase disease-risk for aHUS, but were not more common in patients with as compared to those without renal insufficiency. Taken together, our results show that the majority of the congenital TTP patients with renal insufficiency studied do not carry rare genetic mutations in complement or complement regulatory genes.

Geochemistry and oxygen and iron isotope ratios of mafic rocks

Recycling of oceanic crust into the deep mantle via subduction is a widely accepted mechanism for creating compositional heterogeneity in the upper mantle and for explaining the distinct geochemistry of mantle plumes. The oxygen isotope ratios (d18O) of some ocean island basalts (OIB) span values both above and below that of unmetasomatised upper mantle (5.5 ± 0.4 per mil) and provide support for this hypothesis, as it is widely assumed that most variations in d18O are produced by near-surface low-temperature processes. Here we show a significant linear relationship between d18O and stable iron isotope ratios (d57Fe) in a suite of pristine eclogite xenoliths. The d18O values of both bulk samples and garnets range from values within error of normal mantle to significantly lighter values. The observed range and correlation between d18O and d57Fe is unlikely to be inherited from oceanic crust, as d57Fe values determined for samples of hydrothermally altered oceanic crust do not differ significantly from the mantle value and show no correlation with d18O. It is proposed that the correlated d57Fe and d18O variations in this particular eclogite suite are predominantly related to isotopic fractionation by disequilibrium partial melting although modification by melt percolation processes cannot be ruled out. Fractionation of Fe and O isotopes by removal of partial melt enriched in isotopically heavy Fe and O is supported by negative correlations between bulk sample d57Fe and Cr content and bulk sample and garnet d18O and Sc contents, as Cr and Sc are elements that become enriched in garnet- and pyroxene-bearing melt residues. Melt extraction could take place either during subduction, where the eclogites represent the residues of melted oceanic lithosphere, or could take place during long-term residence within the lithospheric mantle, in which case the protoliths of the eclogites could be of either crustal or mantle origin. This modification of both d57Fe and d18O by melting processes and specifically the production of low-d18O signatures in mafic rocks implies that some of the isotopically light d18O values observed in OIB and eclogite xenoliths may not necessarily reflect near-surface processes or components.

GESTÃO DO CONHECIMENTO: UM ESTUDO SOBRE A RELAÇÃO ENTRE A LIDERANÇA TRANSFORMACIONAL, A CONVERSÃO DO CONHECIMENTO E A EFICÁCIA ORGANIZACIONAL

Este estudo teve como objetivo principal analisar a relação entre a Liderança Transformacional, a Conversão do Conhecimento e a Eficácia Organizacional. Foram considerados como pressupostos teóricos conceitos consolidados sobre os temas desta relação, além de recentes pesquisas já realizadas em outros países e contextos organizacionais. Com base nisto identificou-se potencial estudo de um modelo que relacionasse estes três conceitos. Para tal considera-se que as organizações que buscam atingir Vantagem Competitiva e incorporam a Knowledge-Based View possam conquistar diferenciação frente a seus concorrentes. Nesse contexto o conhecimento ganha maior destaque e papel protagonista nestas organizações. Dessa forma criar conhecimento através de seus colaboradores, passa a ser um dos desafios dessas organizações ao passo que sugere melhoria de seus indicadores Econômicos, Sociais, Sistêmicos e Políticos, o que se define por Eficácia Organizacional. Portanto os modos de conversão do conhecimento nas organizações, demonstram relevância, uma vez que se cria e se converte conhecimentos através da interação entre o conhecimento existente de seus colaboradores. Essa conversão do conhecimento ou modelo SECI possui quatro modos que são a Socialização, Externalização, Combinação e Internalização. Nessa perspectiva a liderança nas organizações apresenta-se como um elemento capaz de influenciar seus colaboradores, propiciando maior dinâmica ao modelo SECI de conversão do conhecimento. Se identifica então na liderança do tipo Transformacional, características que possam influenciar colaboradores e entende-se que esta relação entre a Liderança Transformacional e a Conversão do Conhecimento possa ter influência positiva nos indicadores da Eficácia Organizacional. Dessa forma esta pesquisa buscou analisar um modelo que explorasse essa relação entre a liderança do tipo Transformacional, a Conversão do Conhecimento (SECI) e a Eficácia Organizacional. Esta pesquisa teve o caráter quantitativo com coleta de dados através do método survey, obtendo um total de 230 respondentes válidos de diferentes organizações. O instrumento de coleta de dados foi composto por afirmativas relativas ao modelo de relação pesquisado com um total de 44 itens. O perfil de respondentes concentrou-se entre 30 e 39 anos de idade, com a predominância de organizações privadas e de departamentos de TI/Telecom, Docência e Recursos Humanos respectivamente. O tratamento dos dados foi através da Análise Fatorial Exploratória e Modelagem de Equações Estruturais via Partial Least Square Path Modeling (PLS-PM). Como resultado da análise desta pesquisa, as hipóteses puderam ser confirmadas, concluindo que a Liderança Transformacional apresenta influência positiva nos modos de Conversão do Conhecimento e que; a Conversão do Conhecimento influencia positivamente na Eficácia Organizacional. Ainda, concluiu-se que a percepção entre os respondentes não apresenta resultado diferente sobre o modelo desta pesquisa entre quem possui ou não função de liderança.

Meta-analysis of short term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis

Objective: To determine whether short term, oral low dose prednisolone (⩽15 mg daily) is superior to placebo and non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis.

Depletion of Acyl-Coenzyme A-Binding Protein Affects Sphingolipid Synthesis and Causes Vesicle Accumulation and Membrane Defects in Saccharomyces cerevisiae

Deletion of the yeast gene ACB1 encoding Acb1p, the yeast homologue of the acyl-CoA-binding protein (ACBP), resulted in a slower growing phenotype that adapted into a faster growing phenotype with a frequency >1:105. A conditional knockout strain (Y700pGAL1-ACB1) with the ACB1 gene under control of the GAL1 promoter exhibited an altered acyl-CoA profile with a threefold increase in the relative content of C18:0-CoA, without affecting total acyl-CoA level as previously reported for an adapted acb1Δ strain. Depletion of Acb1p did not affect the general phospholipid pattern, the rate of phospholipid synthesis, or the turnover of individual phospholipid classes, indicating that Acb1p is not required for general glycerolipid synthesis. In contrast, cells depleted for Acb1p showed a dramatically reduced content of C26:0 in total fatty acids and the sphingolipid synthesis was reduced by 50–70%. The reduced incorporation of [3H]myo-inositol into sphingolipids was due to a reduced incorporation into inositol-phosphoceramide and mannose-inositol-phosphoceramide only, a pattern that is characteristic for cells with aberrant endoplasmic reticulum to Golgi transport. The plasma membrane of the Acb1p-depleted strain contained increased levels of inositol-phosphoceramide and mannose-inositol-phosphoceramide and lysophospholipids. Acb1p-depleted cells accumulated 50- to 60-nm vesicles and autophagocytotic like bodies and showed strongly perturbed plasma membrane structures. The present results strongly suggest that Acb1p plays an important role in fatty acid elongation and membrane assembly and organization.

Radial and longitudinal diffusion of myoglobin in single living heart and skeletal muscle cells

We have used a fluorescence recovery after photobleaching (FRAP) technique to measure radial diffusion of myoglobin and other proteins in single skeletal and cardiac muscle cells. We compare the radial diffusivities, Dr (i.e., diffusion perpendicular to the long fiber axis), with longitudinal ones, Dl (i.e., parallel to the long fiber axis), both measured by the same technique, for myoglobin (17 kDa), lactalbumin (14 kDa), and ovalbumin (45 kDa). At 22°C, Dl for myoglobin is 1.2 × 10−7 cm2/s in soleus fibers and 1.1 × 10−7 cm2/s in cardiomyocytes. Dl for lactalbumin is similar in both cell types. Dr for myoglobin is 1.2 × 10−7 cm2/s in soleus fibers and 1.1 × 10−7 cm2/s in cardiomyocytes and, again, similar for lactalbumin. Dl and Dr for ovalbumin are 0.5 × 10−7 cm2/s. In the case of myoglobin, both Dl and Dr at 37°C are about 80% higher than at 22°C. We conclude that intracellular diffusivity of myoglobin and other proteins (i) is very low in striated muscle cells, ≈1/10 of the value in dilute protein solution, (ii) is not markedly different in longitudinal and radial direction, and (iii) is identical in heart and skeletal muscle. A Krogh cylinder model calculation holding for steady-state tissue oxygenation predicts that, based on these myoglobin diffusivities, myoglobin-facilitated oxygen diffusion contributes 4% to the overall intracellular oxygen transport of maximally exercising skeletal muscle and less than 2% to that of heart under conditions of high work load.

Essentials of physiological chemistry.

Includes bibliography.

The respiratory exchange of animals and man,

Bibliography: p. 151-168.

The anatomy and physiology of capillaries.

Bibliography: p. [268]-276.

GESTÃO DO CONHECIMENTO: UM ESTUDO SOBRE A RELAÇÃO ENTRE A LIDERANÇA TRANSFORMACIONAL, A CONVERSÃO DO CONHECIMENTO E A EFICÁCIA ORGANIZACIONAL

Este estudo teve como objetivo principal analisar a relação entre a Liderança Transformacional, a Conversão do Conhecimento e a Eficácia Organizacional. Foram considerados como pressupostos teóricos conceitos consolidados sobre os temas desta relação, além de recentes pesquisas já realizadas em outros países e contextos organizacionais. Com base nisto identificou-se potencial estudo de um modelo que relacionasse estes três conceitos. Para tal considera-se que as organizações que buscam atingir Vantagem Competitiva e incorporam a Knowledge-Based View possam conquistar diferenciação frente a seus concorrentes. Nesse contexto o conhecimento ganha maior destaque e papel protagonista nestas organizações. Dessa forma criar conhecimento através de seus colaboradores, passa a ser um dos desafios dessas organizações ao passo que sugere melhoria de seus indicadores Econômicos, Sociais, Sistêmicos e Políticos, o que se define por Eficácia Organizacional. Portanto os modos de conversão do conhecimento nas organizações, demonstram relevância, uma vez que se cria e se converte conhecimentos através da interação entre o conhecimento existente de seus colaboradores. Essa conversão do conhecimento ou modelo SECI possui quatro modos que são a Socialização, Externalização, Combinação e Internalização. Nessa perspectiva a liderança nas organizações apresenta-se como um elemento capaz de influenciar seus colaboradores, propiciando maior dinâmica ao modelo SECI de conversão do conhecimento. Se identifica então na liderança do tipo Transformacional, características que possam influenciar colaboradores e entende-se que esta relação entre a Liderança Transformacional e a Conversão do Conhecimento possa ter influência positiva nos indicadores da Eficácia Organizacional. Dessa forma esta pesquisa buscou analisar um modelo que explorasse essa relação entre a liderança do tipo Transformacional, a Conversão do Conhecimento (SECI) e a Eficácia Organizacional. Esta pesquisa teve o caráter quantitativo com coleta de dados através do método survey, obtendo um total de 230 respondentes válidos de diferentes organizações. O instrumento de coleta de dados foi composto por afirmativas relativas ao modelo de relação pesquisado com um total de 44 itens. O perfil de respondentes concentrou-se entre 30 e 39 anos de idade, com a predominância de organizações privadas e de departamentos de TI/Telecom, Docência e Recursos Humanos respectivamente. O tratamento dos dados foi através da Análise Fatorial Exploratória e Modelagem de Equações Estruturais via Partial Least Square Path Modeling (PLS-PM). Como resultado da análise desta pesquisa, as hipóteses puderam ser confirmadas, concluindo que a Liderança Transformacional apresenta influência positiva nos modos de Conversão do Conhecimento e que; a Conversão do Conhecimento influencia positivamente na Eficácia Organizacional. Ainda, concluiu-se que a percepção entre os respondentes não apresenta resultado diferente sobre o modelo desta pesquisa entre quem possui ou não função de liderança.

Relationship between sunlight and the age of onset of bipolar disorder:an international multisite study

Background - The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. Methods - Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. Results - There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. Limitations - Recall bias for onset and family history data. Conclusions - A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

Influence of birth cohort on age of onset cluster analysis in bipolar I disorder

PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

Influence of light exposure during early life on the age of onset of bipolar disorder

Background: Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association. Methods: Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4N and 70.7N, and 1.2S and 41.3S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation. Results: More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model. Conclusions: Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.