@article{LiChenDongetal.2014, author = {Li, Jian and Chen, You-Peng and Dong, Yun-Peng and Yu, Cal-Hong and Lu, Yong-Ping and Xiao, Xiao-Min and Hocher, Berthold}, title = {The impact of umbilical blood flow regulation on fetal development differs in diabetic and non-diabetic pregnancy}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {39}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000355815}, pages = {369 -- 377}, year = {2014}, abstract = {Background/Aims: Diabetes is well-known to influence endothelial function. Endothelial function and blood flow regulation might be different in diabetic and non-diabetic pregnancy. However, the impact of umbilical blood flow regulation in gestational diabetes on fetal development is unknown so far. Methods: In a prospective birth cohort study, we analyzed the association of the umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) and fetal size measures (biparietal diameter, head circumference, abdominal circumference, femur length and birth weight) in 519 non-gestational diabetes mellitus pregnancies (controls) and 226 gestational diabetes mellitus pregnancies in middle (day 160.32 +/- 16.29 of gestation) and late (day 268.12 +/- 13.04 of gestation) pregnancy. Results: Multiple regression analysis considering confounding factors (gestational day of ultrasound examination, offspring sex, maternal body mess index before pregnancy, maternal age at delivery, maternal body weight at delivery and maternal hypertension) showed that umbilical artery Doppler indices (pulsatility index, resistance index and systolic/diastolic ratio) were associated with fetal head circumference and femur length in middle gestational diabetes mellitus pregnancy but not in non-gestational diabetes mellitus pregnancy. Head circumference, biparietal diameter, abdominal circumference and femur length in mid gestation were smaller in fetus of gestational diabetes mellitus pregnancy versus non-gestational diabetes mellitus pregnancy. In contrast to non-gestational diabetes mellitus pregnancy in late gestation, umbilical artery Doppler indices in gestational diabetes mellitus pregnancy were not associated with ultrasound measures of fetal growth. Birth weight was slightly increased in gestational diabetes mellitus pregnancy as compared to non-gestational diabetes mellitus pregnancy. Conclusions: The impact of umbilical blood flow on fetal growth is time dependent in human gestational diabetes mellitus and non-gestational diabetes mellitus pregnancy. In gestational diabetes mellitus pregnancy umbilical blood flow is critical for organ development in much earlier stages of pregnancy as compared to non-gestational diabetes mellitus pregnancy. The physiological and molecular pathways why there is a catch up growth in later times of gestational diabetes mellitus pregnancy resulting in larger gestational diabetes mellitus babies at birth needs to be addressed in further studies.}, language = {en} } @article{PutraTsuprykovVonWebskyetal.2014, author = {Putra, Sulistyo Emantoko Dwi and Tsuprykov, Oleg and Von Websky, Karoline and Ritter, Teresa and Reichetzeder, Christoph and Hocher, Berthold}, title = {Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {60}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {11}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2014.140317}, pages = {1871 -- 1877}, year = {2014}, abstract = {Background: Western blot is the gold standard method to determine individual protein expression levels. However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disadvantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein. Methods: In this study we established a one dot two development signals (ODTDS) dot blot method employing two different signal development systems. The first signal from the protein of interest was detected by horseradish peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phosphatase (AP). Results: Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between both methods were low (1.04 - 5.71\%) as assessed by coefficient of variation. Conclusions: ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes without a reduction in results accuracy.}, language = {en} } @article{LongardtSchmiedchenRailaetal.2014, author = {Longardt, Ann Carolin and Schmiedchen, B. and Raila, Jens and Schweigert, Florian J. and Obladen, M. and Buehrer, Christoph and Loui, A.}, title = {Characterization of the vitamin A transport in preterm infants after repeated high-dose vitamin A injections}, series = {European journal of clinical nutrition}, volume = {68}, journal = {European journal of clinical nutrition}, number = {12}, publisher = {Nature Publ. Group}, address = {London}, issn = {0954-3007}, doi = {10.1038/ejcn.2014.202}, pages = {1300 -- 1304}, year = {2014}, abstract = {BACKGROUND/OBJECTIVES: Preterm infants have low vitamin A stores at birth, and parenteral administration of high-dose vitamin A reduces pulmonary morbidity. The aim was to characterize vitamin A transport and status. SUBJECTS/METHODS: Prospective study of 69 preterm infants (median birth weight 995 g, gestational age 28 weeks), in which 51 received 5000 IU vitamin A three times per week intramuscular (i.m.) for 4 weeks and 18 infants without i.m. vitamin A served as controls. Serum retinol, retinyl palmitate, total retinol-binding protein 4 (RBP4), retinol-unbound RBP4 (apo-RBP4) and transthyretin concentrations were determined at days 3 (D3) and 28 (D28) of life. RESULTS: D3 retinol concentrations were low for the entire group (382 (285/531) nmol/l; median/interquartile range) and unrelated to gestational age. D28 retinol was unchanged in controls (382 (280/471) nmol/l), but increased in the vitamin A group (596 (480/825) nmol/l; P < 0.001). A similar pattern was observed for RBP4. The calculated retinol-to-RBP4 ratio rose in vitamin A infants (D3: 0.81 (0.57/0.94), D28: 0.98 (0.77/1.26); P < 0.01) but not in controls. In the vitamin A group, the retinol-to-RBP4 ratio was 41 in 15\% of all infants on D3 and in 45\% of infants on D28, but was <= 1 in all, but one, controls on D28. CONCLUSIONS: In preterm infants receiving a 4-week course of high-dose i. m. vitamin A, serum retinol concentrations increased by 55\%, with molar concentrations of retinol exceeding those of RBP4 in 45\% of the infants suggesting transport mechanisms other than RBP4.}, language = {en} } @misc{ReichetzederTsuprykovHocher2014, author = {Reichetzeder, Christoph and Tsuprykov, Oleg and Hocher, Berthold}, title = {Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2014.02.025}, pages = {141 -- 148}, year = {2014}, abstract = {Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase Ill trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).}, language = {en} } @article{VignonZellwegerRelleRahnenfuehreretal.2014, author = {Vignon-Zellweger, Nicolas and Relle, Katharina and Rahnenfuehrer, Jan and Schwab, Karima and Hocher, Berthold and Theuring, Franz}, title = {Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2013.12.003}, pages = {219 -- 225}, year = {2014}, abstract = {Aims: The nitric oxide and endothelin systems are key components of a local paracrine hormone network in the heart. We previously reported that diastolic dysfunction observed in mice lacking the endothelial nitric oxide synthase (eNOS-/-) can be prevented by a genetic overexpression of ET-1. Sexual dimorphisms have been reported in both ET-1 and NO systems. Particularly, eNOS-/- mice present sex related phenotypic differences. Main methods: We used the ET-1 transgenic (ET+/+), eNOS-/-, and crossbred ET+/+ eNOS-/- mice, and wild type controls. We measured cardiac function by heart catheterization. Cardiac ventricles were collected for histological and molecular profiling. Key findings: We report here that (i) the level of ET-1 expression in eNOS-/- mice was elevated in males but not in females. (ii) Left ventricular end-diastolic blood pressure was higher in male eNOS-/- mice than in females. (ii) eNOS-/- males but not females developed cardiomyocyte hypertrophy. (iv) Perivascular fibrosis of intra-cardiac arteries developed in female ET+/+ and eNOS-/- mice but not in males. Additionally, (v) the cardiac expression of metalloprotease-9 was higher in eNOS-/- males compared to females. Finally, (vi) cardiac proteome analysis revealed that the protein abundance of the oxidative stress related enzyme superoxide dismutase presented with sexual dimorphism in eNOS-/- and ET+/+ mice. Significance: These results indicate that the cardiac phenotypes of ET-1 transgenic mice and eNOS knockout mice are sex specific. Since both systems are key players in the pathogenesis of cardiovascular diseases, our findings might be important in the context of gender differences in patients with such diseases. (C) 2013 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).}, language = {en} } @article{HeunischvonEinemAlteretal.2014, author = {Heunisch, Fabian and von Einem, Gina and Alter, Markus L. and Weist, Andreas and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold}, title = {Urinary ET-1 excretion after exposure to radio-contrast media in diabetic patients and patients with preexisting mild impaired renal function}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2013.12.233}, pages = {440 -- 445}, year = {2014}, abstract = {Aims: Contrast media-induced nephropathy (CIN) is associated with increased morbidity and mortality. The renal endothelin system has been associated with disease progression of various acute and chronic renal diseases. However, robust data coming from adequately powered prospective clinical studies analyzing the short and long-term impacts of the renal ET system in patients with CIN are missing so far. We thus performed a prospective study addressing this topic. Main methods: We included 327 patients with diabetes or renal impairment undergoing coronary angiography. Blood and spot urine were collected before and 24 h after contrast media (CM) application. Patients were followed for 90 days for major clinical events like need for dialysis, unplanned rehospitalization or death. Key findings: The concentration of ET-1 and the urinary ET-1/creatinine ratio decreased in spot urine after CM application (ET-1 concentration: 0.91 +/- 1.23pg/ml versus 0.63 +/- 1.03pg/ml, p<0.001; ET-1/creatinine ratio: 0.14 +/- 0.23 versus 0.09 +/- 0.19, p<0.001). The urinary ET-1 concentrations in patients with CIN decreased significantly more than in patients without CIN (-0.26 +/- 1.42pg/ml vs. -0.79 +/- 1.69pg/ml, p=0.041), whereas the decrease of the urinary ET-1/creatinine ratio was not significantly different (non-CIN patients: -0.05 +/- 0.30; CIN patients: -0.11 +/- 0.21, p=0.223). Urinary ET-1 concentrations as well as the urinary ET-1/creatinine ratio were not associated with clinical events (need for dialysis, rehospitalization or death) during the 90day follow-up after contrast media exposure. However, the urinary ET-1 concentration and the urinary ET-1/creatinine ratio after CM application were higher in those patients who had a decrease of GFR of at least 25\% after 90days of follow-up. Significance: In general the ET-1 system in the kidney seems to be down-regulated after contrast media application in patients with moderate CIN risk. Major long-term complications of CIN (need for dialysis, rehospitalization or death) are not associated with the renal ET system. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.}, language = {en} } @article{YangLaiDengetal.2014, author = {Yang, Fang and Lai, Xinlong and Deng, Li and Liu, Xiaoxiao and Li, Jian and Zeng, Shuixiu and Zhang, Cheng and Hocher, Carl-Friedrich and Hocher, Berthold}, title = {Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children}, series = {Life sciences : molecular, cellular and functional basis of therapy}, volume = {118}, journal = {Life sciences : molecular, cellular and functional basis of therapy}, number = {2}, publisher = {Elsevier}, address = {Oxford}, issn = {0024-3205}, doi = {10.1016/j.lfs.2014.04.010}, pages = {446 -- 450}, year = {2014}, abstract = {Aims:This study aims to investigate the relationship between plasma endothelin-1 (ET-1) concentrations, ET-1 gene polymorphisms in loci rs5370, rs1630736, 3A/4A and clinical features of primary nephrotic syndrome (NS) in children. Materials and methods: Thirty-six children with primary NS were selected as case group, and 94 healthy children were selected as control group. All subjects were genotyped for three single nucleotide polymorphisms (SNPs) (rs5370, rs10478694 [3A4A) and rs 1630736) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using a radio-immunoassay. Key findings: Plasma ET-1 concentrations were higher in NS patients (P = 0.007) as compared to healthy children. The allele frequencies between control and NS patients were significantly different only with respect to the rs10478694 SNP of the ET-1 gene. The allele frequencies between control and NS patients for the rs5370 SNP showed a trend towards difference (P = 0.057). Plasma cholesterol in NS patients is associated with both: the Cl genotype in locus rs5370 and the 3A4A genotype in locus rs10478694 (P < 0.05 in both cases). Significance: The ET systems might play a disease modifying role in pediatric NS. Plasma cholesterol, a hallmark of NS. seems to be associated with genetic variations within the human ET-1 gene. (C) 2014 Elsevier Inc. All rights reserved.}, language = {en} } @inproceedings{BaranyaiGoedtelArmbrustNestleretal.2014, author = {Baranyai, Dorothea and Goedtel-Armbrust, Ute and Nestler, Sebastian and Kleuser, Burkhard and Wojnowski, Leszek}, title = {A role for cutaneous CYP3A in vitamin D homeostasis?}, series = {NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY}, volume = {387}, booktitle = {NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY}, publisher = {Springer}, address = {New York}, issn = {0028-1298}, pages = {S27 -- S27}, year = {2014}, language = {en} } @article{PrueferSchuchardtToelleetal.2014, author = {Pruefer, Jasmin and Schuchardt, Mirjam and Toelle, Markus and Pruefer, Nicole and Hoehne, Matthias and Zidek, Walter and van der Giet, Markus}, title = {Harmful effects of the azathioprine metabolite 6-mercaptopurine in vascular cells: Induction of mineralization}, series = {PLoS one}, volume = {9}, journal = {PLoS one}, number = {7}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0101709}, pages = {8}, year = {2014}, abstract = {Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteochondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis.}, language = {en} } @article{BrentenMorrisSaltetal.2014, author = {Brenten, Thomas and Morris, Penelope J. and Salt, Carina and Raila, Jens and Kohn, Barbara and Brunnberg, Leo and Schweigert, Florian J. and Zentek, Juergen}, title = {Energy intake, growth rate and body composition of young Labrador Retrievers and Miniature Schnauzers fed different dietary levels of vitamin A}, series = {The British journal of nutrition : an international journal devoted to the science of human and animal nutrition}, volume = {111}, journal = {The British journal of nutrition : an international journal devoted to the science of human and animal nutrition}, number = {12}, publisher = {Cambridge Univ. Press}, address = {Cambridge}, issn = {0007-1145}, doi = {10.1017/S0007114514000543}, pages = {2104 -- 2111}, year = {2014}, abstract = {Research in rodents has shown that dietary vitamin A reduces body fat by enhancing fat mobilisation and energy utilisation; however, their effects in growing dogs remain unclear. In the present study, we evaluated the development of body weight and body composition and compared observed energy intake with predicted energy intake in forty-nine puppies from two breeds (twenty-four Labrador Retriever (LAB) and twenty-five Miniature Schnauzer (MS)). A total of four different diets with increasing vitamin A content between 5.24 and 104.80 mu mol retinol (5000-100 000 IU vitamin A)/4184 kJ (1000 kcal) metabolisable energy were fed from the age of 8 weeks up to 52 (MS) and 78 weeks (LAB). The daily energy intake was recorded throughout the experimental period. The body condition score was evaluated weekly using a seven-category system, and food allowances were adjusted to maintain optimal body condition. Body composition was assessed at the age of 26 and 52 weeks for both breeds and at the age of 78 weeks for the LAB breed only using dual-energy X-ray absorptiometry. The growth curves of the dogs followed a breed-specific pattern. However, data on energy intake showed considerable variability between the two breeds as well as when compared with predicted energy intake. In conclusion, the data show that energy intakes of puppies particularly during early growth are highly variable; however, the growth pattern and body composition of the LAB and MS breeds are not affected by the intake of vitamin A at levels up to 104.80 mu mol retinol (100 000 IU vitamin A)/4184 kJ (1000 kcal).}, language = {en} }