University of Erlangen Nu rnberg

Erlangen, Germany

University of Erlangen Nu rnberg

Erlangen, Germany
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Tyralla K.,University of Erlangen Nu rnberg | Adamczak M.,University of Heidelberg | Benz K.,University of Erlangen Nu rnberg | Campean V.,University of Erlangen Nu rnberg | And 4 more authors.
PLoS ONE | Year: 2011

Aims: Patients with renal failure develop cardiovascular alterations which contribute to the higher rate of cardiac death. Blockade of the renin angiotensin system ameliorates the development of such changes. It is unclear, however, to what extent ACE-inhibitors can also reverse existing cardiovascular alterations. Therefore, we investigated the effect of high dose enalapril treatment on these alterations. Methods: Male Sprague Dawley rats underwent subtotal nephrectomy (SNX, n = 34) or sham operation (sham, n = 39). Eight weeks after surgery, rats were sacrificed or allocated to treatment with either high-dose enalapril, combination of furosemide/dihydralazine or solvent for 4 weeks. Heart and aorta were evaluated using morphometry, stereological techniques and TaqMan PCR.Results: After 8 and 12 weeks systolic blood pressure, albumin excretion, and left ventricular weight were significantly higher in untreated SNX compared to sham. Twelve weeks after SNX a significantly higher volume density of cardiac interstitial tissue (2.5760.43% in SNX vs 1.5060.43% in sham, p,0.05) and a significantly lower capillary length density (45326355 mm/mm3 in SNX vs 50236624 mm/mm3 in sham, p,0.05) were found. Treatment of SNX with enalapril from week 8-12 significantly improved myocardial fibrosis (1.6360.25%, p,0.05), but not capillary reduction (39086486 mm/ mm3) or increased intercapillary distance. In contrast, alternative antihypertensive treatment showed no such effect. Significantly increased media thickness together with decreased vascular smooth muscles cell number and a disarray of elastic fibres were found in the aorta of SNX animals compared to sham. Both antihypertensive treatments failed to cause complete regression of these alterations. Conclusions: The study indicates that high dose ACE-I treatment causes partial, but not complete, reversal of cardiovascular changes in SNX. © 2011 Tyralla et al.

Ohlendorf C.,University of Bremen | Fey M.,University of Bremen | Massaferro J.,CONICET | Haberzettl T.,Friedrich - Schiller University of Jena | And 10 more authors.
Palaeogeography, Palaeoclimatology, Palaeoecology | Year: 2014

Hydrological changes that occurred during the last 4700years have been reconstructed using multi-proxy analyses of sediment cores from the volcanic crater lake of Laguna Cha´ltel (50°S, 71°W). The chronology is based on AMS 14C age modeling constrained by paleomagnetic secular variations. Chemical and physical properties of the lake water together with results of lake-water surface-temperature monitoring, as well as sediment characteristics reveal conspicuous features archived as different sedimentary carbonate phases and morphologies which are attributed to lake-level changes.Sedimentological, geochemical and biological proxies together suggest the development from an initial playa lake-phase towards a system with progressively rising lake level. In detail, proxies indicate the existence of an ephemeral lake since 4700. cal BP until a glauberite-bearing carbonate crust formed around 4040. cal BP which probably is associated to the globally recognized 4.2. ka event. This crust is interpreted as a desiccation event terminating the ephemeral lake phase. Following this desiccation a shift towards conditions with a positive hydrological balance of Laguna Cha´ltel occurs, which leads to the development of a saline lake with ooid formation between 4040 and 3200. cal BP. Further lake-level increase with initially high minerogenic input until 2700. cal BP resulted in a lake freshening which allowed the preservation of diatoms. Sigmoidal and star shaped carbonate crystals occurred until 1720. cal BP indicating a syn- or post-depositional formation of ikaite. Anoxic conditions and increased deposition of clay and sand through fluvial and eolian input are interpreted as a further lake-level rise and/or a prolonged winter ice cover culminating during the Little Ice Age. The highest lake level was probably reached at that time and since then dropped to its present day height.Previous studies have shown that the southern hemisphere westerly winds (SWW) exert an oppositional control on hydrological regimes at the eastern and the western sides of the Patagonian Andes. At Laguna Cha´ltel SWW forcing is changing evaporation rates by varying wind intensities, air temperatures and lake ice coverages as well as by precipitation rates (easterly vs. westerly sources of moisture). Our data suggests that the lake-level history of Laguna Cha´ltel reflects changes in the SWW during the last 4.7. ka on the eastern side of the Andes. However, the elevated location of Laguna Cha´ltel on an 800. m high plateau at the leeward side of the Andes potentially leads to a local overprint of the SWW influence on the hydrological balance. © 2014 Elsevier B.V.

Westhoff J.H.,University of Heidelberg | Schildhorn C.,University of Heidelberg | Schildhorn C.,Hannover Medical School | Jacobi C.,Hannover Medical School | And 9 more authors.
Journal of the American Society of Nephrology | Year: 2010

Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and firstgeneration telomerase-deficient mice. Critically short telomeres, increased expression of the cellcycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourthgeneration telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury. Copyright © 2010 by the American Society of Nephrology.

Neumann H.,University of Erlangen Nu Rnberg | Neumann H.,Friedrich - Alexander - University, Erlangen - Nuremberg | Fry L.C.,University of Alabama at Birmingham | Nagel A.,University of Erlangen Nu Rnberg | And 3 more authors.
Current Opinion in Gastroenterology | Year: 2014

PURPOSE OF REVIEW: Here, we review the clinical applications of small bowel capsule endoscopy. Moreover, we provide an outlook on the exceptional future developments of small bowel capsule endoscopy. We discuss clinical algorithms for diagnosis of small bowel diseases. Multiple studies have shown the potential of capsule endoscopy for identification of the bleeding source located in the small bowel and the increased diagnostic yield over radiographic studies. Capsule endoscopy could detect villous atrophy and severe complications in patients with nonresponsive celiac disease. In addition, small bowel capsule endoscopy was proven as a valid tool to diagnose polyps and tumors and Crohn's disease. Summary Major current clinical indications of capsule endoscopy in the small bowel include evaluation of obscure gastrointestinal bleeding, diagnosis and surveillance of small bowel polyps and tumors, celiac disease and Crohn's disease. Recent developments have also passed the way for small bowel capsule endoscopy to become a therapeutic instrument. © 2014 Wolters Kluwer Health.

Kaercher T.,Augenarztpraxis | Dietz J.,University of Erlangen Nu Rnberg | Jacobi C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Berz R.,InfraMedic GmbH | Schneider H.,University of Erlangen Nu Rnberg
Current Eye Research | Year: 2015

Purpose: X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical characteristics include meibomian gland disorder and the resulting hyperevaporative dry eye. In this study, we evaluated meibography and ocular infrared thermography as novel methods to diagnose XLHED.Methods: Eight infants, 12 boys and 14 Male adults with XLHED and 12 healthy control subjects were subjected to a panel of tests including the ocular surface disease index (OSDI), meibography and infrared thermography, non-invasive measurement of tear film break-up time (NIBUT) and osmolarity, Schirmers test, lissamine green staining and fluorescein staining. Sensitivity and specificity were determined for single tests and selected test combinations.Results: Meibography had 100% sensitivity and specificity for identifying XLHED. Infrared thermography, a completely non-invasive procedure, revealed a typical pattern for Male subjects with XLHED. It was, however, less sensitive (86% for adults and 67% for children) than meibography or a combination of established routine tests. In adults, OSDI and NIBUT were the best single routine tests (sensitivity of 86% and 71%, respectively), whereas increased tear osmolarity appeared as a rather unspecific ophthalmic symptom. In children, NIBUT was the most convincing routine test (sensitivity of 91%).Conclusions: Meibography is the most reliable ophthalmic examination to establish a clinical diagnosis in individuals with suspected hypohidrotic ectodermal dysplasia, even before genetic test results are available. Tear film tests and ocular surface staining are less sensitive in children, but very helpful for estimating the severity of ocular surface disease in individuals with known XLHED. © 2014 Informa Healthcare USA, Inc. All rights reserved.

El-Baba C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Mahadevan V.,SASTRA University | Fahlbusch F.B.,University of Erlangen Nu rnberg | S S.M.,SASTRA University | And 3 more authors.
Molecular Cancer | Year: 2014

Background: Thymoquinone (TQ) was shown to reduce tumor growth in several cancer models both in vitro and in vivo. So far only a few targets of TQ, including protein kinases have been identified. Considering that kinases are promising candidates for targeted anticancer therapy, we studied the complex kinase network regulated by TQ.Methods: Novel kinase targets influenced by TQ were revealed by in silico analysis of peptide array data obtained from TQ-treated HCT116wt cells. Western blotting and kinase activity assays were used to determine changes in kinase expression patterns in colorectal cancer cells (HCT116wt, DLD-1, HT29). To study the viability/apoptotic effects of combining the PAK1 inhibitor IPA-3 and TQ, crystal violet assay and AnnexinV/PI staining were employed. Interactions between PAK1 and ERK1/2 were investigated by co-immunoprecipitation and modeled by docking studies. Transfection with different PAK1 mutants unraveled the role of TQ-induced changes in PAK1 phosphorylation and TQ ´s effects on PAK1 scaffold function.Results: Of the 104 proteins identified, 50 were upregulated ≥2 fold by TQ and included molecules in the AKT-MEK-ERK1/2 pathway. Oncogenic PAK1 emerged as an interesting TQ target. Time-dependent changes in two PAK1 phosphorylation sites generated a specific kinase profile with early increase in pPAKThr212 followed by late increase in pPAKThr423. TQ induced an increase of pERK1/2 and triggered the early formation of an ERK1/2-PAK1 complex. Modeling confirmed that TQ binds in the vicinity of Thr212 accompanied by conformational changes in ERK2-PAK1 binding. Transfecting the cells with the non-phosphorylatable mutant T212A revealed an increase of pPAKThr423 and enhanced apoptosis. Likewise, an increase in apoptosis was observed in cells transfected with both the kinase-dead K299R mutant and PAK1 siRNA. Using structural modeling we suggest that TQ interferes also with the kinase domain consequently disturbing its interaction with pPAKThr423, finally inhibiting MEK-ERK1/2 signaling and disrupting its prosurvival function. pERK1/2 loss was also validated in vivo.Conclusions: Our study shows for the first time that the small molecule TQ directly binds to PAK1 changing its conformation and scaffold function. Because TQ affects the central RAF/MEK/ERK1/2 pathway, the combination of TQ with targeted therapies is worth considering for future anticancer treatments. © 2014 El-Baba et al.; licensee BioMed Central Ltd.

Zeltner R.,Max Planck Institute for the Science of Light | Zeltner R.,University of Erlangen Nu rnberg | Sedlmeir F.,Max Planck Institute for the Science of Light | Sedlmeir F.,University of Erlangen Nu rnberg | And 5 more authors.
Laser Science, LS 2014 | Year: 2014

We report on a refractometric sensor based on crystalline MgF2 Whispering Gallery Mode resonators. High sensitivity, small resonance line widths and good thermal stability provide a limit of detection of 4x10-6 refractive index units. © 2014 OSA.

Kohler E.M.,Friedrich - Alexander - University, Erlangen - Nuremberg | Kohler E.M.,University of Erlangen Nu Rnberg | Brauburger K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Behrens J.,Friedrich - Alexander - University, Erlangen - Nuremberg | Schneikert J.,Friedrich - Alexander - University, Erlangen - Nuremberg
Oncogene | Year: 2010

The adenomatous polyposis coli (APC) protein is a negative regulator of the mitogenic transcription factor Β-catenin by stimulating its proteasomal degradation. This involves several APC domains, including the binding sites for axin/conductin, the recently described Β-Catenin Inhibitory Domain (CID) and the third 20 amino acid repeat (20R3) that is a Β-catenin-binding site. The four 15 amino acid repeats (15R) and the 20R1 are also Β-catenin- binding sites, but their role in Β-catenin degradation has remained unclear. We show here that binding of Β-catenin to the 15R of APC is necessary and sufficient to target Β-catenin for degradation whereas binding to the 20R1 is neither necessary nor sufficient. The first 15R displays the highest affinity for Β-catenin in the 15R-20R1 module. Biallelic mutations of the APC gene lead tocolon cancer in familial adenomatous polyposis coli (FAP) and result in the synthesis of truncated products lacking domains involved in Β-catenin degradation but still having a minimal length. The analysis of the distribution of truncating mutations along the APC sequence in colorectal tumours from FAP patients revealed that the first 15R is one target of the positive selection of mutations that lead to tumour development. © 2010 Macmillan Publishers Limited All rights reserved.

Brackmann F.,University of Erlangen Nu Rnberg | Krumbholz M.,University of Erlangen Nu Rnberg | Langer T.,University of Erlangen Nu Rnberg | Rascher W.,University of Erlangen Nu Rnberg | And 2 more authors.
Journal of Pediatric Hematology/Oncology | Year: 2013

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. Copyright © 2013 by Lippincott Williams & Wilkins.

PubMed | University of Erlangen Nu rnberg
Type: Case Reports | Journal: Journal of medical genetics | Year: 2011

Spontaneous read-through of a premature termination codon (PTC) has so far not been observed in patients carrying nonsense mutations. This report describes a patient with junctional epidermolysis bullosa who was expected to die because of compound heterozygous nonsense mutations in the gene LAMA3 (R943X/R1159X), but was rescued by spontaneous read-through of the R943X allele.FACS analysis of cells carrying various PTCs surrounded by their natural neighbouring codons revealed significant reporter gene expression despite the PTC only for this patients genetic context. Gene expression could be abolished by replacing the first or third nucleotide before, or one of the two nucleotides following the PTC. Site-directed mutagenesis was used to identify genotypes allowing PTC read-through. The genetic context of the LAMA3 mutation R943X is close to a hypothetical consensus sequence for maximum PTC read-through. Bioinformatic analysis showed that this consensus sequence is present in four sequences from the NCBI reference database, each of which contains another in-frame termination codon three or four codons apart. This indicates strong selective pressure against leaky termination codons in the human genome. This patients mutated full length mRNA escaped nonsense-mediated decay, leading to LAMA3 mRNA levels similar to those of a healthy control, and full length laminin 3 could be detected in culture supernatant of the patients keratinocytes. Immunofluorescence analyses of skin biopsies and continuous clinical improvement of the patients condition suggested accumulation of intact laminin-332 in the epidermal basement membrane. These findings provide important clues for the prediction of PTC read-through in human genetic disease.

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