Estimating the confidence level of white matter connections obtained with MRI tractography.

BACKGROUND: Since the emergence of diffusion tensor imaging, a lot of work has been done to better understand the properties of diffusion MRI tractography. However, the validation of the reconstructed fiber connections remains problematic in many respects. For example, it is difficult to assess whether a connection is the result of the diffusion coherence contrast itself or the simple result of other uncontrolled parameters like for example: noise, brain geometry and algorithmic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we propose a method to estimate the respective contributions of diffusion coherence versus other effects to a tractography result by comparing data sets with and without diffusion coherence contrast. We use this methodology to assign a confidence level to every gray matter to gray matter connection and add this new information directly in the connectivity matrix. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that whereas we can have a strong confidence in mid- and long-range connections obtained by a tractography experiment, it is difficult to distinguish between short connections traced due to diffusion coherence contrast from those produced by chance due to the other uncontrolled factors of the tractography methodology.

Development of mental disorders one year after exposure to psychosocial stressors; a cohort study in primary care patients with a physical complaint.

BACKGROUND: Mental disorders, common in primary care, are often associated with physical complaints. While exposure to psychosocial stressors and development or presence of principal mental disorders (i.e. depression, anxiety and somatoform disorders defined as multisomatoforme disorders) is commonly correlated, temporal association remains unproven. The study explores the onset of such disorders after exposure to psychosocial stressors in a cohort of primary care patients with at least one physical symptom. METHOD: The cohort study SODA (SOmatization, Depression and Anxiety) was conducted by 21 private-practice GPs and three fellow physicians in a Swiss academic primary care centre. GPs included patients via randomized daily identifiers. Depression, anxiety or somatoform disorders were identified by the full Patient Health Questionnaire (PHQ), a validated procedure to identify mental disorders based on DSM-IV criteria. The PHQ was also used to investigate exposure to psychosocial stressors (before the index consultation and during follow up) and the onset of principal mental disorders after one year of follow up. RESULTS: From November 2004 to July 2005, 1020 patients were screened for inclusion. 627 were eligible and 482 completed the PHQ one year later and were included in the analysis (77%). At one year, prevalence of principal mental disorders was 30/153 (19.6% CI95% 13.6; 26.8) for those initially exposed to a major psychosocial stressor and 26/329 (7.9% CI95% 5.2; 11.4) for those not. Stronger association exists between psychosocial stressors and depression (RR = 2.4) or anxiety (RR = 3.5) than multisomatoforme disorders (RR = 1.8). Patients who are "bothered a lot" (subjective distress) by a stressor are therefore 2.5 times (CI95% 1.5; 4.0) more likely to experience a mental disorder at one year. A history of psychiatric comorbidities or psychological treatment was not a confounding factor for developing a principal mental disorder after exposure to psychosocial stressors. CONCLUSION: This primary care study shows that patients with physical complaints exposed to psychosocial stressors had a higher risk for developing mental disorders one year later. This temporal association opens the field for further research in preventive care for mental diseases in primary care patients.

The structure of nervous tissue and of Gram-positive bacteria studied by cryo-electron microscopy of vitreous sections

Résumé La structure, ou l'architecture, des êtres vivants définit le cadre dans lequel la physique de la vie s'accomplit. La connaissance de cette structure dans ses moindres détails est un but essentiel de la biologie. Son étude est toutefois entravée par des limitations techniques. Malgré son potentiel théorique, la microscopie électronique n'atteint pas une résolution atomique lorsqu'elle est appliquée ä la matièxe biologique. Cela est dû en grande partie au fait qu'elle contient beaucoup d'eau qui ne résiste pas au vide du microscope. Elle doit donc être déshydratée avant d'être introduite dans un microscope conventionnel. Des artéfacts d'agrégation en découlent inévitablement. La cryo-microscopie électronique des sections vitreuses (CEMOVIS) a ëté développée afin de résoudre cela. Les spécimens sont vitrifiés, c.-à-d. que leur eau est immobilisée sans cristalliser par le froid. Ils sont ensuite coupés en sections ultrafines et celles-ci sont observées à basse température. Les spécimens sont donc observés sous forme hydratée et non fixée; ils sont proches de leur état natif. Durant longtemps, CEMOVIS était très difficile à exécuter mais ce n'est plus le cas. Durant cette thèse, CEMOVIS a été appliqué à différents spécimens. La synapse du système nerveux central a été étudiée. La présence dans la fente synaptique d'une forte densité de molécules organisées de manière périodique a été démontrée. Des particules luminales ont été trouvées dans Ies microtubules cérébraux. Les microtubules ont servi d'objets-test et ont permis de démontrer que des détails moléculaires de l'ordre du nm sont préservés. La compréhension de la structure de l'enveloppe cellulaire des bactéries Grampositives aété améliorée. Nos observations ont abouti à l'élaboration d'un nouveau modèle hypothétique de la synthèse de la paroi. Nous avons aussi focalisé notre attention sur le nucléoïde bactérien et cela a suscité un modèle de la fonction des différents états structuraux du nucléoïde. En conclusion, cette thèse a démontré que CEMOVIS est une excellente méthode poux étudier la structure d'échantillons biologiques à haute résolution. L'étude de la structure de divers aspects des êtres vivants a évoqué des hypothèses quant à la compréhension de leur fonctionnement. Summary The structure, or the architecture, of living beings defines the framework in which the physics of life takes place. Understanding it in its finest details is an essential goal of biology. Its study is however hampered by technical limitations. Despite its theoretical potential, electron microscopy cannot resolve individual atoms in biological matter. This is in great part due to the fact. that it contains a lot of water that cannot stand the vacuum of the microscope. It must therefore be dehydrated before being introduced in a conventional mìcroscope. Aggregation artefacts unavoidably happen. Cryo-electron microscopy of vitreous sections (CEMOVIS) has been developed to solve this problem. Specimens are vitrified, i.e. they are rapidly cooled and their water is immobilised without crystallising by the cold. They are then. sectioned in ultrathin slices, which are observed at low temperatures. Specimens are therefore observed in hydrated and unfixed form; they are close to their native state. For a long time, CEMOVIS was extremely tedious but this is not the case anymore. During this thesis, CEMOVIS was applied to different specimens. Synapse of central nervous system was studied. A high density of periodically-organised molecules was shown in the synaptic cleft. Luminal particles were found in brain microtubules. Microtubules, used as test specimen, permitted to demonstrate that molecular details of the order of nm .are preserved. The understanding of the structure of cell envelope of Gram-positive bacteria was improved. Our observations led to the elaboration of a new hypothetic model of cell wall synthesis. We also focused our attention on bacterial nucleoids and this also gave rise to a functional model of nucleoid structural states. In conclusion, this thesis demonstrated that CEMOVIS is an excellent method for studying the structure of bìologìcal specimens at high resolution. The study of the structure of various aspects of living beings evoked hypothesis for their functioning.

Las comunidades de líquenes de las rocas silíceas no volcánicas del SE de España

This study contains the results of a survey based on 200 relevés made, following the methodology of Klement (1955), in the provinces of Murcia, Almeria and Albacete, from the coast to 2000 msm, on siliceous rocks, mainly metamorphic schists and, more rarely, on quartzite. The climate is predominantly mediterranean and arid (from 180 to 500 mm of annual rainfall), and belongs to I11 and III(1V) types of Walter and Lieth, in the low regions, and to IV4 in the mountains. The coastal zone and also a lot of south-facing slopes enjoy fairly warm winters.

ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis.

The GTPases Rab3a and Rab27a and their effectors Granuphilin/Slp4 and Noc2 are essential regulators of neuroendocrine secretion. Chronic exposure of pancreatic beta-cells to supraphysiological glucose levels decreased selectively the expression of these proteins. This glucotoxic effect was mimicked by cAMP-raising agents and blocked by PKA inhibitors. We demonstrate that the transcriptional repressor ICER, which is induced in a PKA-dependent manner by chronic hyperglycemia and cAMP-raising agents, is responsible for the decline of the four genes. ICER overexpression diminished the level of Granuphilin, Noc2, Rab3a and Rab27a by binding to cAMP responsive elements located in the promoters of these genes and inhibited exocytosis of beta-cells in response to secretagogues. Moreover, the loss in the expression of the genes of the secretory machinery caused by glucose and cAMP-raising agents was prevented by an antisense construct that reduces ICER levels. We propose that induction of inappropriate ICER levels lead to defects in the secretory process of pancreatic beta-cells possibly contributing, in conjunction with other known deleterious effects of hyperglycemia, to defective insulin release in type 2 diabetes.

Glucose uptake, utilization, and signaling in GLUT2-null islets.

We previously reported that pancreatic islet beta-cells from GLUT2-null mice lost the first phase but preserved the second phase of glucose-stimulated insulin secretion (GSIS). Furthermore, we showed that the remaining secretory activity required glucose uptake and metabolism because it can be blocked by inhibition of oxidative phosphorylation. Here, we extend these previous studies by analyzing, in GLUT2-null islets, glucose transporter isoforms and glucokinase expression and by measuring glucose usage, GSIS, and glucose-stimulated insulin mRNA biosynthesis. We show that in the absence of GLUT2, no compensatory expression of either GLUT1 or GLUT3 is observed and that glucokinase is expressed at normal levels. Glucose usage by isolated islets was increased between 1 and 6 mmol/l glucose but was not further increased between 6 and 20 mmol/l glucose. Parallel GSIS measurements showed that insulin secretion was not stimulated between 2.8 and 6 mmol/l glucose but was increased by >4-fold between 6 and 20 mmol/l glucose. Stimulation by glucose of total protein and insulin biosynthesis was also markedly impaired in the absence of GLUT2. Finally, we re-expressed GLUT2 in GLUT2-null beta-cells using recombinant lentiviruses and demonstrated a restoration of normal GSIS. Together, these data show that in the absence of GLUT2, glucose can still be taken up by beta-cells, albeit at a low rate, and that this transport activity is unlikely to be attributed to GLUT1 or GLUT3. This uptake activity, however, is limiting for normal glucose utilization and signaling to secretion and translation. These data further demonstrate the key role of GLUT2 in murine beta-cells for glucose signaling to insulin secretion and biosynthesis.

En torno a los efectos de la edad en el aprendizaje escolar de una lengua extrangera

The purpose of this article is to treat a currently much debated issue, the effects of age on second language learning. To do so, we contrast data collected by our research team from over one thousand seven hundred young and adult learners with four popular beliefs or generalizations, which, while deeply rooted in this society, are not always corroborated by our data.Two of these generalizations about Second Language Acquisition (languages spoken in the social context) seem to be widely accepted: a) older children, adolescents and adults are quicker and more efficient at the first stages of learning than are younger learners; b) in a natural context children with an early start are more liable to attain higher levels of proficiency. However, in the context of Foreign Language Acquisition, the context in which we collect the data, this second generalization is difficult to verify due to the low number of instructional hours (a maximum of some 800 hours) and the lower levels of language exposure time provided. The design of our research project has allowed us to study differences observed with respect to the age of onset (ranging from 2 to 18+), but in this article we focus on students who began English instruction at the age of 8 (LOGSE Educational System) and those who began at the age of 11 (EGB). We have collected data from both groups after a period of 200 (Time 1) and 416 instructional hours (Time 2), and we are currently collecting data after a period of 726 instructional hours (Time 3). We have designed and administered a variety of tests: tests on English production and reception, both oral and written, and within both academic and communicative oriented approaches, on the learners' L1 (Spanish and Catalan), as well as a questionnaire eliciting personal and sociolinguistic information. The questions we address and the relevant empirical evidence are as follows: 1. "For young children, learning languages is a game. They enjoy it more than adults."Our data demonstrate that the situation is not quite so. Firstly, both at the levels of Primary and Secondary education (ranging from 70.5% in 11-year-olds to 89% in 14-year-olds) students have a positive attitude towards learning English. Secondly, there is a difference between the two groups with respect to the factors they cite as responsible for their motivation to learn English: the younger students cite intrinsic factors, such as the games they play, the methodology used and the teacher, whereas the older students cite extrinsic factors, such as the role of their knowledge of English in the achievement of their future professional goals. 2 ."Young children have more resources to learn languages." Here our data suggest just the opposite. The ability to employ learning strategies (actions or steps used) increases with age. Older learners' strategies are more varied and cognitively more complex. In contrast, younger learners depend more on their interlocutor and external resources and therefore have a lower level of autonomy in their learning. 3. "Young children don't talk much but understand a lot"This third generalization does seem to be confirmed, at least to a certain extent, by our data in relation to the analysis of differences due to the age factor and productive use of the target language. As seen above, the comparably slower progress of the younger learners is confirmed. Our analysis of interpersonal receptive abilities demonstrates as well the advantage of the older learners. Nevertheless, with respect to passive receptive activities (for example, simple recognition of words or sentences) no great differences are observed. Statistical analyses suggest that in this test, in contrast to the others analyzed, the dominance of the subjects' L1s (reflecting a cognitive capacity that grows with age) has no significant influence on the learning process. 4. "The sooner they begin, the better their results will be in written language"This is not either completely confirmed in our research. First of all, we perceive that certain compensatory strategies disappear only with age, but not with the number of instructional hours. Secondly, given an identical number of instructional hours, the older subjects obtain better results. With respect to our analysis of data from subjects of the same age (12 years old) but with a different number of instructional hours (200 and 416 respectively, as they began at the ages of 11 and 8), we observe that those who began earlier excel only in the area of lexical fluency. In conclusion, the superior rate of older learners appears to be due to their higher level of cognitive development, a factor which allows them to benefit more from formal or explicit instruction in the school context. Younger learners, however, do not benefit from the quantity and quality of linguistic exposure typical of a natural acquisition context in which they would be allowed to make use of implicit learning abilities. It seems clear, then, that the initiative in this country to begin foreign language instruction earlier will have positive effects only if it occurs in combination with either higher levels of exposure time to the foreign language, or, alternatively, with its use as the language of instruction in other areas of the curriculum.

Physiology of GLP-1--lessons from glucoincretin receptor knockout mice.

GLP-1 has both peripheral and central actions, as this hormone is secreted by gut endocrine cells and brainstem neurons projecting into the hypothalamus and other brain regions. GLP-1 has multiple regulatory functions participating in the control of glucose homeostasis, beta-cell proliferation and differentiation, food intake, heart rate and even learning. GLP-1 action depends on binding to a specific G-coupled receptor linked to activation of the adenylyl cyclase pathway. Analysis of mice with inactivation of the GLP-1 receptor gene has provided evidence that absence of GLP-1 action in the mouse, despite this hormone potent physiological effects when administered in vivo, only leads to mild abnormalities in glucose homeostasis without any change in body weight. However, a critical role for this hormone and its receptor was demonstrated in the function of the hepatoportal vein glucose sensor, in contrast to that of the pancreatic beta-cells, although absence of both GLP-1 and GIP receptors leads to a more severe phenotype characterized by a beta-cell-autonomous defect in glucose-stimulated insulin secretion. Together, the studies of these glucoincretin receptor knockout mice provide evidence that these hormones are part of complex regulatory systems where multiple redundant signals are involved.

Tolerância de porta-enxertos de videira ao alumínio do solo

Onze porta-enxertos e duas cultivares americanas de videira (Vitis spp) foram avaliadas mediante níveis de saturação por Al no solo (Cambissolo Húmico álico), objetivando alcançar a tolerância diferenciada ao Al. O trabalho foi conduzido em casa de vegetação, com seis tratamentos completamente casualizados e quatro repetições, na Embrapa-Centro Nacional de Pesquisa de Uva e Vinho, em Bento Gonçalves, RS, no período de 1987 a 1990. As características avaliadas foram: altura das plantas, comprimento das raízes, peso da matéria seca da parte aérea e das raízes e teores de P, K, Ca e Mg em folhas e raízes. Diante dos acréscimos ou aumentos verificados em cada característica (variação %) e por cultivar, foi possível estabelecer a tolerância diferenciada das cultivares. O teor de K na parte aérea não foi afetado pelos níveis de saturação por Al, enquanto os teores de Ca e Mg foram os mais afetados. O teor de P teve um comportamento estável entre os níveis de saturação por Al. As cultivares Isabel e Cunningham apresentaram diferença na tolerância ao Al do solo; a Cunningham teve melhor comportamento. Os porta-enxertos R99, Rupestris du Lot e Kober 5BB, juntamente com Isabel, foram os mais sensíveis ao Al, e P1103, 101-14 e 196-17Cl foram os mais tolerantes.

cDNA cloning and mapping of a novel islet-brain/JNK-interacting protein.

IB1/JIP-1 is a scaffold protein that regulates the c-Jun NH(2)-terminal kinase (JNK) signaling pathway, which is activated by environmental stresses and/or by treatment with proinflammatory cytokines including IL-1beta and TNF-alpha. The JNKs play an essential role in many biological processes, including the maturation and differentiation of immune cells and the apoptosis of cell targets of the immune system. IB1 is expressed predominantly in brain and pancreatic beta-cells where it protects cells from proapoptotic programs. Recently, a mutation in the amino-terminus of IB1 was associated with diabetes. A novel isoform, IB2, was cloned and characterized. Overall, both IB1 and IB2 proteins share a very similar organization, with a JNK-binding domain, a Src homology 3 domain, a phosphotyrosine-interacting domain, and polyacidic and polyproline stretches located at similar positions. The IB2 gene (HGMW-approved symbol MAPK8IP2) maps to human chromosome 22q13 and contains 10 coding exons. Northern and RT-PCR analyses indicate that IB2 is expressed in brain and in pancreatic cells, including insulin-secreting cells. IB2 interacts with both JNK and the JNK-kinase MKK7. In addition, ectopic expression of the JNK-binding domain of IB2 decreases IL-1beta-induced pancreatic beta-cell death. These data establish IB2 as a novel scaffold protein that regulates the JNK signaling pathway in brain and pancreatic beta-cells and indicate that IB2 represents a novel candidate gene for diabetes.

Naisen tehtävä : aviovaimot dementiapotilaan omaishoitajina

English summary: A woman's lot : wives as caregivers to their demented husbands

Prevalence and Distribution of Young Driver Distraction Errors in Naturalistic Driving, TPF-5(207), 2014

Naturalistic driving studies are the latest resource for gathering data associated with driver behavior. The University of Iowa has been studying teen driving using naturalistic methods since 2006. By instrumenting teen drivers’ vehicles with event-triggered video recorders (ETVR), we are able to record a 12-second video clip every time a vehicle exceeds a pre-set g-force threshold. Each of these video clips contains valuable data regarding the frequency and types of distractions present in vehicles driven by today’s young drivers. The 16-year old drivers who participated in the study had a distraction present in nearly half of the events that were captured. While a lot of attention has been given to the distractions associated with technology in the vehicle (cell phones, navigation devices, entertainment systems, etc.), the most frequent type of distraction coded was the presence of teen passengers engaging in conversation (45%). Cognitive distractions, such as singing along with the radio, were the second most common distraction. Cell phone use was the third most common distraction, detected in only 10% of the events containing distraction.

Insulin-secreting beta-cell dysfunction induced by human lipoproteins.

Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting beta-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDL-induced apoptosis of beta-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of beta-cell survival and may therefore contribute to the beta-cell dysfunction observed during the development of type 2 diabetes.

Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.

A complementary DNA for a glucagon-like peptide-1 receptor was isolated from a human pancreatic islet cDNA library. The isolated clone encoded a protein with 90% identity to the rat receptor. In stably transfected fibroblasts, the receptor bound [125I]GLP-1 with high affinity (Kd = 0.5 nM) and was coupled to adenylate cyclase as detected by a GLP-1-dependent increase in cAMP production (EC50 = 93 pM). Two peptides from the venom of the lizard Heloderma suspectum, exendin-4 and exendin-(9-39), displayed similar ligand binding affinities to the human GLP-1 receptor. Whereas exendin-4 acted as an agonist of the receptor, inducing cAMP formation, exendin-(9-39) was an antagonist of the receptor, inhibiting GLP-1-induced cAMP production. Because GLP-1 has been proposed as a potential agent for treatment of NIDDM, our present data will contribute to the characterization of the receptor binding site and the development of new agonists of this receptor.