Brain Glucose Transport and Phosphorylation Under Acute Insulin-Induced Hypoglycemia in Mice: An 18F-FDG PET Study.

We addressed the questions of how cerebral glucose transport and phosphorylation change under acute hypoglycemia and what the underlying mechanisms of adaptation are. METHODS: Quantitative (18)F-FDG PET combined with the acquisition of real-time arterial input function was performed on mice. Hypoglycemia was induced and maintained by insulin infusion. PET data were analyzed with the 2-tissue-compartment model for (18)F-FDG, and the results were evaluated with Michaelis-Menten saturation kinetics. RESULTS: Glucose clearance from plasma to brain (K1,glc) and the phosphorylation rate constant increased with decreasing plasma glucose (Gp), in particular at a Gp of less than 2.5 mmol/L. Estimated cerebral glucose extraction ratios taking into account an increased cerebral blood flow (CBF) at a Gp of less than 2 mmol/L were between 0.14 and 0.79. CBF-normalized K1,glc values were in agreement with saturation kinetics. Phosphorylation rate constants indicated intracellular glucose depletion at a Gp of less than 2-3 mmol/L. When brain regions were compared, glucose transport under hypoglycemia was lowest in the hypothalamus. CONCLUSION: Alterations in glucose transport and phosphorylation, as well as intracellular glucose depletion, under acute hypoglycemia can be modeled by saturation kinetics taking into account an increase in CBF. Distinct transport kinetics in the hypothalamus may be involved in its glucose-sensing function.

Anti-TNF Therapy in the Swiss Inflammatory Bowel Disease G8 Cohort

Background: A nti-TNF d rugs (Infliximab (IFX), Adalimumab (ADA), Certolizumab pegol (CZP)) are effective in inducing and maintaining response a nd remission in i nflammatory bowel disease (IBD). Insufficient response or side effects may lead to a switch o f the anti-TNF d rug. W e aimed to e valuate the frequency and reasons for anti-TNF switches. Methods: Analysis of data from the Swiss Inflammatory Bowel Disease Cohort (SIBDCS). Eighty percent of included patients were recruited in hospitals and 20% from private practice. Results: From 2,058 patients ( 1,172 with Crohn's disease (CD), 842 with ulcerative colitis (UC) and 44 with indeterminate colitis (IC)), 772 received at least one anti-TNF. Forty-eight % of patients w ith CD, 23% with U C, a nd 30% with IC w ere ever treated with an anti-TNF drug. There was no gender difference with respect to the frequency of a nti-TNF treatment. A total of 584 patients (76%) were treated with one, 142 (18%) with two, and 46 (6%) with three anti-TNF (of which 32 were female). A total of 89% patients were treated with IFX, 28% ADA and 13% with CZP. Overall response rate (defined as drop in CDAI >100 points) to anti-TNF was 50%, with best response rates for the first used anti-TNF. Reasons t o switch t he anti-TNF w ere in 11% a primary non-response, in 38% a loss of response and in 36% anti-TNF s ide effects o r intolerance ( reasons for 15% of treatment failures not documented). Conclusion: A nti-TNF d rugs were used in h alf of the CD patients a nd in o ne quarter of U C patients. Anti-TNF d rug switch d ue to insufficient response a nd/or side effects w as necessary in one quarter of IBD patients. IFX was mainly used as first-line therapy. Best response rates were observed for the first used anti-TNF. Following analyses will identify risk median treatment duration as well as risk factors for anti-TNF switch.

Hepatic Manifestations of Wilson Disease - CHUV Experience 2005-2010

Background and aim: Wilson disease (WD) is an inherited disorder ofhepatic copper excretion leading to toxic accumulation of copper in theliver as well as the brain, cornea, and other organs. The defect is due tomutations of the copper-transporting ATPase ATP7B. Here, we describethe adult cases of hepatic WD diagnosed at the CHUV between 2005and 2010.Methods: Clinical manifestions, results of diagnostic tests, and follow-upof adult patients with hepatic WD were recorded systematically.Results: Seven new adult cases of hepatic WD were diagnosed in ourcenter between 2005 and 2010. Three were women and 4 men, with amedian a ge at d iagnosis o f 24 (range, 1 8-56) years. Three patientspresented with acute liver failure (ALF), three with persistently elevatedliver function tests, and one with a dvanced cirrhosis. None hadneurological manifestations. Only one patient, presenting with ALF, had aKayser-Fleischer corneal ring. Median ceruloplasmin levels at diagnosiswere 0.13 (range, <0.03-0.30) g/l, median 24 h urinary copper excretion6.3 (range, 0.4-62.0) μmol/24 h, and median hepatic copperconcentration 591 (range, 284-1049) μg/g. At least one mutation in theATP7B g ene was i dentified in a ll patients. Allelic frequency of t hecommon H1069Q mutation was 14%. Two patients presenting with ALFand the one with advanced cirrhosis underwent successful l ivertransplantation. One patient with ALF recovered under chelator therapy.D-penicillamine was used as first-line chelator treatment, with a switch totrientine due to adverse effects in 2 out of 4 patients u nder l ong-termtreatment.Conclusions: The clinical presentation of WD and the performance ofdiagnostic tests are variable. A high index of suspicion i n clinicallycompatible situations i s key, with a combination of tests allowing thediagnosis of WD.

Drugs Associated with Hepatotoxicity and their Reporting Frequency of Liver Adverse Events in VigiBase (TM) Unified List Based on International Collaborative Work

BACKGROUND Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans. OBJECTIVE (i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase). DATA SOURCES AND EXTRACTION (i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase. DATA SYNTHESIS After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF. CONCLUSIONS This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Revisão dos gêneros Sitalces, Eusitalces e Parasitalces (Orthoptera, Acrididae, Abracrini) e descrição de três novos gêneros

Revisão dos gêneros Sitalces, Eusitalces e Parasitalces (Orthoptera, Acrididae, Abracrini) e descrição de três novos gêneros. Os gêneros sulamericanos de Abracrini Sitalces Stål, 1878, Eusitalces Bruner, 1911, Parasitalces Bruner, 1911, Liebermannacris gen. nov., Robustusacris gen. nov., e Arimacris gen. nov. são revisados, descritos, redescritos e redefinidos. Quatro espécies são novas combinações: Liebermannacris dorsualis (Giglio-Tos, 1898) comb. nov., Liebermannacris punctifrons (Stål,1878) comb. nov., Robustusacris balzapambae (Rehn, 1913) comb. nov., e Arimacris trinitatis (Bruner, 1906) comb. nov., todas removidas de Sitalces Stål, 1878. Nove espécies são novos sinônimos: Sitalces robustus Bruner, 1908 (de S. volxemi Stål, 1878); S. infuscatus Bruner, 1908, S. nudus Bruner, 1908, S. ovatipennis Bruner, 1908, S. madeirensis Rehn, 1916 (de Liebermannacris dorsualis (Giglio-Tos, 1898); S. rubripes Hebard, 1924 (de Robustusacris balzapambae (Rehn, 1913); E. amazonicus Günther, 1940 e S. apolinari Hebard, 1923 (de Eusitalces vittatus Bruner, 1911); E. rubripes Günther, 1940 (de P. vulneratus (Bruner,1919)). Lectótipos e paralectótipos são designados. São fornecidas chaves para identificação, medidas, mapa de distribuição geográfica e ilustrações dos gêneros e espécies.

Uusi institutionalismi EU-tutkimuksessa : suurista integraatioteorioista päätöksenteon ja verkostojen tutkimukseen

Olli Rehn

Melhoria da estrutura de um latossolo por sistemas de culturas em plantio direto nos Campos Gerais do Paraná

O plantio direto de qualidade depende de um manejo adequado do solo que promova melhorias em sua estrutura. Isso está associado ao sistema de culturas adotado. O objetivo deste trabalho foi avaliar a contribuição de sistemas de culturas de longo prazo (18 anos) na qualidade estrutural de um Latossolo Vermelho mesoférrico argiloso sob plantio direto nos Campos Gerais do Paraná. Foram avaliados cinco sistemas de culturas: trigo-soja [Tr-So]; aveia-milho-trigo-soja [Av-Mi-Tr-So]; ervilhaca-milho-trigo-soja [Er-Mi-Tr-So]; azevém-milho-azevém-soja [Az-Mi-Az-So]; e alfafa-milho [Alf-Mi]. Amostras de solo foram coletadas nas camadas de 0-5, 5-10 e 10-20 cm, em anéis volumétricos e em blocos com estrutura preservada. Na camada de 0-5 cm, as menores densidades de solo tenderam a ocorrer nos sistemas Av-Mi-Tr-So (0,96 Mg m-3) e Er-Mi-Tr-So (0,93 Mg m-3). Nas camadas de 5-10 e 10-20 cm, as menores densidades de solo ocorreram no sistema Alf-Mi (1,14 e 1,17 Mg m-3, respectivamente). Tendência coerente foi observada para a macroporosidade, que na camada superficial foi maior nos sistemas Av-Mi-Tr-So (0,29 m³ m-3) e Er-Mi-Tr-So (0,30 m³ m-3) e, nas camadas de 5-10 e 10-20 cm, tendeu a ser maior no sistema Alf-Mi (0,19 m³ m-3). A microporosidade não apresentou tendência clara entre os sistemas. A condutividade hidráulica saturada teve relação direta com a macroporosidade, com Er-Mi-Tr-So apresentando o maior valor na camada de 0-5 cm (224 mm h-1) e Alf-Mi nas camadas de 5-10 (170 mm h-1) e 10-20 cm (147 mm h-1). O sistema Er-Mi-Tr-So apresentou o menor diâmetro médio ponderado úmido de agregados na camada de 0-5 cm (2,39 mm), e o Tr-So, o maior (3,04 mm). Os maiores valores de resistência mecânica do solo à penetração foram observados no sistema Tr-So, superando 1,5 MPa na camada de 7,5 a 22,5 cm de profundidade. O sistema Alf-Mi apresentou o menor grau de compactação (0,2 MPa cm). Os resultados são atribuídos, principalmente, à ação das raízes das espécies que constituem os sistemas de culturas e à intensidade de tráfego de máquinas em cada sistema. Considerando a camada de 0-20 cm como um todo, o sistema semiperene Alf-Mi possui maior capacidade de promover melhorias na qualidade estrutural do solo, em comparação aos sistemas baseados em cultivos de espécies anuais. Sistemas bianuais de rotação, baseados em plantas de cobertura como aveia-preta ou ervilhaca, promovem melhorias na qualidade estrutural do solo em relação à sucessão trigo-soja.

MRS glucose mapping and PET joining forces: re-evaluation of the lumped constant in the rat brain under isoflurane anaesthesia.

Although numerous positron emission tomography (PET) studies with (18) F-fluoro-deoxyglucose (FDG) have reported quantitative results on cerebral glucose kinetics and consumption, there is a large variation between the absolute values found in the literature. One of the underlying causes is the inconsistent use of the lumped constants (LCs), the derivation of which is often based on multiple assumptions that render absolute numbers imprecise and errors hard to quantify. We combined a kinetic FDG-PET study with magnetic resonance spectroscopic imaging (MRSI) of glucose dynamics in Sprague-Dawley rats to obtain a more comprehensive view of brain glucose kinetics and determine a reliable value for the LC under isoflurane anaesthesia. Maps of Tmax /CMRglc derived from MRSI data and Tmax determined from PET kinetic modelling allowed to obtain an LC-independent CMRglc . The LC was estimated to range from 0.33 ± 0.07 in retrosplenial cortex to 0.44 ± 0.05 in hippocampus, yielding CMRglc between 62 ± 14 and 54 ± 11 μmol/min/100 g, respectively. These newly determined LCs for four distinct areas in the rat brain under isoflurane anaesthesia provide means of comparing the growing amount of FDG-PET data available from translational studies.

Nouveau recueil des factums du procez : d'entre défunt M. l'abbé Furetière, l'un des quarante de l'Académie françoise, et quelques-uns des autres membres de la même Académie... ([Reprod.], Dernière éd. considérablement augmentée) / [A. Furetière]

[Factum. Furetière, Antoine. 1655-1688]

Élémens de grammaire générale : appliqués à la langue française. T. 2 / par M. l'abbé Sicard,...

Collection : Archives de la linguistique française ; 364