Modulation of genetic associations with serum urate levels by body-mass-index in humans.

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

Isotope ratio mass spectrometry as a tool for source inference in forensic science: a critical review

Isotope ratio mass spectrometry (IRMS) has been used in numerous fields of forensic science in a source inference perspective. This review compiles the studies published on the application of isotope ratio mass spectrometry (IRMS) to the traditional fields of forensic science so far. It completes the review of Benson et al. [1] and synthesises the extent of knowledge already gathered in the following fields: illicit drugs, flammable liquids, human provenancing, microtraces, explosives and other specific materials (packaging tapes, safety matches, plastics, etc.). For each field, a discussion assesses the state of science and highlights the relevance of the information in a forensic context. Through the different discussions which mark out the review, the potential and limitations of IRMS, as well as the needs and challenges of future studies are emphasized. The paper elicits the various dimensions of the source which can be obtained from the isotope information and demonstrates the transversal nature of IRMS as a tool for source inference.

Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma.

BACKGROUND: HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma. RESULTS: We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively. CONCLUSIONS: Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma.

Sagittal abdominal diameter is a better predictor than body mass index for duration of laparoscopic left colectomy.

BACKGROUND: Visceral obesity (VO) increases technical difficulty in laparoscopic surgery. The body mass index (BMI) does not always correlate to intra-abdominal fat distribution. Our hypothesis was that simple anthropometric measures that reflect VO, could predict technical difficulty in laparoscopic colorectal surgery, as reflected by the operative time, more accurately than the BMI. METHODS: Charts of all consecutive patients who underwent laparoscopic left colon resection in our institution between 2007 and 2010 were reviewed retrospectively. On a preoperative CT scan, anthropometric measures were taken on an axial plane at the L4-L5 level. Demographic, operative and anthropometric CT measures were correlated with the operative time. Logistic regression analysis was performed to assess the value of anthropometric CT measures or BMI to predict the duration of the colectomy. RESULTS: 121 patients with elective left colon resection for benign (56%) or malignant disease (44%) were included. There were 74 sigmoid resections (61%), 21 left hemicolectomies (17%) and 26 low anterior resections (22%). A longer sagittal abdominal diameter (≥24.8 cm) was significantly associated with longer corrected operative time (248 vs. 228 min, p = 0.043). In multivariate analysis, greater sagittal abdominal diameter, sagittal internal diameter and abdominal perimeter were significantly associated with longer operative time. No significant association was found for the BMI neither in univariate nor in multivariate analysis. CONCLUSIONS: This study suggests that simple linear measures taken on a CT scan, such as sagittal abdominal diameter, sagittal internal diameter and abdominal perimeter, may predict longer operative time in laparoscopic left colonic resections more accurately than BMI.

Identification of carotenoids using mass spectrometry

The present review compiles positive MS fragmentation data of selected carotenoids obtained using various ionization techniques and matrices. In addition, new experimental data from the analysis of carotenoids in transgenic maize and rice callus are provided. Several carotenes and oxygen-functionalized carotenoids containing epoxy, hydroxyl, and ketone groups were ionized by atmospheric pressure chemical ionization (APCI)-tandem mass spectrometry (MS/MS) in positive ion mode. Thus, on the basis of the information obtained from the literature and our own experiments, we identified characteristic carotenoid ions that can be associated to functional groups in the structures of these compounds. In addition, pigments with a very similar structure were differentiated through comparison of the intensities of their fragments. The data provide a basis for the structural elucidation of carotenoids by mass spectrometry (MS).

The measurement of ice velocity, mass balance and thinning-rate on Johnsons Glacier, Livingston Island, South Shetland Islands, Antarctica

A network of twenty stakes was set up on Johnsons Glacier in order to determine its dynamics. During the austral summers from 1994-95 to 1997-98, we estimated surface velocities, mass balances and ice thickness variations. Horizontal velocity increased dow nstream from 1 m a- 1 near the ice divides to 40 m a- 1 near the ice terminus. The accumulation zone showed low accumulation rates (maximum of 0,6 m a- 1 (ice)), whereas in the lower part of the glacier, ablation rates were 4,3 m a- 1 (ice). Over the 3-year study period, both in the accumulation and ablation zones, we detected a reduction in the ice surface level ranging from 2 to 10 m from the annual ve rt ical velocities and ice-thinning data, the mass balance was obtained and compared with the mass balance field values, resulting in similar estimates. Flux values were calculated using cross-section data and horizontal velocities, and compared with the results obtained by means of mass balance and ice thinning data using the continuity equation. The two methods gave similar results.

Uusien energianormien vaikutus pientalojen rakenteisiin ympäristön kannalta

Tehokkaimpia keinoja vähentää rakennusten lämmitysenergian kulutusta ja lämmityksen aiheuttavia hiilidioksidi- ja happamoitavia päästöjä on tiukentaa rakentamismääräysten lämmöneristysvaatimuksia. Hyvin lämmöneristetyissä, tiiveissä ja ilmanvaihdoltaan optimoiduissa taloissa on pienet lämpöhäviöt. Näin ympäristöä kuormittava vaikutus saadaan paljon vähemmäksi kuin nykynormien mukaisissa asuinrakennuksissa. Johtumislämpöhäviö pienenee suoraan eristekerroksia paksuntamalla ja siihen on helpointa vaikuttaa. Mitä suurempiin eristepaksuuksiin mennään sen suuremmaksi tulee konvektion osuus kokonaislämpöhäviöstä. Tulevaisuudessa parempia ratkaisuja haetaan erityisesti konvektiosta ja säteilystä aiheutuvien lämpöhäviöiden pienentämiseksi. Eristeen osastointi ilmanpitävillä, vesihöyryä diffuusisesti läpäisevillä pystysuuntaisilla konvektiokatkoilla vähentää tehokkaasti paksun seinäeristeen kuljettumis-ilmavirtauksia. Katkoina käytetään erilaisia kalvoja ja rakennuspapereita, joilla on pieni emissiviteetti. Katkojen merkitys kasvaa, kun mennään uusien normien mukaisiin eristepaksuuksiin. Lämmöneriste voidaan toteuttaa myös kokoamalla ohuita kalvoja paketiksi, jotka jakavat ilmatilan ja siis eristeelle varatun paksuuden suljettuihin ilmaväleihin. Kun kalvoiksi valitaan pieniemissiviteettisiä pintoja, saadaan säteilylämmönsiirto lähes eliminoiduksi. Tällaisen ilmatilan lämmönjohtumisluku lähestyy paikallaan pysyvän ilman lämmönjohtumislukua, l = 0,025 W/Km, eli tällä rakennesysteemillä on mahdollista toteuttaa ohuempia rakenteita kuin perinteisillä eristeillä. Hygroskooppisen massan käyttö sisäilman kosteutta tasaavana rakenteena voi olla tulevaisuutta. Kehitystyö tuottaa uusia, kosteusteknisesti toimivia sovelluksia. Toisaalta palomääräykset tulevat kehitystyötä vastaan. Hygroskooppinen pintamateriaali on kevyt (pieni tiheys) ja paloteknisesti arka. Suoraa sähkölämmitystä ei voida pitää ympäristöystävällisenä. Sen jalostusketju on pitkä ja monivaiheinen. Millä peruspolttoaineella sähköä tuotetaan, vaikuttaa asiaan luonnollisestikin. Suoraa sähkölämmitystä voidaan suositella vain yksinäisen ihmisen taloudessa lämmitysmuotona taloudellisista syistä. Halvan polttoaineen säästöllä ei voida maksaa suuria laiteinvestointeja. Aurinkoenergian hyvä hyödyntäminen edellyttää hyvää säätöä, joka kytkee lämmityksen pois päältä silloin, kun aurinko lämmittää. Auringon hetkelliset säteilytehot ovat suuria verrattuna rakenteen lämpöhäviöihin ja huonetilojen lämmöntarpeeseen. Ratkaisu aurinkoenergian hetkellisyyteen ja paikallisuuteen on energian siirtäminen lämmöntarpeen mukaan rakennuksen eri osiin ja sen varastoiminen päivätasolla. Kun varastoivasta massasta ei ole suoraa yhteyttä ulos, voidaan kerääjäeristeeltä saatu lämpö käyttää häviöttömästi huonetilojen lämmittämiseen. Vaikka lämmitysenergian käytössä päästään 30 % vähennyksiin uudisrakennusten osalta, ei kokonaisenergian käyttö merkittävästi pienene, jos taloussähkön kulutus pysyy vakiona. Sama pätee myös CO2 -päästöihin. Saavutettava etu lämmitys-energian kulutuksessa voidaan hukata yhä suurenevaksi taloussähkön käytöksi, mikä olisi erityisen huono asia ympäristön kannalta.

Contribution of Intronic miR-338-3p and Its Hosting Gene AATK to Compensatory β-Cell Mass Expansion.

The elucidation of the mechanisms directing β-cell mass regeneration and maintenance is of interest, because the deficit of β-cell mass contributes to diabetes onset and progression. We previously found that the level of the microRNA (miRNA) miR-338-3p is decreased in pancreatic islets from rodent models displaying insulin resistance and compensatory β-cell mass expansion, including pregnant rats, diet-induced obese mice, and db/db mice. Transfection of rat islet cells with oligonucleotides that specifically block miR-338-3p activity increased the fraction of proliferating β-cells in vitro and promoted survival under proapoptotic conditions without affecting the capacity of β-cells to release insulin in response to glucose. Here, we evaluated the role of miR-338-3p in vivo by injecting mice with an adeno-associated viral vector permitting specific sequestration of this miRNA in β-cells. We found that the adeno-associated viral construct increased the fraction of proliferating β-cells confirming the data obtained in vitro. miR-338-3p is generated from an intron of the gene coding for apoptosis-associated tyrosine kinase (AATK). Similarly to miR-338-3p, we found that AATK is down-regulated in rat and human islets and INS832/13 β-cells in the presence of the cAMP-raising agents exendin-4, estradiol, and a G-protein-coupled Receptor 30 agonist. Moreover, AATK expression is reduced in islets of insulin resistant animal models and selective silencing of AATK in INS832/13 cells by RNA interference promoted β-cell proliferation. The results point to a coordinated reduction of miR-338-3p and AATK under insulin resistance conditions and provide evidence for a cooperative action of the miRNA and its hosting gene in compensatory β-cell mass expansion.

DTC-OHJATUN TAHTIKONEKÄYTÖN PYÖRIMISNOPEUSSÄÄDÖN ANALYYSI INTEGROIDUN SIMULOINTIMALLIN AVULLA

Työssä rakennettiin integroitu simulointimalli sähkökäytölle, jonka mekaniikka koostuu joustava-akselisesta kaksimassa systeemistä. Lisäksi tarkasteltiin kyseiselle sähkökäytölle ominaisia piirteitä ja niiden aiheuttamia ongelmia eri sovelluksissa, sekä tutkittiin teollisuudessa yleisesti esiintyvän pyörimisnopeussäädön, PI-säädön, parametrien vaikutusta kyseisen mekaniikan omaaviin sähkökäyttöihin. Taajuusmuuttajalle kehiteltiin yksinkertaistettu simulointimalli, jolla pystytään pienentämään merkittävästi simuloinnin laskenta-aikaa. Vääntövärähtelyiden kompensointiin tutkittiin optimaalista tilasäätöä, jossa Kalman suotimella estimoidaan systeemin tilojen lisäksi myös kuormamomentti ja jossa nopeussäätö suunnitellaan lineaarisella neliöllisellä menetelmällä (Linear Quadratic).

Use of the dried blood spot sampling process coupled with fast gas chromatography and negative-ion chemical ionization tandem mass spectrometry: application to fluoxetine, norfluoxetine, reboxetine, and paroxetine analysis.

The objective of this work was to combine the advantages of the dried blood spot (DBS) sampling process with the highly sensitive and selective negative-ion chemical ionization tandem mass spectrometry (NICI-MS-MS) to analyze for recent antidepressants including fluoxetine, norfluoxetine, reboxetine, and paroxetine from micro whole blood samples (i.e., 10 microL). Before analysis, DBS samples were punched out, and antidepressants were simultaneously extracted and derivatized in a single step by use of pentafluoropropionic acid anhydride and 0.02% triethylamine in butyl chloride for 30 min at 60 degrees C under ultrasonication. Derivatives were then separated on a gas chromatograph coupled with a triple-quadrupole mass spectrometer operating in negative selected reaction monitoring mode for a total run time of 5 min. To establish the validity of the method, trueness, precision, and selectivity were determined on the basis of the guidelines of the "Société Française des Sciences et des Techniques Pharmaceutiques" (SFSTP). The assay was found to be linear in the concentration ranges 1 to 500 ng mL(-1) for fluoxetine and norfluoxetine and 20 to 500 ng mL(-1) for reboxetine and paroxetine. Despite the small sampling volume, the limit of detection was estimated at 20 pg mL(-1) for all the analytes. The stability of DBS was also evaluated at -20 degrees C, 4 degrees C, 25 degrees C, and 40 degrees C for up to 30 days. Furthermore, the method was successfully applied to a pharmacokinetic investigation performed on a healthy volunteer after oral administration of a single 40-mg dose of fluoxetine. Thus, this validated DBS method combines an extractive-derivative single step with a fast and sensitive GC-NICI-MS-MS technique. Using microliter blood samples, this procedure offers a patient-friendly tool in many biomedical fields such as checking treatment adherence, therapeutic drug monitoring, toxicological analyses, or pharmacokinetic studies.

Residues of b-lactams and quinolones in tissues and milk samples. Confirmatory analysis by liquid chromatography-mass spectrometry

The aim of this work is to optimize and validate methods for the multiresidue determination of series of families of antibiotics as quinolones, penicillins and cephalosporins included in European regulation in food samples using LC-MS/MS. Different extraction techniques and clean-up applied to antibiotics in meat were compared. The quality parameters were established according with EU guideline. The developed method was applied to 49 positive raw milk samples from animal medicated with different antibiotics; the 63% of the analyzed samples were found to be compliant. ___________________________________________________________________________________________