Maternal cholestasis during pregnancy programs metabolic disease in offspring

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

AIMS The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

EChO

A dedicated mission to investigate exoplanetary atmospheres represents a major milestone in our quest to understand our place in the universe by placing our Solar System in context and by addressing the suitability of planets for the presence of life. EChO—the Exoplanet Characterisation Observatory—is a mission concept specifically geared for this purpose. EChO will provide simultaneous, multi-wavelength spectroscopic observations on a stable platform that will allow very long exposures. The use of passive cooling, few moving parts and well established technology gives a low-risk and potentially long-lived mission. EChO will build on observations by Hubble, Spitzer and ground-based telescopes, which discovered the first molecules and atoms in exoplanetary atmospheres. However, EChO’s configuration and specifications are designed to study a number of systems in a consistent manner that will eliminate the ambiguities affecting prior observations. EChO will simultaneously observe a broad enough spectral region—from the visible to the mid-infrared—to constrain from one single spectrum the temperature structure of the atmosphere, the abundances of the major carbon and oxygen bearing species, the expected photochemically-produced species and magnetospheric signatures. The spectral range and resolution are tailored to separate bands belonging to up to 30 molecules and retrieve the composition and temperature structure of planetary atmospheres. The target list for EChO includes planets ranging from Jupiter-sized with equilibrium temperatures T eq up to 2,000 K, to those of a few Earth masses, with T eq \u223c 300 K. The list will include planets with no Solar System analog, such as the recently discovered planets GJ1214b, whose density lies between that of terrestrial and gaseous planets, or the rocky-iron planet 55 Cnc e, with day-side temperature close to 3,000 K. As the number of detected exoplanets is growing rapidly each year, and the mass and radius of those detected steadily decreases, the target list will be constantly adjusted to include the most interesting systems. We have baselined a dispersive spectrograph design covering continuously the 0.4–16 μm spectral range in 6 channels (1 in the visible, 5 in the InfraRed), which allows the spectral resolution to be adapted from several tens to several hundreds, depending on the target brightness. The instrument will be mounted behind a 1.5 m class telescope, passively cooled to 50 K, with the instrument structure and optics passively cooled to \u223c45 K. EChO will be placed in a grand halo orbit around L2. This orbit, in combination with an optimised thermal shield design, provides a highly stable thermal environment and a high degree of visibility of the sky to observe repeatedly several tens of targets over the year. Both the baseline and alternative designs have been evaluated and no critical items with Technology Readiness Level (TRL) less than 4–5 have been identified. We have also undertaken a first-order cost and development plan analysis and find that EChO is easily compatible with the ESA M-class mission framework.

Data base on pelagic ciliates grazing and growth rate as a function of size, prey size and type compiled from the literature

Microzooplankton (the 20 to 200 µm size class of zooplankton) is recognised as an important part of marine pelagic ecosystems. In terms of biomass and abundance pelagic ciliates are one of the important groups of organism in microzooplankton. However, their rates - grazing and growth - , feeding behaviour and prey preferences are poorly known and understood. A set of data was assembled in order to derive a better understanding of pelagic ciliates rates, in response to parameters such as prey concentration, prey type (size and species), temperature and their own size. With these objectives, literature was searched for laboratory experiments with information on one or more of these parameters effect studied. The criteria for selection and inclusion in the database included: (i) controlled laboratory experiment with a known ciliates feeding on a known prey; (ii) presence of ancillary information about experimental conditions, used organisms - cell volume, cell dimensions, and carbon content. Rates and ancillary information were measured in units that meet the experimenter need, creating a need to harmonize the data units after collection. In addition different units can link to different mechanisms (carbon to nutritive quality of the prey, volume to size limits). As a result, grazing rates are thus available as pg C/(ciliate*h), µm**3/(ciliate*h) and prey cell/(ciliate*h); clearance rate was calculated if not given and growth rate is expressed as the growth rate per day.

CLIMA ORGANIZACIONAL E BURNOUT: UM ESTUDO COM SERVIDORES PÚBLICOS FEDERAIS

As condições inadequadas vivenciadas nas organizações afligem não só os trabalhadores da iniciativa privada, pois são igualmente encontradas no segmento estatal, contrariando a expectativa de que o aparato governamental eliminaria as condições insalubres e criaria outras melhores nas quais prevalecesse à promoção de saúde. Diante desse panorama questionou-se porque, uma vez que, pelo menos do ponto de vista da sociedade leiga, esses servidores estão submetidos a condições privilegiadas de trabalho. O presente estudo objetivou identificar e descrever possíveis relações entre o clima organizacional e o burnout em servidores públicos de uma instituição federal de ensino. Objetivou-se ainda descrever o clima organizacional predominante. A pesquisa realizada teve cunho quantitativo, tipo estudo de caso e exploratória. A coleta de dados deu-se por meio das escalas ECO (escala de clima organizacional), ECB (escala de caracterização do burnout) e um questionário sociodemográfico, todos os instrumentos autoaplicáveis eletronicamente disponíveis à instituição. Participaram do estudo 201 servidores públicos federais, com idade média de 37 anos, majoritariamente de nível superior e casados. Os resultados revelaram que cerca de um quarto dos participantes raramente experimentaram burnout, no entanto outra quarta parte deles frequentemente experimentaram altos níveis de burnout, resultado bastante expressivo. Os servidores perceberam clima organizacional mediano, destacando-se a boa coesão entre os colegas de trabalho e a percepção de baixa recompensa. Merece destaque a grande dispersão entre as percepções de clima, o que permite inferir haver subclimas não identificados nesta investigação, possivelmente ocasionados por uma força de clima fraca e pela participação dos servidores de unidades de ensino geograficamente distintas, geridas por gestores locais com relativa autonomia. Os resultados dos cálculos de correlação revelaram que, quanto menos os participantes percebem apoio da chefia e da organização, coesão entre colegas, e mais controle/pressão, mais exaustos se sentem, mais desumanizam as pessoas com quem tratam e mais se decepcionam no trabalho e vice-versa. Conforto físico menor está associado a maior desumanização e a mais decepção no trabalho e vice-versa; e que controle/pressão, relaciona-se positiva e fracamente com desumanização e vice-versa. Desta forma, a hipótese de que existe associação entre burnout e clima organizacional foi confirmada. Os resultados também revelaram que os servidores com burnout, perceberam pior clima organizacional que os seus pares sem burnout, confirmando a segunda hipótese. Esses servidores também se mostraram neutros quanto à percepção de apoio da chefia e conforto físico; não percebem controle pressão, nem recompensa; todavia percebem coesão entre os colegas. Esses resultados sugerem que os participantes têm se apoiado nessas relações para suportar a indiferença e ausência de estímulos experimentados no trabalho. Os resultados obtidos nesse estudo permitiram concluir que o clima organizacional é fraco, provavelmente influenciado por uma cultura organizacional fraca, explicando a heterogeneidade da percepção do clima organizacional pelos servidores. Além disso, embora haja burnout entre poucos participantes, há que se atentar que cerca de um quarto deles, encontra-se acometido desta síndrome e isto poderá contagiar os demais.

A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window

The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide therapeutic window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 ± 22% when the treatment is started 12 h before ischemia and by 63 ± 35% when started even 4 h after the onset of ischemia. The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1β-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E2 production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant therapeutic window.

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine/spermine N1-acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N1-acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N1,N2-bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N1,N11-diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N1,N11-diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.