Of flies, mice and men: a systematic approach to understanding the early life origins of chronic lung disease.

Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.

Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment.

Despite a low positive predictive value, diagnostic tests such as complete blood count (CBC) and C-reactive protein (CRP) are commonly used to evaluate whether infants with risk factors for early-onset neonatal sepsis (EOS) should be treated with antibiotics. We investigated the impact of implementing a protocol aiming at reducing the number of diagnostic tests in infants with risk factors for EOS in order to compare the diagnostic performance of repeated clinical examination with CBC and CRP measurement. The primary outcome was the time between birth and the first dose of antibiotics in infants treated for suspected EOS. Among the 11,503 infants born at ≥35 weeks during the study period, 222 were treated with antibiotics for suspected EOS. The proportion of infants receiving antibiotics for suspected EOS was 2.1% and 1.7% before and after the change of protocol (p = 0.09). Reduction of diagnostic tests was associated with earlier antibiotic treatment in infants treated for suspected EOS (hazard ratio 1.58; 95% confidence interval [CI] 1.20-2.07; p <0.001), and in infants with neonatal infection (hazard ratio 2.20; 95% CI 1.19-4.06; p = 0.01). There was no difference in the duration of hospital stay nor in the proportion of infants requiring respiratory or cardiovascular support before and after the change of protocol. Reduction of diagnostic tests such as CBC and CRP does not delay initiation of antibiotic treatment in infants with suspected EOS. The importance of clinical examination in infants with risk factors for EOS should be emphasised.

Equilibrium of the simultaneous etherification ofisobutene and isoamylenes with ethanol inliquid-phase

The simultaneous etherification of isobutene and isoamylenes with ethanol has been studied using macroreticu-lar acid ion-exchange resins as catalyst. Most of the experiments were carried out over Amberlyst-35. In addition,Amberlyst-15 and Purolite CT-275 were also tested. Chemical equilibrium of four chemical reactions was studied:ethyl tert-butyl ether formation, tert-amyl ethyl ether formation from isoamylenes (2-methyl-1-butene and 2-methyl-2-butene) and isomerization reaction between both isoamylenes. Equilibrium data were obtained in a batchwisestirred tank reactor operated at 2.0 MPa and within the temperature range from 323 to 353 K. Experimental molarstandard enthalpy and entropy changes of reaction were determined for each reaction. From these data, the molarenthalpy change of formation of ethyl tert-butyl ether and tert-amyl ethyl ether were estimated. Besides, the chemical equilibrium between both diisobutene dimers, 2,4,4-trimethyl-1-pentene and 2,4,4-trimethyl-2-pentene, wasevaluated. A good agreement between thermodynamic results for the simultaneous etherification carried out in thiswork and those obtained for the isolated ethyl tert-butyl ether and tert-amyl ethyl ether systems was obtained.

Observation of a continuous interior crisis in the Hindmarsh-Rose neuron model.

Interior crises are understood as discontinuous changes of the size of a chaotic attractor that occur when an unstable periodic orbit collides with the chaotic attractor. We present here numerical evidence and theoretical reasoning which prove the existence of a chaos-chaos transition in which the change of the attractor size is sudden but continuous. This occurs in the Hindmarsh¿Rose model of a neuron, at the transition point between the bursting and spiking dynamics, which are two different dynamic behaviors that this system is able to present. Moreover, besides the change in attractor size, other significant properties of the system undergoing the transitions do change in a relevant qualitative way. The mechanism for such transition is understood in terms of a simple one-dimensional map whose dynamics undergoes a crossover between two different universal behaviors

Effectiveness of substituting cyclosporin A with tacrolimus in reducing gingival overgrowth in renal transplant patients

Objectives: This study aims to evaluate the effectiveness of periodontal therapy combined with tacrolimus in the suppression of gingival overgrowth (GO) and the effect on GO of changing from cyclosporin A to tacrolimus. Patients and Methods: Sixteen renal transplant patients, averaging 52 years of age, whose kidney function was stable and were receiving treatment with cyclosporin A, were randomly assigned to one of two groups. In the experimental group, patients were instructed in oral hygiene and underwent periodontal treatment, whereas in the control group, only oral hygiene instructions were given. After the first visit and the change of medication from cyclosporine to tacrolimus in both groups, periodic clinical revisions were carried out for 3 months in order to assess the evolution of GO. Results: All patients showed a progressive decrease in GO. There were no statistically significant differences between the two groups (p>0.05). A greater decrease in GO occurred within the first month after changing the medication. Conclusions: No improved effectiveness in reducing GO was observed for periodontal therapy in combination with tacrolimus. Tacrolimus is an alternative to cyclosporine when attempting to avoid GO in patients with kidney transplants

Strategies and tools for preventing neurotoxicity: to test, to predict and how to do it

A change in paradigm is needed in the prevention of toxic effects on the nervous system, moving from its present reliance solely on data from animal testing to a prediction model mostly based on in vitro toxicity testing and in silico modeling. According to the report published by the National Research Council (NRC) of the US National Academies of Science, high-throughput in vitro tests will provide evidence for alterations in"toxicity pathways" as the best possible method of large scale toxicity prediction. The challenges to implement this proposal are enormous, and provide much room for debate. While many efforts address the technical aspects of implementing the vision, many questions around it need also to be addressed. Is the overall strategy the only one to be pursued? How can we move from current to future paradigms? Will we ever be able to reliably model for chronic and developmental neurotoxicity in vitro? This paper summarizes four presentations from a symposium held at the International Neurotoxicology Conference held in Xi"an, China, in June 2011. A. Li reviewed the current guidelines for neurotoxicity and developmental neurotoxicity testing, and discussed the major challenges existing to realize the NCR vision for toxicity testing. J. Llorens reviewed the biology of mammalian toxic avoidance in view of present knowledge on the physiology and molecular biology of the chemical senses, taste and smell. This background information supports the hypothesis that relating in vivo toxicity to chemical epitope descriptors that mimic the chemical encoding performed by the olfactory system may provide a way to the long term future of complete in silico toxicity prediction. S. Ceccatelli reviewed the implementation of rodent and human neural stem cells (NSCs) as models for in vitro toxicity testing that measures parameters such as cell proliferation, differentiation and migration. These appear to be sensitive endpoints that can identify substances with developmental neurotoxic potential. C. Sun ol reviewed the use of primary neuronal cultures in testing for neurotoxicity of environmental pollutants, including the study of the effects of persistent exposures and/or in differentiating cells, which allow recording of effects that can be extrapolated to human developmental neurotoxicity.

Effect of n-3 fatty acids on markers of brain injury and incidence of sepsis-associated delirium in septic patients.

BACKGROUND: Data regarding immunomodulatory effects of parenteral n-3 fatty acids in sepsis are conflicting. In this study, the effect of administration of parenteral n-3 fatty acids on markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients was investigated. METHODS: Fifty patients with sepsis were randomized to receive either 2 ml/kg/day of a lipid emulsion containing highly refined fish oil (equivalent to n-3 fatty acids 0.12 mg/kg/day) during 7 days after admission to the intensive care unit or standard treatment. Markers of brain injury and inflammatory mediators were measured on days 1, 2, 3 and 7. Assessment for sepsis-associated delirium was performed daily. The primary outcome was the difference in S-100β from baseline to peak level between both the intervention and the control group, compared by t-test. Changes of all markers over time were explored in both groups, fitting a generalized estimating equations model. RESULTS: Mean difference in change of S-100β from baseline to peak level was 0.34 (95% CI: -0.18-0.85) between the intervention and control group, respectively (P = 0.19). We found no difference in plasma levels of S-100β, neuron-specific enolase, interleukin (IL)-6, IL-8, IL-10, and C-reactive protein between groups over time. Incidence of sepsis-associated delirium was 75% in the intervention and 71% in the control groups (risk difference 4%, 95% CI -24-31%, P = 0.796). CONCLUSION: Administration of n-3 fatty acids did not affect markers of brain injury, incidence of sepsis-associated delirium, and inflammatory mediators in septic patients.

Isentropic Exergy and Pressure of the Shock Wave Caused by the Explosion of a Pressure Vessel

An accidental burst of a pressure vessel is an uncontrollable and explosion-like batch process. In this study it is called an explosion. The destructive effectof a pressure vessel explosion is relative to the amount of energy released in it. However, in the field of pressure vessel safety, a mutual understanding concerning the definition of explosion energy has not yet been achieved. In this study the definition of isentropic exergy is presented. Isentropic exergy is the greatest possible destructive energy which can be obtained from a pressure vessel explosion when its state changes in an isentropic way from the initial to the final state. Finally, after the change process, the gas has similar pressure and flow velocity as the environment. Isentropic exergy differs from common exergy inthat the process is assumed to be isentropic and the final gas temperature usually differs from the ambient temperature. The explosion process is so fast that there is no time for the significant heat exchange needed for the common exergy.Therefore an explosion is better characterized by isentropic exergy. Isentropicexergy is a characteristic of a pressure vessel and it is simple to calculate. Isentropic exergy can be defined also for any thermodynamic system, such as the shock wave system developing around an exploding pressure vessel. At the beginning of the explosion process the shock wave system has the same isentropic exergyas the pressure vessel. When the system expands to the environment, its isentropic exergy decreases because of the increase of entropy in the shock wave. The shock wave system contains the pressure vessel gas and a growing amount of ambient gas. The destructive effect of the shock wave on the ambient structures decreases when its distance from the starting point increases. This arises firstly from the fact that the shock wave system is distributed to a larger space. Secondly, the increase of entropy in the shock waves reduces the amount of isentropic exergy. Equations concerning the change of isentropic exergy in shock waves are derived. By means of isentropic exergy and the known flow theories, equations illustrating the pressure of the shock wave as a function of distance are derived. Amethod is proposed as an application of the equations. The method is applicablefor all shapes of pressure vessels in general use, such as spheres, cylinders and tubes. The results of this method are compared to measurements made by various researchers and to accident reports on pressure vessel explosions. The test measurements are found to be analogous with the proposed method and the findings in the accident reports are not controversial to it.

The effects of productivity on profitability: a case study at firm level using an activity-based costing approach

Productivity and profitability are important concepts and measures describing the performance and success of a firm. We know that increase in productivity decreases the costs per unit produced and leads to better profitability. This common knowledge is not, however, enough in the modern business environment. Productivity improvement is one means among others for increasing the profitability of actions. There are many means to increase productivity. The use of these means presupposes operative decisions and these decisions presuppose informationabout the effects of these means. Productivity improvement actions are in general made at floor level with machines, cells, activities and human beings. Profitability is most meaningful at the level of the whole firm. It has been very difficult or even impossible to analyze closely enough the economical aspects of thechanges at floor level with the traditional costing systems. New ideas in accounting have only recently brought in elements which make it possible to considerthese phenomena where they actually happen. The aim of this study is to supportthe selection of objects to productivity improvement, and to develop a method to analyze the effects of the productivity change in an activity on the profitability of a firm. A framework for systemizing the economical management of productivity improvement is developed in this study. This framework is a systematical way with two stages to analyze the effects of productivity improvement actions inan activity on the profitability of a firm. At the first stage of the framework, a simple selection method which is based on the worth, possibility and the necessity of the improvement actions in each activity is presented. This method is called Urgency Analysis. In the second stage it is analyzed how much a certain change of productivity in an activity affects the profitability of a firm. A theoretical calculation model with which it is possible to analyze the effects of a productivity improvement in monetary values is presented. On the basis of this theoretical model a tool is made for the analysis at the firm level. The usefulness of this framework was empirically tested with the data of the profit center of one medium size Finnish firm which operates in metal industry. It is expressedthat the framework provides valuable information about the economical effects of productivity improvement for supporting the management in their decision making.

An outbreak of Arthroderma vanbreuseghemii dermatophytosis at a veterinary school associated with an infected horse.

We report a case of an outbreak of inflammatory dermatophytoses caused by Arthroderma vanbreuseghemii (formally Trichophyton mentagrophytes pro parte) that involved an infected horse, the owner and at least 20 students, staff and stablemen at a veterinary school in Bern (Switzerland) that presented highly inflammatory dermatitis of the body and the face. Transmission from human to human was also recorded as one patient was the partner of an infected person. Both the phenotypic characteristics and ITS sequence of the dermatophytes isolated from the horse and patients were identical, consistent with the conclusion that the fungus originated from the horse. Three infected persons had not been in direct contact with the horse. Although direct transmission from human to human cannot be ruled out, fomites were most likely the source of infection for these three patients. Inspection of the literature at the end of the nineteenth and beginning of the twentieth century revealed that this dermatophyte was frequently transmitted from horses to humans in contact with horses (stablemen, coachmen, carters and artillery soldiers). The rarity of the present case report at the present time is likely related to the transformation of civilisation from the nineteenth century to nowadays in Europe with the change of horse husbandry. In addition, the inadequate immune response of the horse and the high number of people in contact with it at the equine clinic may explain the exceptional aspect of this case report.

Thick XML client and technology of its construction

Nykyään kolmeen kerrokseen perustuvat client-server –sovellukset ovat suuri kinnostuskohde sekä niiden kehittäjille etta käyttäjille. Tietotekniikan nopean kehityksen ansiosta näillä sovelluksilla on monipuolinen käyttö teollisuuden eri alueilla. Tällä hetkellä on olemassa paljon työkaluja client-server –sovellusten kehittämiseen, jotka myös tyydyttävät asiakkaiden asettamia vaatimuksia. Nämä työkalut eivät kuitenkaan mahdollista joustavaa toimintaa graafisen käyttöliittyman kanssa. Tämä diplomityö käsittelee client-server –sovellusten kehittamistä XML –kielen avulla. Tämä lähestymistapa mahdollistaa client-server –sovellusten rakentamista niin, että niiden graafinen käyttöliittymä ja ulkonäkö olisivat helposti muokattavissa ilman ohjelman ytimen uudelleenkääntämistä. Diplomityö koostuu kahdesta ostasta: teoreettisesta ja käytännöllisestä. Teoreettinen osa antaa yleisen tiedon client-server –arkkitehtuurista ja kuvailee ohjelmistotekniikan pääkohdat. Käytannöllinen osa esittää tulokset, client-server –sovellusten kehittämisteknologian kehittämislähestymistavan XML: ää käyttäen ja tuloksiin johtavat usecase– ja sekvenssidiagrammit. Käytännöllinen osa myos sisältää esimerkit toteutetuista XML-struktuureista, jotka kuvaavat client –sovellusten kuvaruutukaavakkeiden esintymisen ja serverikyselykaaviot.

The Bacterium Frischella perrara Causes Scab Formation in the Gut of its Honeybee Host.

UNLABELLED: Honeybees harbor well-defined bacterial communities in their guts. The major members of these communities appear to benefit the host, but little is known about how they interact with the host and specifically how they interface with the host immune system. In the pylorus, a short region between the midgut and hindgut, honeybees frequently exhibit scab-like structures on the epithelial gut surface. These structures are reminiscent of a melanization response of the insect immune system. Despite the wide distribution of this phenotype in honeybee populations, its cause has remained elusive. Here, we show that the presence of a common member of the bee gut microbiota, the gammaproteobacterium Frischella perrara, correlates with the appearance of the scab phenotype. Bacterial colonization precedes scab formation, and F. perrara specifically localizes to the melanized regions of the host epithelium. Under controlled laboratory conditions, we demonstrate that exposure of microbiota-free bees to F. perrara but not to other bacteria results in scab formation. This shows that F. perrara can become established in a spatially restricted niche in the gut and triggers a morphological change of the epithelial surface, potentially due to a host immune response. As an intermittent colonizer, this bacterium holds promise for addressing questions of community invasion in a simple yet relevant model system. Moreover, our results show that gut symbionts of bees engage in differential host interactions that are likely to affect gut homeostasis. Future studies should focus on how these different gut bacteria impact honeybee health. IMPORTANCE: As pollinators, honeybees are key species for agricultural and natural ecosystems. Their guts harbor simple communities composed of characteristic bacterial species. Because of these features, bees are ideal systems for studying fundamental aspects of gut microbiota-host interactions. However, little is known about how these bacteria interact with their host. Here, we show that a common member of the bee gut microbiota causes the formation of a scab-like structure on the gut epithelium of its host. This phenotype was first described in 1946, but since then it has not been much further characterized, despite being found in bee populations worldwide. The scab phenotype is reminiscent of melanization, a conserved innate immune response of insects. Our results show that high abundance of one member of the bee gut microbiota triggers this specific phenotype, suggesting that the gut microbiota composition can affect the immune status of this key pollinator species.

The New Era of Value Creation. Case: Sonera Zed

Tutkielman tavoitteena on selvittää kuinka arvonluonti-ideologia on muuttunut arvoketjuajattelusta arvoverkkomalliin ja mitä tekijöitä tarvitaan toimivan arvoverkon rakentamiseen. Teoriaosuus käsittelee arvonmuodostuksen muutosta kokonaisvaltaisesti. Tuloksena saavutetaan arvoverkko. Tutkielman empiirisessä osassa käytetään hyväksi laadullista case-tutkimusta. Teemahaastattelut ovat pääasiallinen empiirisen tiedon lähde. Tuloksena saatuja empiirisen osan tietoja verrataan teoriakappaleen vastaaviin tuloksiin. Case-yritys, Sonera zed, on suomalainen mobiiliportaaliyritys, joka tarjoaa matkapuhelimien lisäarvopalveluita loppuasiakkaille. Case-yrityksen operaatiomalli on rakentaa näitä palveluita yhteistyössä muiden yritysten kanssa. Empiirisen osan tavoite on selvittää toimiiko teoreettinen arvoverkkomalli myös tosielämässä. Arvoverkkomallia hyödynnetään case-yrityksessä vain osittain. Mallia käytetään hyväksi osa-alueilla missä yrityksellä ei ole omia kompetensseja. Sen sijaan alueilla joilla yritys omaa ydinosaamista, ei arvoverkkomallia hyödynnetä tarpeeksi. Tästä huolimatta uskotaan, että oikein hyödynnettynä arvoverkko kykenisi tarjoamaan merkittävää kilpailuetua kilpailijoihin nähden, mikäli mallia hyödynnettäisiin matkapuhelimien lisäarvopalvelutuotannon joka vaiheessa.

The development of decision limits for the GH-2000 detection methodology using additional insulin-like growth factor-I and amino-terminal pro-peptide of type III collagen assays.

The GH-2000 and GH-2004 projects have developed a method for detecting GH misuse based on measuring insulin-like growth factor-I (IGF-I) and the amino-terminal pro-peptide of type III collagen (P-III-NP). The objectives were to analyze more samples from elite athletes to improve the reliability of the decision limit estimates, to evaluate whether the existing decision limits needed revision, and to validate further non-radioisotopic assays for these markers. The study included 998 male and 931 female elite athletes. Blood samples were collected according to World Anti-Doping Agency (WADA) guidelines at various sporting events including the 2011 International Association of Athletics Federations (IAAF) World Athletics Championships in Daegu, South Korea. IGF-I was measured by the Immunotech A15729 IGF-I IRMA, the Immunodiagnostic Systems iSYS IGF-I assay and a recently developed mass spectrometry (LC-MS/MS) method. P-III-NP was measured by the Cisbio RIA-gnost P-III-P, Orion UniQ? PIIINP RIA and Siemens ADVIA Centaur P-III-NP assays. The GH-2000 score decision limits were developed using existing statistical techniques. Decision limits were determined using a specificity of 99.99% and an allowance for uncertainty because of the finite sample size. The revised Immunotech IGF-I - Orion P-III-NP assay combination decision limit did not change significantly following the addition of the new samples. The new decision limits are applied to currently available non-radioisotopic assays to measure IGF-I and P-III-NP in elite athletes, which should allow wider flexibility to implement the GH-2000 marker test for GH misuse while providing some resilience against manufacturer withdrawal or change of assays. Copyright © 2015 John Wiley & Sons, Ltd.