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ABSTRACT: With mid-gestation the production of placental corticotropin-releasing hormone (CRH) starts to steadily increase. The fetal peptide CRH excerts direct functions at the feto-maternal interface (vasodilatation, timing of birth) via its interaction with progesterone and indirectly ensures maturation and growth of fetal organ systems for delivery by driving fetal cortisol production via its induction of adrenocorticotropic hormone release. This feedback loop is tightly controlled by the amount of enzymatic cortisol/cortisone turnover in the placental syncytiotrophoblast by 11β-hydroxy-steroid dehydrogenase type 2 (11β-HSD2). Traditionally, placental tissue hormones have been quantified by immunological methods (e.g. RIA or ELISA), which have the drawback of possible cross-reactivity and tissue perturbations. Most importantly, it is not possible to quantify CRH and steroid hormones, such as cortisol, cortisone and progesterone together in the same sample with these methods. Hence, we aimed to develop and validate a quantitative mass spectrometry (MS) method for multi-modal quantification of these placental hormones: While CRH was readily detectable throughout the placenta, the placental levels of progesterone and especially cortisol and cortisone were higher at the placental base facing the maternal side. The HPLC-MS/MS procedure showed excellent selectivity and sufficient limit of quantification in placental tissue homogenates to allow for simultaneous detection of CRH, cortisol and cortisone, and progesterone.
Steroids 05/2013; · 2.83 Impact Factor
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ABSTRACT: OBJECTIVE: The adaptor protein p66Shc generates mitochondrial reactive oxygen species and translates oxidative signals into apoptosis. We aimed to analyze potential alterations in total methylation and in p66Shc activation in placental tissues from women delivering intrauterine growth restricted neonates (IUGR) versus appropriate for gestational age (AGA) and small for gestational age (SGA) neonates. METHOD: DNA methylation of the p66Shc promoter and of long interspersed nuclear elements (LINE-1), as a marker for total methylation, was quantified by automatic pyrosequencing in 15 IUGR, 25 AGA and 15 SGA placentas. Placental gene expression of p66Shc was determined by TaqMan real-time polymerase chain reaction. RESULTS: No significant difference was found for LINE-1 methylation between IUGR, AGA and SGA newborns. DNA methylation of the p66Shc promoter was significantly decreased in the IUGR compared with the AGA group (p < 0.0001) and the SGA group (p < 0.0001). However, analysis of placental p66Shc gene expression did not show a significant difference between the three groups. CONCLUSION: It remains speculative if the decreased p66Shc promoter methylation might play a role in the pathophysiology of endothelial dysfunction and cardiovascular disease after IUGR. © 2013 John Wiley & Sons, Ltd.
Prenatal Diagnosis 03/2013; · 2.11 Impact Factor
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ABSTRACT: Abstract Background: Determination of pediatric reference intervals (RIs) for laboratory quantities, including hematological quantities, is complex. The measured quantities vary by age, and obtaining samples from healthy children is difficult. Many widely used RIs are derived from small sample numbers and are split into arbitrary discrete age intervals. Use of intra-laboratory RIs specific to the examined population and analytical device used is not yet fully established. Indirect methods address these issues by deriving RIs from clinical laboratory databases which contain large datasets of both healthy and pathological samples. Methods: A refined indirect approach was used to create continuous age-dependent RIs for blood count quantities and sodium from birth to adulthood. The dataset for each quantity consisted of 60,000 individual samples from our clinical laboratory. Patient samples were separated according to age, and a density function of the proportion of healthy samples was estimated for each age group. The resulting RIs were merged to obtain continuous RIs from birth to adulthood. Results: The obtained RIs were compared to RIs generated by identical laboratory instruments, and to population-specific RIs created using conventional methods. This comparison showed a high concordance of reference limits and their age-dependent dynamics. Conclusions: The indirect approach reported here is well-suited to create continuous, intra-laboratory RIs from clinical laboratory databases and showed that the RIs generated are comparable to those created using established methods. The procedure can be transferred to other laboratory quantities and can be used as an alternative method for RI determination where conventional approaches are limited.
Clinical Chemistry and Laboratory Medicine 02/2013; · 2.15 Impact Factor
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Carlos Menendez-Castro,
Karl F Hilgers,
Kerstin Amann,
Christoph Daniel,
Nada Cordasic,
Rainer Wachtveitl,
Fabian Fahlbusch,
Christian Plank,
Jörg Dötsch, Wolfgang Rascher,
Andrea Hartner
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ABSTRACT: Background
Intrauterine growth restriction (IUGR) leads to low nephron number and higher incidence of renal disease. We hypothesized that IUGR induces early podocyte alterations based on a dysregulation of Wilms' tumour suppressor gene 1 (WT1), a key player of nephrogenesis and mediator of podocyte integrity.MethodsIUGR was induced in rats by maternal protein restriction during pregnancy. Kidneys were harvested from male offspring at Days 1 and 70 of life. qRT-PCR, immunohistochemistry and electron microscopy were performed in renal tissue. Albuminuria was assessed by enzyme-linked immunosorbent assay.ResultsAt Day 70 of life, higher albuminuria and overt alterations of podocyte ultrastructure were detected in IUGR animals in spite of normal blood pressure. Moreover, we found increased glomerular immunoreactivity and expression of desmin, while synaptopodin and nephrin were decreased. Glomerular immunoreactivity and expression of WT1 were increased in IUGR animals at this time point with an altered expressional ratio of WT1 +KTS and -KTS isoforms. These changes of WT1 expression were already present at the time of birth.ConclusionsIUGR results in early podocyte damage possibly due to a dysregulation of WT1. We suggest that an imbalance of WT1 isoforms to the disadvantage of -KTS affects nephrogenesis in IUGR rats and that persistent dysregulation of WT1 results in a reduced ability to maintain podocyte integrity, rendering IUGR rats more susceptible for renal disease.
Nephrology Dialysis Transplantation 12/2012; · 3.40 Impact Factor
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ABSTRACT: BACKGROUND:: Kabuki syndrome is a rare condition characterized by distinct dysmorphic features and a broad spectrum of organ anomalies. Differentiating it from other syndromes can be difficult, particularly in patients with incomplete phenotypic manifestation. Recently, MLL2 gene mutations were identified as the underlying genetic cause of Kabuki syndrome in the majority of cases. OBSERVATIONS:: We report the case of an adolescent with an uncommon combination of manifestations, including hypogammaglobulinemia and severe chronic thrombopenia associated with a novel MLL2 mutation. CONCLUSIONS:: This report adds to the growing knowledge on the mutational and phenotypic spectrum of Kabuki syndrome.
Journal of Pediatric Hematology/Oncology 10/2012; · 1.16 Impact Factor
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ABSTRACT: BACKGROUND: The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. However, the auto- and paracrine actions of CRH on the syncytiotrophoblast itself are unknown. Intrauterine growth restriction (IUGR) is accompanied by an increase in placental CRH, which could be of pathophysiological relevance for the dysregulation in syncytialisation seen in IUGR placentas. METHODS: We aimed to determine the effect of CRH on isolated primary trophoblastic cells in vitro. After CRH stimulation the trophoblast syncytialisation rate was monitored via syncytin-1 gene expression and beta-hCG (beta-human chorionic gonadotropine) ELISA in culture supernatant. The expression of the IUGR marker genes leptin and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) was measured continuously over a period of 72 h. We hypothesized that CRH might attenuate syncytialisation, induce leptin, and reduce 11beta-HSD2 expression in primary villous trophoblasts, which are known features of IUGR. RESULTS: CRH did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. Following syncytialisation, CRH treatment significantly increased leptin and 11beta-HSD2 expression, as well as leptin secretion into culture supernatant after 48 h. CONCLUSION: The relevance of CRH for placental physiology is underlined by the present in vitro study. The induction of leptin and 11beta-HSD2 in the syncytiotrophoblast by CRH might promote fetal nutrient supply and placental corticosteroid metabolism in the phase before labour induction.
Reproductive Biology and Endocrinology 09/2012; 10(1):80. · 2.05 Impact Factor
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Asia N Rashed,
Ian C K Wong,
Noel Cranswick,
Barbara Hefele,
Stephen Tomlin,
John Jackman,
Kenneth Lee,
Kam-Lun E Hon,
Jeffrey Ong,
Maisoon Ghaleb,
Siew Siang Chua,
Tea Ming Hui, Wolfgang Rascher,
Antje Neubert
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ABSTRACT: A previous meta-analysis reported that 9.5% of hospitalized children suffered from an adverse drug reaction (ADR); however, reported incidences among studies varied.
To enhance the knowledge of ADRs in paediatric hospitalized patients at a global level we investigated the incidence and characteristics of ADRs in hospitalized children in European and non-European countries.
A prospective observational cohort study was conducted in academic and non-academic hospitals in five countries: Australia, Germany, Hong Kong, Malaysia and the UK. Children aged 0-18 years admitted during a 3-month period (between 1 October 2008 and 31 December 2009) were recruited. The main outcome measures were incidence, causality and outcome of ADRs.
A total of 1278 patients (1340 admissions) were included [Australia n = 146 (149 admissions), Germany n = 376 (407), Hong Kong n = 143 (149), Malaysia n = 300 (314) and the UK n = 313 (321)]. The median age was 2 years (interquartile range [IQR] 0-7). Patients received a total of 5367 drugs (median 3; IQR 2-5) and median length of hospital stay was 4 days (IQR 3-7). A total of 380 ADRs were identified in 211 patients. The resultant ADR incidence of 16.5% (95% CI 14.5, 18.7) varied significantly between countries (p < 0.001). The highest incidences were observed in Malaysia and the UK. 65.3% (n = 248) of ADRs were found to be probable, and 24% of the ADRs were serious, with one being fatal.
By comparing data from five countries in Europe, Asia and Australia we have shown that the incidence of ADRs in hospitalized children is at least as high as incidences published in adults. However, the variation between countries was mainly due to different populations and treatment strategies. Particular attention should be given to opioid use in hospitalized children.
Drug Safety 06/2012; 35(6):481-94. · 3.63 Impact Factor
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ABSTRACT: Microdeletions on chromosome 17q12 cause of diverse spectrum of disorders and have only recently been identified as a rare cause of Mayer-Rokitansky-Kuester-Hauser-Syndrome (MRKH), which is characterized by uterus aplasia ± partial/complete vaginal aplasia in females with a regular karyotype. For the first time we report about a patient with a 17q12 microdeletion who is affected by MRKH in combination with a vascular and soft tissue disorder. Repeatedly she suffered from kidney transplant failure caused by consuming membranous nephropathy.
A 38-year-old female patient had been diagnosed with right kidney aplasia, left kidney dysplasia and significantly impaired renal function during infancy. Aged 16 she had to start hemodialysis. Three years later she received her first kidney transplant. Only then she was diagnosed with MRKH. The kidney transplant was lost due to consuming nephrotic syndrome caused by de novo membranous nephropathy, as was a second kidney transplant years later. In addition, a hyperelasticity syndrome affects the patient with congenital joint laxity, kyphoscoliosis, bilateral hip dysplasia, persistent hypermobility of both elbows, knees and hips. Her clinical picture resembles a combination of traits of a hypermobile and a vascular form of Ehlers-Danlos-Syndrome, but no mutations in the COL3A1 gene was underlying. Instead, array-based comparative genomic hybridisation (CGH) detected a heterozygous 1.43 Mb deletion on chromosome 17q12 encompassing the two renal developmental genes HNF1β and LHX1.
Deletions of HNF1β have recently drawn significant attention in pediatric nephrology as an important cause of prenatally hyperechogenic kidneys, renal aplasia and renal hypodysplasia. In contrast, membranous nephropathy represents an often-unaccounted cause of nephrotic syndrome in the adult population. A causative connection between theses two conditions has never been postulated, but is suggestive enough in this case to hypothesize it.
BMC Nephrology 05/2012; 13:27. · 2.18 Impact Factor
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ABSTRACT: BACKGROUND: The clinical use of Sodium nitroprusside (SNP) may be associated with an alteration of platelet function. The main focus of this study was the effect of SNP on platelet aggregation in the absence or presence of endothelial cells. METHODS: Platelets were incubated with different concentrations of SNP with and without endothelial cells. Platelet aggregation was induced by ADP. RESULTS: Platelet aggregation was significantly inhibited by all concentrations of SNP. Endothelial cells significantly increased this inhibitory effect of SNP. Time course studies showed an inverse correlation of incubation time to platelet aggregation inhibition in the absence of endothelial cells, and a direct correlation in the presence of endothelial cells. Blocking platelet and endothelial cell guanylate cyclase with 1 H-(1,2,4)-oxadiazolo(4,3-a) quinoxalin-1-one (ODQ), or pretreatment of the endothelial cells with cyclooxygenase - inhibitors, had no influence on the increased inhibitory effect of the endothelial cells. Cyanide reversed the inhibitory effect of SNP completely. CONCLUSION: Endothelial cells play an important role in the SNP mediated inhibition of platelet aggregation. The effect is reversible only by cyanide, not by blocking classical NO signal transduction.
Thrombosis Journal 05/2012; 10(1):6. · 1.31 Impact Factor
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ABSTRACT: Epidemiological studies revealed an association between IUGR (intrauterine growth restriction) and an increased risk of developing CVDs (cardiovascular diseases), such as atherosclerosis or hypertension, in later life. Whether or not IUGR contributes to the development of atherosclerotic lesions, however, is unclear. We tested the hypothesis that IUGR aggravates experimentally induced vascular remodelling. IUGR was induced in rats by maternal protein restriction during pregnancy (8% protein diet). To detect possible differences in the development of vascular injury, a model of carotid artery ligation to induce vascular remodelling was applied in 8-week-old intrauterine-growth-restricted and control rat offspring. Histological and immunohistochemical analyses were performed in the ligated and non-ligated carotid arteries 8 weeks after ligation. IUGR alone neither caused overt histological changes nor significant dedifferentiation of VSMCs (vascular smooth muscle cells). After carotid artery ligation, however, neointima formation, media thickness and media/lumen ratio were significantly increased in rats after IUGR compared with controls. Moreover, dedifferentiation of VSMCs and collagen deposition in the media were more prominent in ligated carotids from rats after IUGR compared with ligated carotids from control rats. We conclude that IUGR aggravates atherosclerotic vascular remodelling induced by a second injury later in life.
Clinical Science 04/2012; 123(7):437-44. · 4.61 Impact Factor
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Fabian B Fahlbusch,
Yousif Dawood,
Andrea Hartner,
Carlos Menendez-Castro,
Stephanie C Nögel,
Anja Tzschoppe,
Holm Schneider,
Pamela Strissel,
Matthias W Beckmann,
Ekkehard Schleussner,
Matthias Ruebner,
Helmuth G Dörr,
Ralf L Schild, Wolfgang Rascher,
Jörg Dötsch
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ABSTRACT: Objective: The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells. Methods: Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O(2). Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas. Results: Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group. Conclusion: Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR.
The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 04/2012; 25(11):2209-15. · 1.36 Impact Factor
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ABSTRACT: Among endogenous adaptive systems to hypoxia, neuroglobin, a recently discovered heme protein, was suggested as a novel oxygen-dependent neuroprotectant. We aimed to characterize i) maturational age-related regulation of neuroglobin in the developing mouse brain under normoxic and hypoxic conditions, and ii) the role of hypoxia-inducible transcription factors (HIFs) as possible mediators of O(2)-dependent regulation of neuroglobin in vitro and in vivo. During early stages of postnatal brain maturation (P0-P14) neuroglobin mRNA levels significantly increased in developing mouse forebrains. By immunohistochemical analysis we confirmed expression of neuroglobin protein in the cytoplasm of developing neurons but not glial cells under normoxic conditions. Exposure of the immature brains (P0, P7) to acute (8% O(2), 6h) and chronic systemic hypoxia (10% O(2), 7 days) led to differential activation of neuroglobin varying with maturational stage (P0, P7) and severity of hypoxia. This observation may indicate that neuroglobin is involved in adaptive responses of immature neurons to acute hypoxia during an early stage of mouse brain maturation (P0). In response to activation of the HIF system by prolyl-4-hydroxylase inhibitor (FG-4497), neuroglobin mRNA expression was significantly up-regulated in primary mouse cortical neurons (DIV6) exposed to normoxia and hypoxia (1% O(2)) compared to non-treated controls. In conclusion, present results strongly indicate that cerebral regulation of neuroglobin is related to maturational stage and that hypoxia-induced neuroglobin up-regulation is modified by the HIF system.
Experimental Neurology 04/2012; 236(1):112-21. · 4.70 Impact Factor
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Pediatric Nephrology 04/2012; 27(11):2049-50. · 2.52 Impact Factor
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Pediatric Nephrology 04/2012; 27(11):2051-2. · 2.52 Impact Factor
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ABSTRACT: The patent ductus arteriosus (PDA) is associated with various complications of prematurity. Cyclooxygenase-inhibitors are the first-line intervention for closure of the PDA. However, the rates of PDA closure still are unsatisfactory. Therefore, an individual trial was performed by changing the strategy for treating neonates with ibuprofen to induce the closure of PDA. In a retrospective study, patients receiving 20, 10, and 10 mg/kg bodyweight ibuprofen (group 1) were compared by chart review with those receiving 10, 5, 5 mg/kg (group 2). The rate of PDA closure, the incidence of side effects related to the use of ibuprofen, and the need for surgical intervention for closure of the PDA were analyzed. A higher rate of closure after three doses in group 1 could be observed (60.9 vs 52.6%; p = 0.75), which was not significant but indicated a clear positive trend. If closure of the PDA was unsuccessful, intravenous ibuprofen was continued for an additional 2 days. After 5 days, 91.3% of PDA in group 1 was closed compared with 68.4% PDA in group 2. In summary, only 8.7% of the group 1 neonates needed surgical closure of PDA after insufficient medicamentous closure compared with 31.6% in group 2 (p = 0.25). Although not statistically significant, a clear positive trend for using the higher-dose medication can be seen. More work dealing with the limitations of a retrospective study must be done. Based on the data from this study, high-dose ibuprofen seems able to increase the rate of effective medicamentous PDA closure without any further unwanted side effects.
Pediatric Cardiology 02/2012; 33(4):586-90. · 1.30 Impact Factor
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ABSTRACT: In recent years, efforts have been made to improve paediatric drug therapy. The aim of this research was to investigate any changes regarding the frequency and nature of adverse drug reactions (ADRs) in hospitalized children in one paediatric general medical ward over a 9-year period.
Two prospective observational cohort studies were conducted at a large University hospital in Germany in 1999 and 2008, respectively. Children aged 0-18 years admitted to the study ward during the study periods were included. ADRs were identified using intensive chart review. Uni- and multivariable regression has been used for data analysis.
A total of 520 patients (574 admissions) were included [1999: n = 144 (167); 2008: n = 376 (407)]. Patients received a total of 2053 drugs [median 3, interquartile range (IQR) 2-5]. 19% of patients did not receive any medication. Median length of stay was 4 days (IQR 3-7; range 1-190 days) with a significantly longer length of stay in 1999. The overall ADR incidence was 13.1% (95% CI, 9.8-16.3) varying significantly between the two study cohorts [1999: 21.9%, 95% CI, 14.7-29.0; 2008: 9.2%, 95% CI, 5.9-12.5 (p<0.001)]. Antibacterials and corticosteroids for systemic use caused most of the ADRs in both cohorts (1999; 2008). Exposure to systemic antibacterials decreased from 62.9% to 43.5% whereas exposure to analgesics and anti-inflammatory drugs increased from 17.4% to 45.2%, respectively. The use of high risk drugs decreased from 75% to 62.2%. In 1999, 45.7% and in 2008 96.2% of ADRs were identified by treating clinicians (p<0.001).
Between 1999 and 2008, the incidence of ADRs decreased significantly. Improved treatment strategies and an increased awareness of ADRs by physicians are most likely to be the cause for this positive development. Nevertheless further research on ADRs particularly in primary care and the establishment of prospective pharmacovigilance systems are still needed.
PLoS ONE 01/2012; 7(9):e44349. · 4.09 Impact Factor
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ABSTRACT: In the normal kidney, the α8 integrin chain is expressed only on mesangial cells and vascular smooth muscle cells. α8 integrin ligates several matrix molecules including fibronectin, osteopontin and fibrillin-1. Recently, we detected de novo expression of α8 integrin on epithelial cells in renal cysts. We hypothesized that the α8 integrin chain is induced in tubular epithelia undergoing dedifferentiation and contributes to the fibrotic response in the tubulointerstitium (TI) after unilateral ureteral obstruction (UUO). After induction of UUO in rats by ligation of the right ureter, increased expression of the α8 integrin chain and its ligands was observed. In the TI, α8 integrin was localized to cytokeratin-positive epithelial cells and to interstitial fibroblasts; and colocalized with its ligands. In mice underexpressing α8 integrin UUO led to collagen deposition and fibroblast activation comparable to wild types. Mice lacking α8 integrin showed even more TI damage, fibroblast activation and collagen deposition after UUO compared to wild type mice. We conclude that the expression of the α8 integrin chain and its ligands is strongly induced in the TI after UUO, but underexpression of α8 integrin does not attenuate TI fibrosis. Mice lacking the α8 integrin chain are even more susceptible to TI damage than wild type mice. Thus, interactions of α8 integrin with its ligands do not seem to contribute to the development or progression of TI fibrosis in UUO. Targeting α8 integrin might not be a useful approach for anti-fibrotic therapy.
PLoS ONE 01/2012; 7(11):e48362. · 4.09 Impact Factor
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Oliver Gross,
Christoph Licht,
Hans J Anders,
Bernd Hoppe,
Bodo Beck,
Burkhard Tönshoff,
Britta Höcker,
Simone Wygoda,
Jochen H H Ehrich,
Lars Pape, [......],
Jean-Pierre Grunfeld,
Patrick Niaudet,
Pierre Cochat,
Laurence Heidet,
Said Lebbah,
Roser Torra,
Tim Friede,
Katharina Lange,
Gerhard A Müller,
Manfred Weber
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ABSTRACT: Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.
Kidney International 12/2011; 81(5):494-501. · 6.61 Impact Factor
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ABSTRACT: Understanding the epidemiology and risk factors of adverse drug reactions (ADRs) is important in order to develop appropriate prevention strategies. This study aimed to identify risk factors associated with ADRs in hospitalised children and recommend strategies to minimise ADRs.
A prospective multicentre cohort study was conducted on paediatric general medical wards in five European and non-European hospitals. ADRs were identified by intensive chart review. Multivariable logistic regression was used to investigate risk factors associated with ADRs. For the risk factor analysis, prescribed drugs were divided into high-risk and low-risk drug groups. Analgesics, anti-epileptics, antibacterials and antimycotics for systemic use, corticosteroids for systemic use and immunosuppressant agents were considered as high-risk groups whereas the remaining drug classes were defined as low-risk drug groups.
A total of 1,253 paediatric patients were identified [Australia (n = 145), Germany (n = 372), Hong Kong (n = 138), Malaysia (n = 291), UK (n = 307)]. A total of 328 ADRs were observed in 16.7% of patients (186/1,115). Use of five or more low-risk drugs per patient or three or more high-risk drugs was a strong predictor for ADRs (OR 4.7, 95% CI 2.4-9.3; OR 6.5, 95% CI 2.7-16.0 respectively; p < 0.001). Older children were more likely to experience ADRs; gender was not significantly associated.
To reduce the risk of ADRs in children, clinicians and pharmacists should aim to minimise polypharmacy and be aware of higher ADR risks associated with some drug groups.
European Journal of Clinical Pharmacology 12/2011; 68(5):801-10. · 2.85 Impact Factor
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ABSTRACT: Cerebral tissue oxygen level modifies crucial processes of neurogenesis, glial and neuronal development during physiological and hypoxic conditions. Whether hypoxia-sensitive factors such as doublecortin (DCX) and hypoxia-inducible transcription factor (HIF)-regulated CXCR4 and SDF-1 modify and activate adaptation to hypoxia in developing brain is not well understood. Present study investigated maturational regulation of oxygen-sensitive developmental genes and proteins in developing mouse brain in relation to the degree of hypoxia.
Physiological expression of HIF-1, CXCR4, SDF-1 and DCX were analyzed in the brain of C57/BL6 mice (P0-P60). In addition, mice (P0, P7) were exposed to normoxia, acute (8% O(2), 6 h) or chronic hypoxia (10% O(2), 7 d) followed by reoxygenation. Gene expression was analyzed by quantitative PCR, proteins were quantified by Western blot analysis and immunohistochemistry.
Cerebral HIF-1α protein, CXCR4 and DCX mRNA levels showed maturational stage-related peak levels at P0/P1, whereas SDF-1 mRNA levels were highest at P17. CXCR4 and SDF-1 mRNA levels were not altered in response to hypoxia. Whereas DCX mRNA levels significantly increased during acute hypoxia, down-regulation of DCX transcripts was found in response to chronic hypoxia compared to controls, and these changes were related to specifically vulnerable brain regions.
Maturational stage-related dynamic changes of HIF-1α, CXCR4, SDF-1 and DCX may reflect involvement of hypoxia-regulated systems in important developmental regulatory processes of the developing brain. Extending the knowledge of differential effects of hypoxia on neurogenesis and dynamic regulatory networks present data provide a basis for future research on gestational age-specific neuroprotective options.
Brain & development 08/2011; 34(4):261-73. · 1.74 Impact Factor
