@article{DorenkampBonaventuraSohnsetal.2012, author = {Dorenkamp, Marc and Bonaventura, Klaus and Sohns, Christian and Becker, Christoph R. and Leber, Alexander W.}, title = {Direct costs and cost-effectiveness of dual-source computed tomography and invasive coronary angiography in patients with an intermediate pretest likelihood for coronary artery disease}, series = {Heart}, volume = {98}, journal = {Heart}, number = {6}, publisher = {BMJ Publ. Group}, address = {London}, issn = {1355-6037}, doi = {10.1136/heartjnl-2011-300149}, pages = {460 -- 467}, year = {2012}, abstract = {Aims The study aims to determine the direct costs and comparative cost-effectiveness of latest-generation dual-source computed tomography (DSCT) and invasive coronary angiography for diagnosing coronary artery disease (CAD) in patients suspected of having this disease. Methods The study was based on a previously elaborated cohort with an intermediate pretest likelihood for CAD and on complementary clinical data. Cost calculations were based on a detailed analysis of direct costs, and generally accepted accounting principles were applied. Based on Bayes' theorem, a mathematical model was used to compare the cost-effectiveness of both diagnostic approaches. Total costs included direct costs, induced costs and costs of complications. Effectiveness was defined as the ability of a diagnostic test to accurately identify a patient with CAD. Results Direct costs amounted to (sic)98.60 for DSCT and to (sic)317.75 for invasive coronary angiography. Analysis of model calculations indicated that cost-effectiveness grew hyperbolically with increasing prevalence of CAD. Given the prevalence of CAD in the study cohort (24\%), DSCT was found to be more cost-effective than invasive coronary angiography ((sic)970 vs (sic)1354 for one patient correctly diagnosed as having CAD). At a disease prevalence of 49\%, DSCT and invasive angiography were equally effective with costs of (sic)633. Above a threshold value of disease prevalence of 55\%, proceeding directly to invasive coronary angiography was more cost-effective than DSCT. Conclusions With proper patient selection and consideration of disease prevalence, DSCT coronary angiography is cost-effective for diagnosing CAD in patients with an intermediate pretest likelihood for it. However, the range of eligible patients may be smaller than previously reported.}, language = {en} } @article{LuethNeuberKleuser2012, author = {L{\"u}th, Anja and Neuber, Corinna and Kleuser, Burkhard}, title = {Novel methods for the quantification of (2E)-hexadecenal by liquid chromatography with detection by either ESI QTOF tandem mass spectrometry or fluorescence measurement}, series = {Analytica chimica acta : an international journal devoted to all branches of analytical chemistry}, volume = {722}, journal = {Analytica chimica acta : an international journal devoted to all branches of analytical chemistry}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0003-2670}, doi = {10.1016/j.aca.2012.01.063}, pages = {70 -- 79}, year = {2012}, abstract = {Sphingosine-1-phosphate lyase (SPL) is the only known enzyme that irreversibly cleaves sphingosine-1-phosphate (S1P) into phosphoethanolamine and (2E)-hexadecenal during the final step of sphingolipid catabolism. Because S1P is involved in a wide range of physiological and diseased processes, determining the activity of the degrading enzyme is of great interest. Therefore, we developed two procedures based on liquid chromatography (LC) for analysing (2E)-hexadecenal, which is one of the two S1P degradation products. After separation, two different quantification methods were performed, tandem mass spectrometry (MS) and fluorescence detection. However, (2E)-hexadecenal as a long-chain aldehyde is not ionisable by electrospray ionisation (ESI) for MS quantification and has an insufficient number of corresponding double bonds for fluorescence detection. Therefore, we investigated 2-diphenylacetyl-1,3-indandione-1-hydrazone (DAIH) as a derivatisation reagent. DAIH transforms the aldehyde into an ionisable and fluorescent analogue for quantitative analysis. Our conditions were optimised to obtain the outstanding limit of detection (LOD) of 1 fmol per sample (30 mu L) for LC-MS/MS and 0.75 pmol per sample (200 mu l) for LC determination with fluorescence detection. We developed an extraction procedure to separate and concentrate (2E)-hexadecenal from biological samples for these measurements. To confirm our new methods, we analysed the (2E)-hexadecenal level of different cell lines and human plasma for the first time ever. Furthermore, we treated HT-29 cells with different concentrations of 4-deoxypyridoxine (DOP), which competitively inhibits pyridoxal-5-phosphate (P5P), an essential cofactor for SPL activity, and observed a significant decrease in (2E)-hexadecenal relative to the untreated cells.}, language = {en} } @article{HenkelFredeSchanzeetal.2012, author = {Henkel, Janin and Frede, Katja and Schanze, Nancy and Vogel, Heike and Sch{\"u}rmann, Annette and Spruß, Astrid and Bergheim, Ina and P{\"u}schel, Gerhard Paul}, title = {Stimulation of fat accumulation in hepatocytes by PGE(2)-dependent repression of hepatic lipolysis, beta-oxidation and VLDL-synthesis}, series = {Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology}, volume = {92}, journal = {Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology}, number = {11}, publisher = {Nature Publ. Group}, address = {New York}, issn = {0023-6837}, doi = {10.1038/labinvest.2012.128}, pages = {1597 -- 1606}, year = {2012}, abstract = {Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE(2), which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE(2)-generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE(2) attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE(2) enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE(2)-dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial beta-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1 alpha, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1 alpha completely blunted the PGE(2)-dependent fat accumulation. PGE(2) enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE(2) synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH. Laboratory Investigation (2012) 92, 1597-1606; doi:10.1038/labinvest.2012.128; published online 10 September 2012}, language = {en} } @article{HesseJaschkeKanzleiteretal.2012, author = {Hesse, Deike and Jaschke, Alexander and Kanzleiter, Timo and Witte, Nicole and Augustin, Robert and Hommel, Angela and P{\"u}schel, Gerhard Paul and Petzke, Klaus-J{\"u}rgen and Joost, Hans-Georg and Schupp, Michael and Sch{\"u}rmann, Annette}, title = {GTPase ARFRP1 is essential for normal hepatic glycogen storage and insulin-like growth factor 1 secretion}, series = {Molecular and cellular biology}, volume = {32}, journal = {Molecular and cellular biology}, number = {21}, publisher = {American Society for Microbiology}, address = {Washington}, issn = {0270-7306}, doi = {10.1128/MCB.00522-12}, pages = {4363 -- 4374}, year = {2012}, abstract = {The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50\% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage.}, language = {en} } @article{ThierbachFlorianWolfrumetal.2012, author = {Thierbach, Rene and Florian, Simone and Wolfrum, Katharina and Voigt, Anja and Drewes, Gunnar and Blume, Urte and Bannasch, Peter and Ristow, Michael and Steinberg, Pablo}, title = {Specific alterations of carbohydrate metabolism are associated with hepatocarcinogenesis in mitochondrially impaired mice}, series = {Human molecular genetics}, volume = {21}, journal = {Human molecular genetics}, number = {3}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0964-6906}, doi = {10.1093/hmg/ddr499}, pages = {656 -- 663}, year = {2012}, abstract = {Friedreich's ataxia is an inherited neurodegenerative disease caused by the reduced expression of the mitochondrially active protein frataxin. We have previously shown that mice with a hepatocyte-specific frataxin knockout (AlbFxn(-/-)) develop multiple hepatic tumors in later life. In the present study, hepatic carbohydrate metabolism in AlbFxn(-/-) mice at an early and late life stage was analyzed. In young (5-week-old) AlbFxn(-/-) mice hepatic ATP, glucose-6-phosphate and glycogen levels were found to be reduced by similar to 74, 80 and 88\%, respectively, when compared with control animals. This pronounced ATP, G6P and glycogen depletion in the livers of young mice reverted in older animals: while half of the mice die before 30 weeks of age, the other half reaches 17 months of age and exhibits glycogen, G6P and ATP levels similar to those in age-matched controls. A key event in this respect seems to be the up-regulation of GLUT1, the predominant glucose transporter in fetal liver parenchyma, which became evident in AlbFxn(-/-) mice being 5-12 weeks of age. The most significant histological findings in animals being 17 or 22 months of age were the appearance of multiple clear cell, mixed cell and basophilic foci throughout the liver parenchyma as well as the development of hepatocellular adenomas and carcinomas. The hepatocarcinogenic process in AlbFxn 2/2 mice shows remarkable differences regarding carbohydrate metabolism alterations when compared with all other chemically and virally driven liver cancer models described up to now.}, language = {en} } @article{IkramFornageSmithetal.2012, author = {Ikram, M. Arfan and Fornage, Myriam and Smith, Albert V. and Seshadri, Sudha and Schmidt, Reinhold and Debette, Stephanie and Vrooman, Henri A. and Sigurdsson, Sigurdur and Ropele, Stefan and Taal, H. Rob and Mook-Kanamori, Dennis O. and Coker, Laura H. and Longstreth, W. T. and Niessen, Wiro J. and DeStefano, Anita L. and Beiser, Alexa and Zijdenbos, Alex P. and Struchalin, Maksim and Jack, Clifford R. and Rivadeneira, Fernando and Uitterlinden, Andre G. and Knopman, David S. and Hartikainen, Anna-Liisa and Pennell, Craig E. and Thiering, Elisabeth and Steegers, Eric A. P. and Hakonarson, Hakon and Heinrich, Joachim and Palmer, Lyle J. and Jarvelin, Marjo-Riitta and McCarthy, Mark I. and Grant, Struan F. A. and St Pourcain, Beate and Timpson, Nicholas J. and Smith, George Davey and Sovio, Ulla and Nalls, Mike A. and Au, Rhoda and Hofman, Albert and Gudnason, Haukur and van der Lugt, Aad and Harris, Tamara B. and Meeks, William M. and Vernooij, Meike W. and van Buchem, Mark A. and Catellier, Diane and Jaddoe, Vincent W. V. and Gudnason, Vilmundur and Windham, B. Gwen and Wolf, Philip A. and van Duijn, Cornelia M. and Mosley, Thomas H. and Schmidt, Helena and Launer, Lenore J. and Breteler, Monique M. B. and DeCarli, Charles and Adair, Linda S. and Ang, Wei and Atalay, Mustafa and vanBeijsterveldt, Toos and Bergen, Nienke and Benke, Kelly and Berry, Diane J. and Coin, Lachlan and Davis, Oliver S. P. and Elliott, Paul and Flexeder, Claudia and Frayling, Tim and Gaillard, Romy and Groen-Blokhuis, Maria and Goh, Liang-Kee and Haworth, Claire M. A. and Hadley, Dexter and Hebebrand, Johannes and Hinney, Anke and Hirschhorn, Joel N. and Holloway, John W. and Holst, Claus and Hottenga, Jouke Jan and Horikoshi, Momoko and Huikari, Ville and Hypponen, Elina and Kilpelainen, Tuomas O. and Kirin, Mirna and Kowgier, Matthew and Lakka, Hanna-Maaria and Lange, Leslie A. and Lawlor, Debbie A. and Lehtimaki, Terho and Lewin, Alex and Lindgren, Cecilia and Lindi, Virpi and Maggi, Reedik and Marsh, Julie and Middeldorp, Christel and Millwood, Iona and Murray, Jeffrey C. and Nivard, Michel and Nohr, Ellen Aagaard and Ntalla, Ioanna and Oken, Emily and Panoutsopoulou, Kalliope and Pararajasingham, Jennifer and Rodriguez, Alina and Salem, Rany M. and Sebert, Sylvain and Siitonen, Niina and Strachan, David P. and Teo, Yik-Ying and Valcarcel, Beatriz and Willemsen, Gonneke and Zeggini, Eleftheria and Boomsma, Dorret I. and Cooper, Cyrus and Gillman, Matthew and Hocher, Berthold and Lakka, Timo A. and Mohlke, Karen L. and Dedoussis, George V. and Ong, Ken K. and Pearson, Ewan R. and Price, Thomas S. and Power, Chris and Raitakari, Olli T. and Saw, Seang-Mei and Scherag, Andre and Simell, Olli and Sorensen, Thorkild I. A. and Wilson, James F.}, title = {Common variants at 6q22 and 17q21 are associated with intracranial volume}, series = {Nature genetics}, volume = {44}, journal = {Nature genetics}, number = {5}, publisher = {Nature Publ. Group}, address = {New York}, organization = {Early Growth Genetics EGG Consorti, Cohorts Heart Aging Res Genomic Ep}, issn = {1061-4036}, doi = {10.1038/ng.2245}, pages = {539 -- +}, year = {2012}, abstract = {During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.}, language = {en} } @article{LiWangChenetal.2012, author = {Li, Jian and Wang, Zi-Neng and Chen, You-Peng and Dong, Yun-Peng and Shuai, Han-Lin and Xiao, Xiao-Min and Reichetzeder, Christoph and Hocher, Berthold}, title = {Late gestational maternal serum cortisol is inversely associated with fetal brain growth}, series = {Neuroscience \& biobehavioral reviews : official journal of the International Behavioral Neuroscience Society}, volume = {36}, journal = {Neuroscience \& biobehavioral reviews : official journal of the International Behavioral Neuroscience Society}, number = {3}, publisher = {Elsevier}, address = {Oxford}, issn = {0149-7634}, doi = {10.1016/j.neubiorev.2011.12.006}, pages = {1085 -- 1092}, year = {2012}, abstract = {To analyze the association between fetal brain growth and late gestational blood serum cortisol in normal pregnancy.Blood total cortisol was quantified at delivery in 432 Chinese mother/child pairs. Key inclusion criteria of the cohort were: no structural anomalies of the newborn, singleton pregnancy, no alcohol abuse, no drug abuse or history of smoking no hypertensive disorders and no impairment of glucose tolerance and no use of steroid medication during pregnancy. Differential ultrasound examination of the fetal body was done in early (gestational day 89.95 +/- 7.31), middle (gestational day 160.17 16.12) and late pregnancy (gestational day 268.89 +/- 12.42). Newborn's cortisol was not correlated with any of the ultrasound measurements during pregnancy nor with birth weight. Multivariable regression analysis, considering timing of the ultrasound examination, the child's sex, maternal BMI, maternal age, maternal body weight at delivery, the timing of cortisol measurement and maternal uterine contraction states, revealed that maternal serum total cortisol was significantly negative correlated with ultrasound parameters describing the fetal brain: late biparietal diameter (R-2 =0.512, p =0.009), late head circumference (R-2 = 0.498, p= 0.001), middle biparietal diameter (R-2= 0.819, p = 0.013), middle cerebellum transverse diameter R-2 = 0.76, p= 0.014) and early biparietal diameter(R-2 = 0.819, p = 0.013). The same analysis revealed that birth weight as well as ultrasound parameters such as abdominal circumference and femur length were not correlated to maternal cortisol levels. In conclusion, our study demonstrates that maternal cortisol secretion within physiological ranges may be inversely correlated to fetal brain growth but not to birth weight. It remains to be demonstrated whether maternal cortisol secretion negatively influencing fetal brain growth translates to adverse neurological outcomes in later life.}, language = {en} } @article{RailaEnjalbertMothesetal.2012, author = {Raila, Jens and Enjalbert, Francis and Mothes, Ralf and Hurtienne, Andrea and Schweigert, Florian J.}, title = {Validation of a new point-of-care assay for determination of ss-carotene concentration in bovine whole blood and plasma}, series = {Veterinary clinical pathology}, volume = {41}, journal = {Veterinary clinical pathology}, number = {1}, publisher = {Wiley-Blackwell}, address = {Malden}, issn = {0275-6382}, doi = {10.1111/j.1939-165X.2012.00400.x}, pages = {119 -- 122}, year = {2012}, abstract = {Background: beta-Carotene is an important precursor of vitamin A, and is associated with bovine fertility. beta-Carotene concentrations in plasma are used to optimize beta-carotene supplementation in cattle, but measurement requires specialized equipment to separate plasma and extract and measure beta-carotene, either using spectrophotometry or high performance liquid chromatography (HPLC). Objective: The objective of this study was to validate a new 2-step point-of-care (POC) assay for measuring beta-carotene in whole blood and plasma. Methods: beta-carotene concentrations in plasma from 166 cows were measured using HPLC and compared with results obtained using a POC assay, the iCheck-iEx-Carotene test kit. Whole blood samples from 23 of these cattle were also evaluated using the POC assay and compared with HPLC-plasma results from the same 23 animals. The POC assay includes an extraction vial (iEx Carotene) and hand-held photometer (iCheck Carotene). Results: Concentrations of beta-carotene in plasma measured using the POC assay ranged from 0.40 to 15.84 mg/L (n = 166). No differences were observed between methods for assay of plasma (mean +/- SD; n = 166): HPLC-plasma 4.23 +/- 2.35 mg/L; POC-plasma 4.49 +/- 2.36 mg/L. Similar good agreement was found when plasma analyzed using HPLC was compared with whole blood analyzed using the POC system (n = 23): HPLC-plasma 3.46 +/- 2.12 mg/L; POC-whole blood 3.67 +/- 2.29 mg/L. Conclusions: Concentrations of beta-carotene can be measured in blood and plasma from cattle easily and rapidly using a POC assay, and results are comparable to those obtained by the highly sophisticated HPLC method. Immediate feedback regarding beta-carotene deficiency facilitates rapid and appropriate optimization of beta-carotene supplementation in feed.}, language = {en} } @article{Schneider2012, author = {Schneider, Birgit}, title = {Climate model simulation visualization from a visual studies perspective}, series = {Wiley interdisciplinary reviews : Climate change}, volume = {3}, journal = {Wiley interdisciplinary reviews : Climate change}, number = {2}, publisher = {Wiley}, address = {Malden}, issn = {1757-7780}, doi = {10.1002/wcc.162}, pages = {185 -- 193}, year = {2012}, abstract = {The article gives an overview on the visualization of climate model data simulation from a visual studies perspective. On one hand the question is raised of what it means culturally when global images are used to communicate scenarios of a changing climate future beyond the field of climate research itself. The product of this process is one of the most widespread icons of climate change, the image of the blue planet that has turned red. On the other hand insights into how these visualizations are designed in the studio of a computer designer are given. The focus here is on the way in which specific visualization software shapes images of a changing global climate. The article takes as its starting point the perspective of visual and media studies, because images have become so crucial in communicating research results of climate science and convincing policy agents and the public. What is special about scientific images depicting climate change is that they have implicitly also become political images. As today various actors and recipient groups are making use of pictures depicting climate change, the article concerns climate science, media studies, computer visualization, cultural studies, and politics alike.}, language = {en} } @article{KemperLutzBaehretal.2012, author = {Kemper, Christoph J. and Lutz, Johannes and B{\"a}hr, Tobias and R{\"u}ddel, Heinz and Hock, Michael}, title = {Construct validity of the anxiety sensitivity index-3 in clinical samples}, series = {Assessment}, volume = {19}, journal = {Assessment}, number = {1}, publisher = {Sage Publ.}, address = {Thousand Oaks}, issn = {1073-1911}, doi = {10.1177/1073191111429389}, pages = {89 -- 100}, year = {2012}, abstract = {Using two clinical samples of patients, the presented studies examined the construct validity of the recently revised Anxiety Sensitivity Index-3 (ASI-3). Confirmatory factor analyses established a clear three-factor structure that corresponds to the postulated subdivision of the construct into correlated somatic, social, and cognitive components. Participants with different primary clinical diagnoses differed from each other on the ASI-3 subscales in theoretically meaningful ways. Specifically, the ASI-3 successfully discriminated patients with anxiety disorders from patients with nonanxiety disorders. Moreover, patients with panic disorder or agoraphobia manifested more somatic concerns than patients with other anxiety disorders and patients with nonanxiety disorders. Finally, correlations of the ASI-3 scales with other measures of clinical symptoms and negative affect substantiated convergent and discriminant validity. Substantial positive correlations were found between the ASI-3 Somatic Concerns and body vigilance, between Social Concerns and fear of negative evaluation and socially inhibited behavior, and between Cognitive Concerns and depression symptoms, anxiety, fear of negative evaluation, and subjective complaints. Moreover, Social Concerns correlated negatively with dominant and intrusive behavior. Results are discussed with respect to the contribution of the ASI-3 to the assessment of anxiety-related disorders.}, language = {en} } @article{KuhlAurichWulfetal.2012, author = {Kuhl, Juliane and Aurich, J{\"o}rg E. and Wulf, Manuela and Hurtienne, A. and Schweigert, Florian J. and Aurich, Christine}, title = {Effects of oral supplementation with beta-carotene on concentrations of beta-carotene, vitamin A and alpha-tocopherol in plasma, colostrum and milk of mares and plasma of their foals and on fertility in mares}, series = {Journal of animal physiology and animal nutrition}, volume = {96}, journal = {Journal of animal physiology and animal nutrition}, number = {3}, publisher = {Wiley-Blackwell}, address = {Malden}, issn = {0931-2439}, doi = {10.1111/j.1439-0396.2011.01150.x}, pages = {376 -- 384}, year = {2012}, abstract = {In this study, effects of oral beta-carotene supplementation to mares (beta-carotene group: 1000 mg/day, n = 15; control group: n = 15) from 2 weeks before foaling until 6 weeks thereafter on concentrations of beta-carotene, vitamin A and a-tocopherol in plasma, colostrum and milk and plasma of their foals were determined. In addition, effects on fertility were studied. Beta-carotene concentrations increased in plasma and colostrum of beta-carotene-supplemented mares compared to control mares (p < 0.05). In mares of both groups, beta-carotene concentrations were higher in colostrum than in milk (p < 0.05). In foals, beta-carotene concentrations increased with colostrum uptake and were higher in foals born to supplemented mares (p < 0.05; control group: 0.0003 +/- 0.0002 mu g/ml on day 0, 0.008 +/- 0.0023 mu g/ml on day 1; beta-carotene group: 0.0005 +/- 0.0003 mu g/ml on day 0, 0.048 +/- 0.018 mu g/ml on day 1). Concentrations of vitamin A and a-tocopherol were higher in colostrum than in milk (p < 0.05) but did not differ between groups. Concentration of a-tocopherol in plasma of mares decreased over time and in foals, increased markedly within 4 days after birth. All but one mare (control group) showed oestrus within 2 weeks post-partum. Occurrence of oestrus did not differ between groups. More mares of the control group (7/7 vs. 5/12 in the beta-carotene group) became pregnant after being bred in first post-partum oestrus (p < 0.05). In conclusion, beta-carotene supplementation to mares increased beta-carotene concentrations in plasma, colostrum and milk of mares and plasma of their foals but had no positive effects on fertility.}, language = {en} } @article{ChenXiaoLietal.2012, author = {Chen, You-Peng and Xiao, Xiao-Min and Li, Jian and Reichetzeder, Christoph and Wang, Zi-Neng and Hocher, Berthold}, title = {Paternal body mass index (BMI) is associated with offspring intrauterine growth in a gender dependent manner}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {5}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0036329}, pages = {9}, year = {2012}, abstract = {Background: Environmental alternations leading to fetal programming of cardiovascular diseases in later life have been attributed to maternal factors. However, animal studies showed that paternal obesity may program cardio-metabolic diseases in the offspring. In the current study we tested the hypothesis that paternal BMI may be associated with fetal growth. Methods and Results: We analyzed the relationship between paternal body mass index (BMI) and birth weight, ultrasound parameters describing the newborn's body shape as well as parameters describing the newborns endocrine system such as cortisol, aldosterone, renin activity and fetal glycated serum protein in a birth cohort of 899 father/mother/child triplets. Since fetal programming is an offspring sex specific process, male and female offspring were analyzed separately. Multivariable regression analyses considering maternal BMI, paternal and maternal age, hypertension during pregnancy, maternal total glycated serum protein, parity and either gestational age (for birth weight) or time of ultrasound investigation (for ultrasound parameters) as confounding showed that paternal BMI is associated with growth of the male but not female offspring. Paternal BMI correlated with birth parameters of male offspring only: birth weight; biparietal diameter, head circumference; abdominal diameter, abdominal circumference; and pectoral diameter. Cortisol was likewise significantly correlated with paternal BMI in male newborns only. Conclusions: Paternal BMI affects growth of the male but not female offspring. Paternal BMI may thus represent a risk factor for cardiovascular diseases of male offspring in later life. It remains to be demonstrated whether this is linked to an offspring sex specific paternal programming of cortisol secretion.}, language = {en} } @article{NairHocherVerkaartetal.2012, author = {Nair, Anil V. and Hocher, Berthold and Verkaart, Sjoerd and van Zeeland, Femke and Pfab, Thiemo and Slowinski, Torsten and Chen, You-Peng and Schlingmann, Karl Peter and Schaller, Andre and Gallati, Sabina and Bindels, Rene J. and Konrad, Martin and H{\"o}nderop, Joost G.}, title = {Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy}, series = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {28}, publisher = {National Acad. of Sciences}, address = {Washington}, issn = {0027-8424}, doi = {10.1073/pnas.1113811109}, pages = {11324 -- 11329}, year = {2012}, abstract = {Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 ((VI)-I-1393, (KE)-E-1584) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6 ((VI)-I-1393) and TRPM6((KE)-E-1584), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T-1391) and TRPM6(S-1583). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6((VI)-I-1393) and TRPM6((KE)-E-1584) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.}, language = {en} } @article{HocherArmbrusterStoevaetal.2012, author = {Hocher, Berthold and Armbruster, Franz Paul and St{\"o}va, Stanka and Reichetzeder, Christoph and Groen, Hans J{\"u}rgen and Lieker, Ina and Khadzhynov, Dmytro and Slowinski, Torsten and Roth, Heinz J{\"u}rgen}, title = {Measuring Parathyroid Hormone (PTH) in patients with oxidative stress - do we need a fourth generation Parathyroid Hormone assay?}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {7}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0040242}, pages = {10}, year = {2012}, abstract = {Oxidation of PTH at methionine residues results in loss of biological activity. PTH may be oxidized in patients with renal disease. The aim of this study was to develop an assay considering oxidation of PTH. Oxidized hPTH was analyzed by high resolution nano-liquid chromatography coupled to ESI-FTT tandem mass spectrometry (nanoLC-ESI-FT-MS/MS) directly and after proteolytic cleavage. The oxidized hPTH(1-84) sample shows TIC-peaks at 18-20 min and several mass peaks due to mass shifts caused by oxidations. No significant signal for oxidized hPTH(1-84) species after removal of oxidized PTH molecules by a specific column with monoclonal antibodies (MAB) raised against the oxidized hPTH was detectable. By using this column in samples from 18 patients on dialysis we could demonstrate that measured PTH concentrations were substantially lower when considering oxidized forms of PTH. The relationship between PTH concentrations determined directly and those concentrations measured after removal of the oxidized PTH forms varies substantially. In some patients only 7\% of traditionally measured PTH was free of oxidation, whereas in other patients 34\% of the traditionally measured PTH was real intact PTH. In conclusion, a huge but not constant proportion of PTH molecules are oxidized in patients requiring dialysis. Since oxidized PTH is biologically inactive, the currently used methods to detect PTH in daily clinical practice may not adequately reflect PTH-related bone and cardiovascular abnormalities in patients on dialysis.}, language = {en} } @article{HaghipourBurgKoberetal.2012, author = {Haghipour, Negar and Burg, Jean-Pierre and Kober, Florian and Zeilinger, Gerold and Ivy-Ochs, Susan and Kubik, Peter W. and Faridi, Mohammad}, title = {Rate of crustal shortening and non-Coulomb behaviour of an active accretionary wedge - the folded fluvial terraces in Makran (SE, Iran)}, series = {Earth \& planetary science letters}, volume = {355}, journal = {Earth \& planetary science letters}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0012-821X}, doi = {10.1016/j.epsl.2012.09.001}, pages = {187 -- 198}, year = {2012}, abstract = {We surveyed fluvial terraces to decipher the Quaternary increment of crustal shortening and shortening rate in the on-shore Makran Accretionary Wedge. We focused on three major catchment basins and associated fold systems. Terrace profiles reconstructed from differential GPS measurements combined with DEM revealed two regional dominant wavelengths, about 5 km in the northern part of the study area and about 15 km to the south. These two wavelengths suggest the existence of two active decollement layers at two rooting depths. The average shortening rate due to folding is estimated at 0.8-1.2 mm/a over the last 130 ka. This accounts for 10-15\% of the shortening rate (similar to 8 mm/a) given by kinematic GPS measurements between Chabahar and Bazman and 3\% of the convergence between Arabia and Eurasia, across the Makran subduction zone. Despite active deformation and a relatively high shortening rate, the geophysical record shows nearly absent seismic activity in Makran. We propose that strain accumulated in folds over intermediate decollement levels within a thick, incompletely lithified sedimentary cover explains the essentially aseismic, recent tectonics in this region. The importance of folds points to imperfect Coulomb behaviour of the wedge. (C) 2012 Elsevier B.V. All rights reserved.}, language = {en} } @article{SchmerbachKalkWengenmayeretal.2012, author = {Schmerbach, K. and Kalk, Philipp. and Wengenmayer, Christina and Lucht, K. and Unger, T. and Hocher, Berthold and Thoene-Reineke, C.}, title = {Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.110622}, pages = {625 -- 633}, year = {2012}, abstract = {Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce. Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies. Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50\% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options. Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.}, language = {en} } @article{AlterKretschmerVonWebskyetal.2012, author = {Alter, Markus L. and Kretschmer, Axel and Von Websky, Karoline and Tsuprykov, Oleg and Reichetzeder, Christoph and Simon, Alexandra and Stasch, Johannes-Peter and Hocher, Berthold}, title = {Early urinary and plasma biomarkers for experimental diabetic Nephropathy}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.111010}, pages = {659 -- 671}, year = {2012}, abstract = {Background: As the prevalence of diabetes rises, its complications such as diabetic nephropathy affect an increaseing number of patients. Consequently, the need for biomarkers in rodent models which reflect the stage and course of diabetic nephropathy is high. This article focuses on Heart-type fatty acid binding protein (H-FABP), osteopontin (OPN), nephrin, and Neutrophil gelatinase-associated lipocalin (NGAL) in urine, and kidney injury molecule (KIM)-1, clusterin, and tissue inhibitior of metalloproteinases (TIMP) 1 in plasma in uni-nephrectomized rats with streptocotozin-induced type 1 diabetes mellitus, a common animal model to explore renal impairment in the setting of diabetes mellitus. Methods: 23 male Wistar rats were uni-nephrectomized and subsequently divided into two study groups. The diabetic group received streptozotocin (STZ) via tail-vein injection, the non-diabetic group received citrate buffer without STZ. Subsequently, blood glucose, body weight, and blood pressure were checked regularly. After 18 weeks, animals were placed in metabolic cages, blood and urine obtained and subsequently organs were harvested after sacrifice. Results: Blood glucose levels were highly increased in diabetic animals throughout the experiment, whereas systolic blood pressure did not differ between the study groups. At study end, classical biomarkers such as urinary albumin and protein and plasma cystatin c were only slightly but not significantly different between groups indicating a very early disease state. In contrast, urinary excretion of H-FABP, OPN, nephrin, and NGAL were highly increased in diabetic animals with a highly significant p-value (p<0.01 each) compared to non-diabetic animals. In plasma, differences were found for calbindin, KIM-1, clusterin, TIMP-1, and OPN. These findings were confirmed by means of the area under the receiver operating characteristic curve (ROC-AUC) analysis. Conclusions: In summary, our study revealed elevated levels of new plasma and urinary biomarkers (urinary osteopontin, urinary nephrin, urinary NGAL, urinary H-FABP, plasma KIM-1, plasma TIMP-1) in uni-nephrectomized diabetic rats, an established rat model of diabetic nephropathy. These biomarkers appeared even before the classical biomarkers of diabetic nephropathy such as albuminuria and urinary protein excretion. The new biomarkers might offer advantage to urinary albumin and plasma cystatin c with respect to early detection.}, language = {en} } @article{ChenLiWangetal.2012, author = {Chen, You-Peng and Li, Jian and Wang, Zi-Neng and Reichetzeder, Christoph and Xu, Hao and Gong, Jian and Chen, Guang-Ji and Pfab, Thiemo and Xiao, Xiao-Min and Hocher, Berthold}, title = {Renin angiotensin aldosterone system and glycemia in pregnancy}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {5-6}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, pages = {527 -- 533}, year = {2012}, abstract = {Background: The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of insulin resistance and type 2 diabetes in the general population. The RAAS is activated during pregnancy. However, it is unknown whether the RAAS contributes to glycemia in pregnant women. Methods: Plasma renin activity (PRA) and plasma aldosterone levels were quantified at delivery in 689 Chinese mothers. An oral glucose tolerance test in fasted women was performed in the second trimester of pregnancy. The diagnosis of gestational diabetes mellitus (GDM) and impaired glucose tolerance during pregnancy were made according to the guidelines of the Chinese Society of Obstetrics. Results: Plasma aldosterone was significantly higher in pregnant women with GDM as compared to those without impairment of glycemic control (normal pregnancies: 0.27 +/- 0.21 ng/mL, GDM: 0.36 +/- 0.30 ng/mL; p<0.05). Regression analyses revealed that PRA was negatively correlated with fasting blood glucose (FBG) (R-2 = 0.03, p = 0.007), whereas plasma aldosterone and aldosterone/PRA ratio were positively correlated with FBG (R-2 = 0.05, p<0.001 and R-2 = 0.03, p = 0.007, respectively). Multivariable regression analysis models considering relevant confounding factors confirmed these findings. Conclusions: This study demonstrated that fasting blood glucose in pregnant women is inversely correlated with the PRA, whereas plasma aldosterone showed a highly significant positive correlation with fasting blood glucose during pregnancy. Moreover, plasma aldosterone is significantly higher in pregnant women with GDM as compared to those women with normal glucose tolerance during pregnancy. Although causality cannot be proven in association studies, these data may indicate that the RAAS during pregnancy contributes to the pathogenesis of insulin resistance/new onset of diabetes during pregnancy.}, language = {en} } @article{VickersCheethamBirminghametal.2012, author = {Vickers, Steven P. and Cheetham, Sharon C. and Birmingham, Gareth D. and Rowley, Helen L. and Headland, Katie R. and Dickinson, Keith and Grempler, Rolf and Hocher, Berthold and Mark, Michael and Klein, Thomas}, title = {Effects of the DPP-4 Inhibitor, Linagliptin, in Diet-Induced obese rats a comparison in Naive and Exenatide-Treated Animals}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2011.110919}, pages = {787 -- 799}, year = {2012}, abstract = {Background: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats. Methods: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period. In a subsequent study, rats received exenatide (either 3 or 30 mu g/kg/day) or vehicle by osmotic mini-pump for 28 days. In addition, groups of animals were dosed orally with linagliptin either alone or in combination with a 3 mu g/kg/day exenatide dose for the study duration. In a final study, rats were administered exenatide (30 mu g/kg/day) or vehicle by osmotic mini-pump for eleven days. Subsequently, exenatide-treated animals were transferred to vehicle or continued exenatide infusion for a further ten days. Animals transferred from exenatide to vehicle were also dosed orally with either vehicle or linagliptin. In all studies, body weight, food and water intake were recorded daily and relevant plasma parameters and carcass composition were determined. Results: In contrast to exenatide, linagliptin did not significantly reduce body weight or carcass fat in DIO rats versus controls. Linagliptin augmented the effect of exenatide to reduce body fat when given in combination but did not affect the body weight response. In rats withdrawn from exenatide, weight regain was observed such that body weight was not significantly different to controls. Linagliptin reduced weight regain after withdrawal of exenatide such that a significant difference from controls was evident. Conclusions: These data demonstrate that linagliptin does not significantly alter body weight in either untreated or exenatide-treated DIO rats, although it delays weight gain after exenatide withdrawal. This finding may suggest the utility of DPP-4 inhibitors in reducing body weight during periods of weight gain.}, language = {en} } @article{HocherGroenSchumannetal.2012, author = {Hocher, Berthold and Groen, Hans J{\"u}rgen and Schumann, Claudia and Tsuprykov, Oleg and Seifert, Susanne and Hitzler, Walter E. and Armbruster, Franz Paul}, title = {Vitamin D status from dried capillary blood samples}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {58}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {7-8}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2012.120429}, pages = {851 -- 855}, year = {2012}, abstract = {Background: Given the huge impact of vitamin D deficiency on a broad spectrum of diseases such as rickets, osteoporosis, mineral bone disease-vascular calcification syndrome, infectious diseases, but also several types of cancer and CNS diseases, reliable and simple methods to analyze the vitamin D status are urgently needed. Methods: We developed an easy technique to determine the 25-OH vitamin D status from dried blood samples on filter paper. This allows determination of the 25-OH vitamin D status independently of venous blood taking, since only sampling of capillary blood is required for this new method. We compared the results of vitamin D measurements from venous blood of 96 healthy blood donors with those from capillary blood taken from the same patients at the same time. The capillary blood was dried on filter paper using the D-Vital ID dry-blood collection system. Results: 25-OH vitamin D concentration data from extracted dried capillary blood filters correlated very well with data obtained after direct measurement of venous blood samples of the same blood donor (R: 0.7936; p<0.0001). The correlation was linear over the whole range of 25-OH vitamin D concentrations seen in this study. A Bland-Altman plot revealed good agreement between both tests. Conclusions: The D-Vital ID dry-blood collection system showed an excellent performance as compared to the classical way of 25-OH vitamin D measurement from venous blood. This new technique will facilitate easy and reliable measurement for vitamin D status, in particular, in rural or isolated areas, developing countries, and field studies.}, language = {en} }