Growth hormone pharmacogenetics: the interactive effect of a microsatellite in the IGF1 promoter region with the GHR-exon 3 and-202 A/C IGFBP3 variants on treatment outcomes of children with severe GH deficiency

Insulin-like growth factor type 1 (IGF1) is a mediator of growth hormone (GH) action, and therefore, IGF1 is a candidate gene for recombinant human GH (rhGH) pharmacogenetics. Lower serum IGF1 levels were found in adults homozygous for 19 cytosine-adenosine (CA) repeats in the IGF1 promoter. The aim of this study was to evaluate the influence of (CA)n IGF1 polymorphism, alone or in combination with GH receptor (GHR)-exon 3 and -202 A/C insulin-like growth factor binding protein-3 (IGFBP3) polymorphisms, on the growth response to rhGH therapy in GH-deficient (GHD) patients. Eighty-four severe GHD patients were genotyped for (CA) n IGF1, -202 A/C IGFBP3 and GHR-exon 3 polymorphisms. Multiple linear regressions were performed to estimate the effect of each genotype, after adjustment for other influential factors. We assessed the influence of genotypes on the first year growth velocity (1st y GV) (n = 84) and adult height standard deviation score (SDS) adjusted for target-height SDS (AH-TH SDS) after rhGH therapy (n = 37). Homozygosity for the IGF1 19CA repeat allele was negatively correlated with 1st y GV (P = 0.03) and AH-TH SDS (P = 0.002) in multiple linear regression analysis. In conjunction with clinical factors, IGF1 and IGFBP3 genotypes explain 29% of the 1st y GV variability, whereas IGF1 and GHR polymorphisms explain 59% of final height-target-height SDS variability. We conclude that homozygosity for IGF1 (CA) 19 allele is associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with severe GHD. Furthermore, this polymorphism exhibits a non-additive interaction with -202 A/C IGFBP3 genotype on the 1st y GV and with GHR-exon 3 genotype on adult height. The Pharmacogenomics Journal (2012) 12, 439-445; doi:10.1038/tpj.2011.13; published online 5 April 2011

The Interactive Effect of GHR-Exon 3 and -202 A/C IGFBP3 Polymorphisms on rhGH Responsiveness and Treatment Outcomes in Patients with Turner Syndrome

Context: There is great interindividual variability in the response to recombinant human (rh) GH therapy in patients with Turner syndrome (TS). Ascertaining genetic factors can improve the accuracy of growth response predictions. Objective: The objective of the study was to assess the individual and combined influence of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on the short-and long-term outcomes of rhGH therapy in patients with TS. Design and Patients: GHR-exon 3 and -202 A/C IGFBP3 genotyping (rs2854744) was correlated with height data of 112 patients with TS who remained prepubertal during the first year of rhGH therapy and 65 patients who reached adult height after 5 +/- 2.5 yr of rhGH treatment. Main Outcome Measures: First-year growth velocity and adult height were measured. Results: Patients carrying at least one GHR-d3 or -202 A-IGFBP3 allele presented higher mean first-year growth velocity and achieved taller adult heights than those homozygous for GHR-fl or -202 C-IGFBP3 alleles, respectively. The combined analysis of GHR-exon 3 and -202 A/C IGFBP3 genotypes showed a clear nonadditive epistatic influence on adult height of patients with TS treated with rhGH (GHR-exon 3 alone, R-2 = 0.27; -202 A/C IGFBP3, R-2 = 0.24; the combined genotypes, R-2 = 0.37 at multiple linear regression). Together with clinical factors, these genotypes accounted for 61% of the variability in adult height of patients with TS after rhGH therapy. Conclusion: Homozygosity for the GHR-exon3 full-length allele and/or the -202C-IGFBP3 allele are associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with TS. (J Clin Endocrinol Metab 97: E671-E677, 2012)

New constraints on the genesis and long-term stability of Os-rich alloys in the Earth's mantle

A variety of seemingly unrelated processes, such as core-mantle interaction, desulfurization, and direct precipitation from a silicate melt have been proposed to explain the formation of Ru-Os-Ir alloys (here referred to as osmiridiums) found in terrestrial mantle rocks. However, no consensus has yet been reached on how these important micrometer-sized phases form. In this paper we report the results of an experimental study on the solubilities of Ru, Os and Ir in sulfide melts (or mattes) as a function of alloy composition at 1300 degrees C. Considering the low solubilities of Ru, Os, and Ir in silicate melts, coupled with their high matte/silicate-melt partition coefficients, our results indicate that these elements concentrate initially at the ppm level in a matte phase in the mantle source region. During partial melting, the extraction of sulfur into silicate melt leads to a decrease in fS(2) that triggers the exsolution of osmiridiums from the refractory matte in the residue. The newly formed osmiridiums may persist in the terrestrial mantle for periods exceeding billions of years. (C) 2012 Elsevier Ltd. All rights reserved.

Vehicle emissions and PM2.5 mass concentrations in six Brazilian cities

In Brazil, the principal source of air pollution is the combustion of fuels (ethanol, gasohol, and diesel). In this study, we quantify the contributions that vehicle emissions make to the urban fine particulate matter (PM2.5) mass in six state capitals in Brazil, collecting data for use in a larger project evaluating the impact of air pollution on human health. From winter 2007 to winter 2008, we collected 24-h PM2.5 samples, employing gravimetry to determine PM2.5 mass concentrations; reflectance to quantify black carbon concentrations; X-ray fluorescence to characterize elemental composition; and ion chromatography to determine the composition and concentrations of anions and cations. Mean PM2.5 concentrations in the cities of Sao Paulo, Rio de Janeiro, Belo Horizonte, Curitiba, Porto Alegre, and Recife were 28, 17.2, 14.7, 14.4, 13.4, and 7.3 mu g/m(3), respectively. In Sao Paulo and Rio de Janeiro, black carbon explained approximately 30% of the PM2.5 mass. We used receptor models to identify distinct source-related PM2.5 fractions and correlate those fractions with daily mortality rates. Using specific rotation factor analysis, we identified the following principal contributing factors: soil and crustal material; vehicle emissions and biomass burning (black carbon factor); and fuel oil combustion in industries (sulfur factor). In all six cities, vehicle emissions explained at least 40% of the PM2.5 mass. Elemental composition determination with receptor modeling proved an adequate strategy to identify air pollution sources and to evaluate their short- and long-term effects on human health. Our data could inform decisions regarding environmental policies vis-a-vis health care costs.

High sodium intake adversely affects oxidative-inflammatory response, cardiac remodelling and mortality after myocardial infarction

Objective: Enhanced sodium intake increases volume overload, oxidative stress and production of proinflammatory cytokines. In animal models, increased sodium intake favours ventricular dysfunction after myocardial infarction (MI). The aim of this study was to investigate, in human subjects presenting with ST-segment elevation MI (STEMI), the impact of sodium intake prior the coronary event. Methods: Consecutive patients (n = 372) admitted within the first 24 h of STEMI were classified by a food intake questionnaire as having a chronic daily intake of sodium higher (HS) or lower (LS) than 1.2 g in the last 90 days before MI. Plasma levels of 8-isoprostane, interleucin-2 (IL-2), tumour necrosis factor type alpha (TNF-alpha), C-reactive protein (CRP) and brain natriuretic peptide (BNP) were measured at admission and at the fifth day. Magnetic resonance imaging was performed immediately after discharge. Total mortality and recurrence of acute coronary events were investigated over 4 years of follow-up. Results: The decrease of 8-isoprostane was more prominent and the increase of IL-2, TNF-alpha and CRP less intense during the first 5 days in LS than in HS patients (p < 0.05). Sodium intake correlated with change in plasma BNP between admission and fifth day (r = 0.46; p < 0.0001). End-diastolic volumes of left atrium and left ventricle were greater in HS than in LS patients (p < 0.05). In the first 30 days after MI and up to 4 years afterwards, total mortality was higher in HS than in LS patients (p < 0.05). Conclusion: Excessive sodium intake increases oxidative stress, inflammatory response, myocardial stretching and dilatation, and short and long-term mortality after STEMI. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Consolidation of international guidelines for the management of canine populations in urban areas and proposal of performance indicators

Consolidation of international guidelines for the management of canine populations in urban areas and proposal of performance indicators The objective of this study is to propose a generic program for the management of urban canine populations with suggestion of performance indicators. The following international guidelines on canine population management were revised and consolidated: World Health Organization, World Organisation for Animal Health, World Society for the Protection of Animals, International Companion Animal Management Coalition, and the Food and Agriculture Organization. Management programs should cover: situation diagnosis, including estimates of population size; social participation with involvement of various sectors in the planning and execution of strategies; educational actions to promote humane values, animal welfare, community health, and responsible ownership (through purchase or adoption); environmental and waste management to eliminate sources of food and shelter; registration and identification of animals; animal health care, reproductive control; prevention and control of zoonoses; control of animal commerce; management of animal behavior and adequate solutions for abandoned animals; and laws regulating responsible ownership, prevention of abandonment and zoonoses. To monitor these actions, four groups of indicators are suggested: animal population indicators, human/animal interaction indicators, public service indicators, and zoonosis indicators. The management of stray canine populations requires political, sanitary, ethologic, ecologic, and humanitarian strategies that are socially acceptable and environmentally sustainable. Such measures must also include the control of zoonoses such as rabies and leishmaniasis, considering the concept of "one health," which benefits both the animals and people in the community.

Assessing the effects of multiple infections and long latency in the dynamics of tuberculosis

In order to achieve a better understanding of multiple infections and long latency in the dynamics of Mycobacterium tuberculosis infection, we analyze a simple model. Since backward bifurcation is well documented in the literature with respect to the model we are considering, our aim is to illustrate this behavior in terms of the range of variations of the model's parameters. We show that backward bifurcation disappears (and forward bifurcation occurs) if: (a) the latent period is shortened below a critical value; and (b) the rates of super-infection and re-infection are decreased. This result shows that among immunosuppressed individuals, super-infection and/or changes in the latent period could act to facilitate the onset of tuberculosis. When we decrease the incubation period below the critical value, we obtain the curve of the incidence of tuberculosis following forward bifurcation; however, this curve envelops that obtained from the backward bifurcation diagram.

Friction and wear of performance of MoDTC and ester-containing lubrificants over steel surfaces under reciprocating conditions

Since the earliest developments of human history, friction has been a major issue. From the invention of the wheel and the use of the first lubricants to the studiesof coated and microtexturized surfaces, significant effort has been put on improvements that couldovercome the resistance to motion. Areview by Holmberg, Andersson and Erdemir[1] shows that, in an average passenger car, about one third of the total energy consumptionis due to friction losses. Of these, another one third is consumed in the engine system. The optimization of the lubricating oil formulation used ininternal combustion enginesis an important way to reduce friction, therefore improving energeticefficiencyand controllingemissions.Lubrication is also a way to assure the required protection to the system by maintaining wear rates in an adequate level, which helps to minimize maintenance costs.

Effects of ocean acidification on the brown alga "Padina pavonica": decalcification due to acute and chronic events

[EN] Since the industrial revolution, anthropogenic CO2 emissions have caused ocean acidification, which particularly affects calcified organisms. Given the fan-like calcified fronds of the brown alga Padina pavonica, we evaluated the acute (shortterm) effects of a sudden pH drop due to a submarine volcanic eruption (October 2011–early March 2012) affecting offshore waters around El Hierro Island (Canary Islands, Spain). We further studied the chronic (long-term) effects of the continuous decrease in pH in the last decades around the Canarian waters. In both the observational and retrospective studies (using herbarium collections of P. pavonica thalli from the overall Canarian Archipelago), the percent of surface calcium carbonate coverage of P. pavonica thalli were contrasted with oceanographic data collected either in situ (volcanic eruption event) or from the ESTOC marine observatory data series (herbarium study). Results showed that this calcified alga is sensitive to acute and chronic environmental pH changes. In both cases, pH changes predicted surface thallus calcification, including a progressive decalcification over the last three decades. This result concurs with previous studies where calcareous organisms decalcify under more acidic conditions. Hence, Padina pavonica can be implemented as a bio-indicator of ocean acidification (at short and long time scales) for monitoring purposes over wide geographic ranges, as this macroalga is affected and thrives (unlike strict calcifiers) under more acidic conditions

Creep and damage models for the service behaviour of structural members

Deformability is often a crucial to the conception of many civil-engineering structural elements. Also, design is all the more burdensome if both long- and short-term deformability has to be considered. In this thesis, long- and short-term deformability has been studied from the material and the structural modelling point of view. Moreover, two materials have been handled: pultruded composites and concrete. A new finite element model for thin-walled beams has been introduced. As a main assumption, cross-sections rigid are considered rigid in their plane; this hypothesis replaces that of the classical beam theory of plane cross-sections in the deformed state. That also allows reducing the total number of degrees of freedom, and therefore making analysis faster compared with twodimensional finite elements. Longitudinal direction warping is left free, allowing describing phenomena such as the shear lag. The new finite-element model has been first applied to concrete thin-walled beams (such as roof high span girders or bridge girders) subject to instantaneous service loadings. Concrete in his cracked state has been considered through a smeared crack model for beams under bending. At a second stage, the FE-model has been extended to the viscoelastic field and applied to pultruded composite beams under sustained loadings. The generalized Maxwell model has been adopted. As far as materials are concerned, long-term creep tests have been carried out on pultruded specimens. Both tension and shear tests have been executed. Some specimen has been strengthened with carbon fibre plies to reduce short- and long- term deformability. Tests have been done in a climate room and specimens kept 2 years under constant load in time. As for concrete, a model for tertiary creep has been proposed. The basic idea is to couple the UMLV linear creep model with a damage model in order to describe nonlinearity. An effective strain tensor, weighting the total and the elasto-damaged strain tensors, controls damage evolution through the damage loading function. Creep strains are related to the effective stresses (defined by damage models) and so associated to the intact material.

Caratterizzazione di membrane metalliche e ionomeriche per applicazioni energetiche

The work of this thesis has been focused on the characterization of metallic membranes for the hydrogen purification from steam reforming process and also of perfluorosulphonic acid ionomeric (PFSI) membranes suitable as electrolytes in fuel cell applications. The experimental study of metallic membranes was divided in three sections: synthesis of palladium and silver palladium coatings on porous ceramic support via electroless deposition (ELD), solubility and diffusivity analysis of hydrogen in palladium based alloys (temperature range between 200 and 400 °C up to 12 bar of pressure) and permeation experiments of pure hydrogen and mixtures containing, besides hydrogen, also nitrogen and methane at high temperatures (up to 600 °C) and pressures (up to 10 bar). Sequential deposition of palladium and silver on to porous alumina tubes by ELD technique was carried out using two different procedures: a stirred batch and a continuous flux method. Pure palladium as well as Pd-Ag membranes were produced: the Pd-Ag membranes’ composition is calculated to be close to 77% Pd and 23% Ag by weight which was the target value that correspond to the best performance of the palladium-based alloys. One of the membranes produced showed an infinite selectivity through hydrogen and relatively high permeability value and is suitable for the potential use as a hydrogen separator. The hydrogen sorption in silver palladium alloys was carried out in a gravimetric system on films produced by ELD technique. In the temperature range inspected, up to 400°C, there is still a lack in literature. The experimental data were analyzed with rigorous equations allowing to calculate the enthalpy and entropy values of the Sieverts’ constant; the results were in very good agreement with the extrapolation made with literature data obtained a lower temperature (up to 150 °C). The information obtained in this study would be directly usable in the modeling of hydrogen permeation in Pd-based systems. Pure and mixed gas permeation tests were performed on Pd-based hydrogen selective membranes at operative conditions close to steam-reforming ones. Two membranes (one produced in this work and another produced by NGK Insulators Japan) showed a virtually infinite selectivity and good permeability. Mixture data revealed the existence of non negligible resistances to hydrogen transport in the gas phase. Even if the decrease of the driving force due to polarization concentration phenomena occurs, in principle, in all membrane-based separation systems endowed with high perm-selectivity, an extensive experimental analysis lack, at the moment, in the palladium-based membrane process in literature. Moreover a new procedure has been introduced for the proper comparison of the mass transport resistance in the gas phase and in the membrane. Another object of study was the water vapor sorption and permeation in PFSI membranes with short and long side chains was also studied; moreover the permeation of gases (i.e. He, N2 and O2) in dry and humid conditions was considered. The water vapor sorption showed strong interactions between the hydrophilic groups and the water as revealed from the hysteresis in the sorption-desorption isotherms and thermo gravimetric analysis. The data obtained were used in the modeling of water vapor permeation, that was described as diffusion-reaction of water molecules, and in the humid gases permeation experiments. In the dry gas experiments the permeability and diffusivity was found to increase with temperature and with the equivalent weight (EW) of the membrane. A linear correlation was drawn between the dry gas permeability and the opposite of the equivalent weight of PFSI membranes, based on which the permeability of pure PTFE is retrieved in the limit of high EW. In the other hand O2 ,N2 and He permeability values was found to increase significantly, and in a similar fashion, with water activity. A model that considers the PFSI membrane as a composite matrix with a hydrophilic and a hydrophobic phase was considered allowing to estimate the variation of gas permeability with relative humidity on the basis of the permeability in the dry PFSI membrane and in pure liquid water.

Tectonic geomorphology and active strain of the Northern Apennines mountain front

The Northern Apennines (NA) chain is the expression of the active plate margin between Europe and Adria. Given the low convergence rates and the moderate seismic activity, ambiguities still occur in defining a seismotectonic framework and many different scenarios have been proposed for the mountain front evolution. Differently from older models that indicate the mountain front as an active thrust at the surface, a recently proposed scenario describes the latter as the frontal limb of a long-wavelength fold (> 150 km) formed by a thrust fault tipped around 17 km at depth, and considered as the active subduction boundary. East of Bologna, this frontal limb is remarkably very straight and its surface is riddled with small, but pervasive high- angle normal faults. However, west of Bologna, some recesses are visible along strike of the mountain front: these perturbations seem due to the presence of shorter wavelength (15 to 25 km along strike) structures showing both NE and NW-vergence. The Pleistocene activity of these structures was already suggested, but not quantitative reconstructions are available in literature. This research investigates the tectonic geomorphology of the NA mountain front with the specific aim to quantify active deformations and infer possible deep causes of both short- and long-wavelength structures. This study documents the presence of a network of active extensional faults, in the foothills south and east of Bologna. For these structures, the strain rate has been measured to find a constant throw-to-length relationship and the slip rates have been compared with measured rates of erosion. Fluvial geomorphology and quantitative analysis of the topography document in detail the active tectonics of two growing domal structures (Castelvetro - Vignola foothills and the Ghiardo plateau) embedded in the mountain front west of Bologna. Here, tilting and river incision rates (interpreted as that long-term uplift rates) have been measured respectively at the mountain front and in the Enza and Panaro valleys, using a well defined stratigraphy of Pleistocene to Holocene river terraces and alluvial fan deposits as growth strata, and seismic reflection profiles relationships. The geometry and uplift rates of the anticlines constrain a simple trishear fault propagation folding model that inverts for blind thrust ramp depth, dip, and slip. Topographic swath profiles and the steepness index of river longitudinal profiles that traverse the anti- clines are consistent with stratigraphy, structures, aquifer geometry, and seismic reflection profiles. Available focal mechanisms of earthquakes with magnitude between Mw 4.1 to 5.4, obtained from a dataset of the instrumental seismicity for the last 30 years, evidence a clear vertical separation at around 15 km between shallow extensional and deeper compressional hypocenters along the mountain front and adjacent foothills. In summary, the studied anticlines appear to grow at rates slower than the growing rate of the longer- wavelength structure that defines the mountain front of the NA. The domal structures show evidences of NW-verging deformation and reactivations of older (late Neogene) thrusts. The reconstructed river incision rates together with rates coming from several other rivers along a 250 km wide stretch of the NA mountain front and recently available in the literature, all indicate a general increase from Middle to Late Pleistocene. This suggests focusing of deformation along a deep structure, as confirmed by the deep compressional seismicity. The maximum rate is however not constant along the mountain front, but varies from 0.2 mm/yr in the west to more than 2.2 mm/yr in the eastern sector, suggesting a similar (eastward-increasing) trend of the apenninic subduction.

Modelling the effects of nitrogen deposition and carbon dioxide enrichment on forest carbon balance

Atmospheric CO2 concentration ([CO2]) has increased over the last 250 years, mainly due to human activities. Of total anthropogenic emissions, almost 31% has been sequestered by the terrestrial biosphere. A considerable contribution to this sink comes from temperate and boreal forest ecosystems of the northern hemisphere, which contain a large amount of carbon (C) stored as biomass and soil organic matter. Several potential drivers for this forest C sequestration have been proposed, including increasing atmospheric [CO2], temperature, nitrogen (N) deposition and changes in management practices. However, it is not known which of these drivers are most important. The overall aim of this thesis project was to develop a simple ecosystem model which explicitly incorporates our best understanding of the mechanisms by which these drivers affect forest C storage, and to use this model to investigate the sensitivity of the forest ecosystem to these drivers. I firstly developed a version of the Generic Decomposition and Yield (G’DAY) model to explicitly investigate the mechanisms leading to forest C sequestration following N deposition. Specifically, I modified the G’DAY model to include advances in understanding of C allocation, canopy N uptake, and leaf trait relationships. I also incorporated a simple forest management practice subroutine. Secondly, I investigated the effect of CO2 fertilization on forest productivity with relation to the soil N availability feedback. I modified the model to allow it to simulate short-term responses of deciduous forests to environmental drivers, and applied it to data from a large-scale forest Free-Air CO2 Enrichment (FACE) experiment. Finally, I used the model to investigate the combined effects of recent observed changes in atmospheric [CO2], N deposition, and climate on a European forest stand. The model developed in my thesis project was an effective tool for analysis of effects of environmental drivers on forest ecosystem C storage. Key results from model simulations include: (i) N availability has a major role in forest ecosystem C sequestration; (ii) atmospheric N deposition is an important driver of N availability on short and long time-scales; (iii) rising temperature increases C storage by enhancing soil N availability and (iv) increasing [CO2] significantly affects forest growth and C storage only when N availability is not limiting.