Les antagonistes du récepteur minératocorticoïde

Mineralocorticoid signaling pathway plays a pivotal role in cardiovascular physiopathology. Evidences from clinical and experimental studies have linked mineralocorticoid hormones with cardiovascular morbiditiy and mortality. Thus, antagonist of the mineralocorticoid receptor (AMR) has reappeared. In addition, a novel mineralocorticoid receptor antagonist has been developped, named eplerenone, which lack the side effect of former ARMs as gynecomastia. Based on two studies named RALES et EPHESUS, guidelines of the european and american societies of cardiology recommend the use of ARMs as a treatment for cardiac failure NYHA III and IV, and post-infarct cardiac failure (ejection fraction < 40%).

Electronic Construction Collaboration - Phase 1, 2009

Bridge construction projects are becoming increasingly complex as the demand for context-sensitive solutions, aesthetic designs, and accelerated bridge construction becomes more prevalent. In addition, the Iowa Department of Transportation (Iowa DOT) is entering a phase of design and construction of large border bridges, such as the I-80 (let 2008 for $56 million) and US 34 bridges over the Missouri River and I-74 over the Mississippi River. Compared to typical construction projects, these bridges generate more contractor Requests for Information (RFIs), Value Engineering (VE) proposals, Requests for Changes (RFCs), and shop drawings. Management of these submittals is a significant challenge for Resident Construction Engineers (RCEs) and other Iowa DOT staff. In addition, some submittals require cross-departmental and project consultant reviews. Commercially available software exists for managing submittals and project collaboration teams; in-house solutions may also be possible. Implementation is intended to speed construction submittal review time, reduce incidence of delay claims, and free up Iowa DOT staff from project management administrative tasks. Researchers from Iowa State University working with the Iowa DOT conducted a multi-pronged approach to indentify a web-based collaboration solution for Iowa DOT bridge projects. An investigation was launched to determine the functional needs of the Iowa DOT. Commercially available software programs were also evaluated to find what functionality is currently available. A Request for Proposals (RFP) was written to select a commercial web-based collaboration solution for pilot testing. In the second phase of research, a solution will be selected and implemented on two pilot projects. Lessons learned from these pilot projects will assist the Iowa DOT in developing and implementing a long-term solution to improve the management of Iowa DOT bridge projects.

Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.

PURPOSE: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. METHODS: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. RESULTS: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. CONCLUSIONS: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin.

A pilot study of the efficacy of IL1 blockade by anakinra in acute calcific periarthritis of the rotator cuff

Background/Purpose: Calcific periarthritis of rotator cuff can induce acute and severe shoulder pain and is accompnied by signs of acute inflammation. The calcific deposits are composed of calcium phosphate crystals such as hydroxyapatite or basic calcium phosphate. These crystals stimulate the production and release of IL1b from macrophages, in an analogous manner to MSU and CPPD crystals. As IL1 blockade is effective in reducing signs and symptoms of inflammation in acute gout, we performed a pilot study to study if it is also effective in calcific periarthritis Methods: 5 consecutive patients were included (mean age: 62, 3 females, 2 males) between March 2011 and March 2012. Symptoms of acute shoulder pain at rest had to be present for _7 days before inclusion, associated with limitation of shoulder mobility and the presence on calcification in the rotator cuff by conventional radiography. None of the patients had responded to at least 48 hours of high doses of NSAIDs. Exclusion criteria included no corticosteroid therapy in the last 2 weeks and the exclusion of other rheumatologic or infectious diseases- .Clinical evaluation consisted of patient assessment of pain (total, rest and activity) by VAS (100mm scale) at days 0, 1, 3, 15, 42 and clinical examination of shoulder mobility at days 0, 3, 15. ESR and CRP were measured at days 0, 3. Plain radiographs were performed at days 0 and 15 and an ultrasound examination (including Doppler) was performed at days 0, 3, 15. Anakinra 100mg daily was administered for 3 consecutive days after the first evaluation (day 0). Rescue analgesics were allowed and recorded. Results: At inclusion, all patients had severe shoulder pain: mean (SD) VAS day pain of 72mm (_25mm), mean VAS night pain of 96 (_ 5) and impaired shoulder mobility. CRP was elevated in all of them (mean of 3X). Treatment with anakinra lead to rapid relief of pain in all patients, starting already on the first night following the first injection. The reduction of VAS pain was particularly striking for rest pain: mean (SD) VAS of 4mm (_ 5) at day 1 and this response was maintained for the 5 patients at the end of the three injections without any need of rescue medication. Mean rest VAS was 6 (_8) at day 3. The effect on day pain was less spectacular: mean (SD) VAS at D1 of 30 (_ 18), at D3 of 27 (_ 11). Shoulder mobility also improved and the CRP normalized in 4 of 5 patients at day 3. At day 42, 4 of 5 the patients were still totally asymptomatic. On X rays and US, the calcifications were reduced in size: mean maximal diameter of 21 mm at day 0 to 12 mm at day 15, but did not disappear in any patient. The main change on US was a significant and rapid (at day 3) reduction of Doppler activity around the calcification. Conclusion: This pilot open study suggests that IL-1_ inhibition may be an interesting therapeutic approach in acute calcific periarthritis, especially in patients who have not responded adequately to NSAIDs. The effect on pain seems to be more rapid (within a few hours) than steroid injection although a randomized controlled study needs to be performed to confirm this observation.

Tuoteturvallisuusriskien hallinta suorituskyvyn johtamisen tukena sähkö- ja elektroniikkateollisuudessa

Eurooppalaisia ja suomalaisia markkinavalvontatilastoja tutkimalla havaitaan, ettei tuoteturvallisuuden hallinta ole itsestään selvää sähkö- ja elektroniikka-alalla. Vuodesta 2000 maaliskuuhun 2006Euroopan markkinoilla havaittiin 3040 vaarallista kuluttajien käyttöön tarkoitettua sähkötuotetta. Työn päätavoitteena on selvittää, miten tuoteturvallisuusriskien hallinta kytkeytyy yrityksen suorituskyvyn johtamiseen. Työssä on käytetty konstruktiivista tutkimusotetta. Aineistopohjaisen analyysin avulla kartoitetaan suorituskyvyn johtamisen teoriaa, suorituskyvyn käytännön mittaamista pienissä ja keskisuurissa yrityksissä sekä tuoteturvallisuusriskejä jariskienhallinnan periaatteita. Lisäksi kartoitetaan lainsäädännön vaatimuksia, tuotesuunnittelua, valmistusta ja osaamista sekä tarkastellaan tuoteturvallisuuden viranomaisvalvonnan tuloksia. Tutkimuksessa analysoidaan kirjallisuutta ja tilastoja etsien tuoteriskien hallinnan ja suorituskyvyn johtamisen välistä yhteyttä. Analyysiä täydennetään tutkimuksen tekijän kokemuksella tuoteturvallisuuden testauksesta ja sertifioinnista, standardisoimistyöstä sekä tuoteturvallisuuden viranomaisvalvonnasta. Riskienhallinta muodostaa parhaimmillaan osan yrityksen johtamis- ja hallintakäytäntöä. Tuoteturvallisuusriskien hallinta on yrityksen strateginen päätös, joka tukee suorituskyvyn johtamista. Työssämallinnetaan kolme toimintatapaa, joilla eri kehitysvaiheessa olevat sähkö- ja elektroniikkateollisuuden valmistajat voivat hallita tuoteturvallisuusriskejään.Työssä kootaan yhteen tuoteturvallisuuden tekijöitä, jotka suorituskyvyn mittareissa monitoroivat tuoteriskien tilaa. Lisäksi kootaan yhteen riskienhallinnan kustannuksia, joilla yritys voi arvioida etukäteen kokonaiskustannuksia.

Pääomasijoittaminen metsäteollisuuteen vuosina 1995-2005

Tutkimuksen tavoitteena oli selvittää metsäteollisuuteen tehtyjä pääomasijoituksia. Tutkimuskohteena olivat kansainväliset metsäteollisuusyritykset ja niihin tehdyt pääomasijoitukset vuosina 1995-2005. Tutkimuksessa tarkasteltiin miten pääomasijoitukset metsäteollisuuteen ovat kehittyneet lukumääräisesti sekä miten metsäteollisuuteen tehtävien pääomasijoitustenkoko on muuttunut tällä ajanjaksolla. Tutkimuksessa tarkasteltiin myös metsäteollisuuteen sijoittavien pääomasijoittajien maantieteellistä jakautumista sekä näiden kohdeyhtiöiden maantieteellistä jakautumista. Tutkimustulosten mukaan pääomasijoittaminen kansainvälisiin metsäteollisuusyrityksiin on lisääntynyt vuosina 1995-2005. Pääomasijoitukset metsäteollisuuteen ovat pysyneet keskimääräiseltä kooltaan samalla tasolla koko tarkasteluajanjakson. Metsäteollisuuden pääomasijoituksista lähes puolet tuli eurooppalaisilta pääomasijoittajilta tarkasteluajanjaksona. Viime vuosina pohjoisamerikkalaiset, eurooppalaiset ja aasialaiset pääomasijoittajat ovat jokainen tarjonneet metsäteollisuuden vuosittaisistapääomasijoituksista lähes yhtä suuren osuuden. Metsäteollisuuteen sijoittavatpääomasijoittajat preferoivat sijoituksissaan omaa maantieteellistä aluettaan.

Territorios baldíos: identidades juveniles indígenas y rurales en América Latina

Las teorías sobre la invención histórica de la infancia y la adolescencia se han basado casi exclusivamente en fuentes occidentales (más exactamente centroeuropeas y anglosajonas), por lo que es urgente una reconceptualización en una óptica diacrónica y transcultural. Una de las conclusiones del encuentro «A criança e o jovem na America Latina», que tuvo lugar en Marilia (Brasil) en noviembre del 2001, organizado por la International Sociological Association, fue la necesidad de reconceptualizar la infancia y la juventud desde una perspectiva latinoamericana (como ámbito geográfico, académico y cultural). En este artículo proponemos retomar, en una perspectiva comparativa y como ejemplo de la riqueza y complejidad de las tareas pendientes, dos casos documentales y etnográficos recabados en nuestras propias indagaciones en México (Feixa, 1998b) y Chile (González, 2004a, 2004b), en la idea de comenzar a cursar esta «asignatura pendiente».

Mechanisms of action of brief alcohol interventions remain largely unknown - a narrative review.

A growing body of evidence has shown the efficacy of brief intervention (BI) for hazardous and harmful alcohol use in primary health care settings. Evidence for efficacy in other settings and effectiveness when implemented at larger scale are disappointing. Indeed, BI comprises varying content; exploring BI content and mechanisms of action may be a promising way to enhance efficacy and effectiveness. Medline and PsychInfo, as well as references of retrieved publications were searched for original research or review on active ingredients (components or mechanisms) of face-to-face BIs [and its subtypes, including brief advice and brief motivational interviewing (BMI)] for alcohol. Overall, BI active ingredients have been scarcely investigated, almost only within BMI, and mostly among patients in the emergency room, young adults, and US college students. This body of research has shown that personalized feedback may be an effective component; specific MI techniques showed mixed findings; decisional balance findings tended to suggest a potential detrimental effect; while change plan exercises, advice to reduce or stop drinking, presenting alternative change options, and moderation strategies are promising but need further study. Client change talk is a potential mediator of BMI effects; change in norm perceptions and enhanced discrepancy between current behavior and broader life goals and values have received preliminary support; readiness to change was only partially supported as a mediator; while enhanced awareness of drinking, perceived risks/benefits of alcohol use, alcohol treatment seeking, and self-efficacy were seldom studied and have as yet found no significant support as such. Research is obviously limited and has provided no clear and consistent evidence on the mechanisms of alcohol BI. How BI achieves the effects seen in randomized trials remains mostly unknown and should be investigated to inform the development of more effective interventions.

Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10-8).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

Kytkettyjen johdannaisten tunnistaminen, tilinpäätöskäsittely ja esiintyminen – IAS 39

Tutkielman tavoitteena oli tutkia IAS 39 -standardissa käsiteltyjen kytkettyjen johdannaisten tunnistamista, tilinpäätöskäsittelyä ja esiintymistä sekä verrata eroja IAS- ja US GAAP –standardien välillä tarkasteltaessa erotetaanko kytketty johdannainen pääsopimuksesta. Lisäksi tutkittiin kytkettyjen johdannaisten esiintymistä neljässä eri toimialan suomalaisessa pörssiyrityksessä. Tutkielmassa päädyttiin johtopäätökseen, että sopimuksen tavanomaiset taloudelliset piirteet ja riskit tulee ymmärtää, jotta pystytään tunnistamaan siihen liittyvä mahdollinen johdannainen. Merkittäviä periaatteellisia eroja IAS- ja US GAAP-standardien välillä ei ollut tarkasteltaessa erotetaanko kytketty johdannainen pääsopimuksesta. Kytketyt johdannaiset ovat vaikea osa-alue yrityksille sekä niiden käsittelymenetelmät ovat ainakin joissain määrin vielä avoimia. Käytännössä monet sopimukset sisältävät näitä johdannaisen kaltaisia ehtoja, vaikka niitä ei vielä olisikaan tunnistettu ja juuri tunnistamisen haastavuuden vuoksi kytketyt johdannaiset ovat luultua yleisempiä. Neljässä suomalaisessa pörssiyrityksessä tehtyjen haastattelujen perusteella kytkettyjä johdannaisia esiintynee erityisesti ulkomaankaupan osto- ja myyntisopimuksissa.

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.

INTRODUCTION: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout. METHODS: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. RESULTS: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. CONCLUSION: There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β - the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout.

Life-time growth patterns of pumpkinseed Lepomis gibbosus introduced to Europe, relative to North American populations

The pumpkinseed Lepomis gibbosus, an omnivorous, nest guarding North American sunfish, was introduced into European waters about 100 years ago. To assess growth performance following introduction, we reviewed the available data for North American and European populations of pumpkinseed and compared the back-calculated age-specific growth for juveniles (standard length, SL, at age two) and adults (age two to five increment) as well as adult body size (SL at age five), von Bertalanffy growth model parameters and the index of growth (in length) performance (φ′). For continental comparisons of growth trajectory, mean growth curves for North American and Europe were calculated with the von Bertalanffy model using pooled data sets for each continent. Juvenile growth rate did not differ between European and North American pumpkinseed, but mean adult body size and adult growth rate were both significantly greater in North American than European populations. Adult body size decreased with increasing latitude (ANOVA) in North American populations, but this was not observed with adult growth rate. In contrast, adult body size tended to increase with latitude in European populations. Adult body size correlated significantly with φ′. The von Bertalanffy model described the overall growth patterns of North American and European populations reasonably well, but on the individual population level, length asymptotes were unrealistic (estimates that were > 20 % of the mean back-calculated size for the oldest age class) for a third of European populations and 80% of the North American populations. In contrast to North American pumpkinseed populations, somatic growth in European populations appears to be compromised by limited, but adequate, food resources, probably due to strong intraspecific interactions. This appears to be especially acute in adults, having potential ramifications for life span and reproductive allocation

A comparison of three established age estimation methods on an adult Spanish sample.

Most current methods for adult skeletal age-at-death estimation are based on American samples comprising individuals of European and African ancestry. Our limited understanding of population variability hampers our efforts to apply these techniques to various skeletal populations around the world, especially in global forensic contexts. Further, documented skeletal samples are rare, limiting our ability to test our techniques. The objective of this paper is to test three pelvic macroscopic methods (1-Suchey-Brooks; 2- Lovejoy; 3- Buckberry and Chamberlain) on a documented modern Spanish sample. These methods were selected because they are popular among Spanish anthropologists and because they never have been tested in a Spanish sample. The study sample consists of 80 individuals (55 ♂ and 25 ♀) of known sex and age from the Valladolid collection. Results indicate that in all three methods, levels of bias and inaccuracy increase with age. The Lovejoy method performs poorly (27%) compared with Suchey-Brooks (71%) and Buckberry and Chamberlain (86%). However, the levels of correlation between phases and chronological ages are low and comparable in the three methods (< 0.395). The apparent accuracy of the Suchey-Brooks and Buckberry and Chamberlain methods is largely based on the broad width of the methods" estimated intervals. This study suggests that before systematic application of these three methodologies in Spanish populations, further statistical modeling and research into the co-variance of chronological age with morphological change is necessary. Future methods should be developed specific to various world populations, and should allow for both precision and flexibility in age estimation.