Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor alpha. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer. Fenofibrate metabolism, which also shows species differences, has not been fully determined in humans and surrogate primates. In the present study, the metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatographytandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.

Increasing Realism and Supporting Content Planning for Dynamic Scenes in a Mixed Reality System incorporating a Time-of-Flight Camera

For broadcasting purposes MIXED REALITY, the combination of real and virtual scene content, has become ubiquitous nowadays. Mixed Reality recording still requires expensive studio setups and is often limited to simple color keying. We present a system for Mixed Reality applications which uses depth keying and provides threedimensional mixing of real and artificial content. It features enhanced realism through automatic shadow computation which we consider a core issue to obtain realism and a convincing visual perception, besides the correct alignment of the two modalities and correct occlusion handling. Furthermore we present a possibility to support placement of virtual content in the scene. Core feature of our system is the incorporation of a TIME-OF-FLIGHT (TOF)-camera device. This device delivers real-time depth images of the environment at a reasonable resolution and quality. This camera is used to build a static environment model and it also allows correct handling of mutual occlusions between real and virtual content, shadow computation and enhanced content planning. The presented system is inexpensive, compact, mobile, flexible and provides convenient calibration procedures. Chroma-keying is replaced by depth-keying which is efficiently performed on the GRAPHICS PROCESSING UNIT (GPU) by the usage of an environment model and the current ToF-camera image. Automatic extraction and tracking of dynamic scene content is herewith performed and this information is used for planning and alignment of virtual content. An additional sustainable feature is that depth maps of the mixed content are available in real-time, which makes the approach suitable for future 3DTV productions. The presented paper gives an overview of the whole system approach including camera calibration, environment model generation, real-time keying and mixing of virtual and real content, shadowing for virtual content and dynamic object tracking for content planning.

Pollen percentage thresholds of Abies alba based on 13-year annual records of pollen deposition in modified Tauber traps: perspectives of application to fossil situations

Abies alba (fir), a submontane tree from Central European mountains and uplands, is of special interest for palaeoecological and palaeoclimate interpretations due to its sensitivity to air and soil humidity. Its present distribution limit in the uplands of SE Poland is still a matter of debate. In the Holocene fir expanded to Poland very late, but early fir populations are supposed to occur in the Šumava Mts (Czech Republic). The study aims: to estimate pollen thresholds for fir presence/absence in Bohemia (Czech Republic) and Poland on the basis of modified Tauber pollen traps; to use these thresholds for tracing fir presence in two pollen diagrams from Poland (Słone and Bezedna lakes) in the border zone between the Roztocze region (with fir forest stands today) and Polesie (where fir has never played an important role); and to investigate how the percentage presence/absence threshold can be used to trace the occurrence and abundance of fir trees in the Šumava Mts based on the pollen diagrams of Rokytecká slat' and Mrtvý luh. The fir pollen thresholds estimated in terms of PAR (pollen accumulation rates or pollen influx) range from 843 (grains cm− 2 year− 1) (Roztocze) to 61 (Krkonoše) and 49 (Šumava). Percentage thresholds range from 0.3% in Krkonoše where fir trees are not present within 4 km to 22% in fir-dominated woodland of the Roztocze, providing evidence of strong underrepresentation of fir in the pollen deposition. Application of these percentage thresholds to the Słone and Bezedna pollen diagrams indicates that occurrence of fir in the region is possible from 3.5 cal ky BP onwards, though the evidence is not decisive. In the Šumava, a low representation of fir pollen (1–2%) reflecting presence of scattered fir trees was detected as early as ca. 7.0 cal ky BP.

Influence of left ventricular relaxation on the pressure half time of aortic regurgitation

BACKGROUND The severity of aortic regurgitation can be estimated using pressure half time (PHT) of the aortic regurgitation flow velocity, but the correlation between regurgitant fraction and PHT is weak. AIM To test the hypothesis that the association between PHT and regurgitant fraction is substantially influenced by left ventricular relaxation. METHODS In 63 patients with aortic regurgitation, subdivided into a group without (n = 22) and a group with (n = 41) left ventricular hypertrophy, regurgitant fraction was calculated using the difference between right and left ventricular cardiac outputs. Left ventricular relaxation was assessed using the early to late diastolic Doppler tissue velocity ratio of the mitral annulus (E/ADTI), the E/A ratio of mitral inflow (E/AM), and the E deceleration time (E-DT). Left ventricular hypertrophy was assessed using the M mode derived left ventricular mass index. RESULTS The overall correlation between regurgitant fraction and PHT was weak (r = 0.36, p < 0.005). In patients without left ventricular hypertrophy, there was a significant correlation between regurgitant fraction and PHT (r = 0.62, p < 0.005), but not in patients with left ventricular hypertrophy. In patients with a left ventricular relaxation abnormality (defined as E/ADTI< 1, E/AM< age corrected lower limit, E-DT >/= 220 ms), no associations between regurgitant fraction and PHT were found, whereas in patients without left ventricular relaxation abnormalities, the regurgitant fraction to PHT relations were significant (normal E/AM: r = 0.57, p = 0.02; E-DT< 220 ms: r = 0.50, p < 0.001; E/ADTI < 1: r = 0.57, p = 0.02). CONCLUSIONS Only normal left ventricular relaxation allows a significant decay of PHT with increasing aortic regurgitation severity. In abnormal relaxation, which is usually present in left ventricular hypertrophy, wide variation in prolonged backward left ventricular filling may cause dissociation between the regurgitant fraction and PHT. Thus the PHT method should only be used in the absence of left ventricular relaxation abnormalities.

When language of instruction and language of application differ: Cognitive costs of bilingual mathematics learning

Bilingual education programs implicitly assume that the acquired knowledge is represented in a language-independent way. This assumption, however, stands in strong contrast to research findings showing that information may be represented in a way closely tied to the specific language of instruction and learning. The present study aims to examine whether and to which extent cognitive costs appear during arithmetic learning when language of instruction and language of retrieving differ. Thirty-nine high school students participating in a bilingual education program underwent a four-day training on multiplication and subtraction problems in one language (German or French), followed by a test session in which they had to solve trained as well as untrained problems in both languages. We found that cognitive costs related to language switching appeared for both arithmetic operations. Implications of our findings are discussed with respect to bilingual education as well as to cognitive mechanisms underlying different arithmetic operations.

Protein quaternary structure determination using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and chemical crosslinking

A means of analyzing protein quaternary structure using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI MS) and chemical crosslinking was evaluated. Proteins of known oligomeric structure, as well as monomeric proteins, were analyzed to evaluate the method. The quaternary structure of proteins of unknown or uncertain structure was investigated using this technique. The stoichiometry of recombinant E. coli carbamoyl phosphate synthetase and recombinant human farnesyl protein transferase were determined to be heterodimers using glutaraldehyde crosslinking, agreeing with the stoichiometry found for the wild type proteins. The stoichiometry of the gamma subunit of E. coli DNA polymerase III holoenzyme was determined in solution without the presence of other subunits to be a homotetramer using glutaraldehyde crosslinking and MALDI MS analysis. Chi and psi subunits of E. coli DNA polymerase III subunits appeared to form a heterodimer when crosslinked with heterobifunctional photoreactive crosslinkers.^ Comparison of relative % peak areas obtained from MALDI MS analysis of crosslinked proteins and densitometric scanning of silver stained sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gels showed excellent qualitative agreement for the two techniques, but the quantitative analyses differed, sometimes significantly. This difference in quantitation could be due to SDS-PAGE conditions (differential staining, loss of sample) or to MALDI MS conditions (differences in ionization and/or detection). Investigation of pre-purified crosslinked monomers and dimers recombined in a specific ratio revealed the presence of mass discrimination in the MALDI MS process. The calculation of mass discrimination for two different MALDI time-of-flight instruments showed the loss of a factor of approximately 2.6 in relative peak area as the m/z value doubles over the m/z range from 30,000 to 145,000 daltons.^ Indirect symmetry was determined for tetramers using glutaraldehyde crosslinking with MALDI MS analysis. Mathematical modelling and simple graphing allowed the determination of the symmetry for several tetramers known to possess isologous D2 symmetry. These methods also distinguished tetramers that did not fit D2 symmetry such as apo-avidin. The gamma tetramer of E. coli DNA polymerase III appears to have isologous D2 symmetry. ^

Success in Offshoring of Application Development – Does Culture Matter?

Recently, offshoring of information systems (IS) services to external vendors has seen considerable growth. Outsourcing to vendors in foreign countries brings about unique challenges which need to be understood and managed effectively. This paper explores cultural differences in IS offshoring arrangements involving German client organizations that outsource application development activities to Indian vendors. For this purpose, a research framework is developed based on both theoretical considerations and specific empirical observations from multiple case studies. The goal is to (1) explore the nature of cultural differences in offshoring arrangements in depth and to (2) analyze the relationship between those cultural differences and offshoring success. Based on the case findings, implications and practices for the management of offshore development projects are outlined.

A test of the Bolton-Scheinkman-Xiong hypothesis of how speculation affects the vesting time of options granted to directors

This paper investigates empirically the Bolton, Scheinkman, and Xiong (2006) hypothesis, according to which initial shareholders may provide incentives to managers to take actions that stimulate speculative bubbles. We test this hypothesis with data on up to 8,544 directors and up to 1,677 companies between 2004-2008. Using vesting time as a measure of the short-term performance weighting in CEO compensation and various alternative measures of the extent of speculation, the findings support the hypothesis: vesting time decreases with more intensive speculation. The results prove robust in various empirical model specifications.

Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation

BACKGROUND Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient's age at the time of the first VTE. PATIENTS AND METHODS Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. RESULTS Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. CONCLUSIONS Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

Posterior Vertical Bite Reconstructions of Erosively Worn Dentitions and the "Stamp Technique" - A Case Series with a Mean Observation Time of 40 Months

PURPOSE In the present case series, the authors report on seven cases of erosively worn dentitions (98 posterior teeth) which were treated with direct resin composite. MATERIALS AND METHODS In all cases, both arches were restored by using the so-called stamp technique. All patients were treated with standardized materials and protocols. Prior to treatment, a waxup was made on die-cast models to build up the loss of occlusion as well as ensure the optimal future anatomy and function of the eroded teeth to be restored. During treatment, teeth were restored by using templates of silicone (ie, two "stamps," one on the vestibular, one on the oral aspect of each tooth), which were filled with resin composite in order to transfer the planned, future restoration (ie, in the shape of the waxup) from the extra- to the intraoral situation. Baseline examinations were performed in all patients after treatment, and photographs as well as radiographs were taken. To evaluate the outcome, the modified United States Public Health Service criteria (USPHS) were used. RESULTS The patients were re-assessed after a mean observation time of 40 months (40.8 ± 7.2 months). The overall outcome of the restorations was good, and almost exclusively "Alpha" scores were given. Only the marginal integrity and the anatomical form received a "Charlie" score (10.2%) in two cases. CONCLUSION Direct resin composite restorations made with the stamp technique are a valuable treatment option for restoring erosively worn dentitions.

The Impact of Human Asset Specificity on the Sourcing of Application Services

The question concerning the circumstances under which it is advantageous for a company to outsource certain information systems functions has been a controversial issue for the last decade. While opponents emphasize the risks of outsourcing based on the loss of strategic potentials and increased transaction costs, proponents emphasize the strategic benefits of outsourcing and high potentials of cost-savings. This paper brings together both views by examining the conditions under which both the strategic potentials as well as savings in production and transaction costs of developing and maintaining software applications can better be achieved in-house as opposed to by an external vendor. We develop a theoretical framework from three complementary theories and test it empirically based on a mail survey of 139 German companies. The results show that insourcing is more cost efficient and advantageous in creating strategic benefits through IS if the provision of application services requires a high amount of firm specific human assets. These relationships, however, are partially moderated by differences in the trustworthiness and intrinsic motivation of internal versus external IS professionals. Moreover, capital shares with an external vendor can lower the risk of high transaction costs as well the risk of loosing the strategic opportunities of an IS.

INFLUENCE OF A CLINIC BASED IMMUNIZATION INFORMATION SYSTEM ON INFANT IMMUNIZATIONS

This study focuses on the impact of a clinic-based intervention program on the immunization status of limited-income urban children. The intervention program consisted of an information session for clinic health care providers and the placement of individualized immunization information labels on clinic notes at the time of each visit. The degree of impact of the intervention on immunization administration was ascertained through a comparison of two similar groups of infants born in the same months of the year immediately before (N = 201) and after (N = 203) the information session and initiation of the labeling system. The timeliness of administration of each diphtheria, pertussis, tetanus and trivalent oral polio vaccine (DPT/TOPV) in the first year series of three was compared pre- to postintervention. Significantly more third immunizations were given the postintervention subjects within ten days of the recommended time of application ( p = .0361). Life table analysis indicated that the probability of an infant's passing one year of age without the administration of the third immunization decreased for postintervention infants (p = .0515). The intervention was most successful in assuring administration of the series of immunizations in those infants who were seen by the health care provider for at least 50% of their first year visits. Results indicate that minor changes in the format of information given a relatively continuous provider can increase completion of immunization series in infants. ^