Publications by authors named "Christina Schneider"

23 Publications

  • Page 1 of 1

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

Liver Int 2021 Jun 14;41(6):1370-1378. Epub 2021 Mar 14.

Department of Medicine I, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.

Background & Aims: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis.

Methods: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI.

Results: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline.

Conclusions: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.
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http://dx.doi.org/10.1111/liv.14842DOI Listing
June 2021

Impact of body mass index, smoking habit, alcohol consumption, physical activity and parity on disease course of women with triple-negative breast cancer.

Arch Gynecol Obstet 2020 02 18;301(2):603-609. Epub 2019 Dec 18.

Department of Gynecology, Obstetrics and Reproductive Medicine, University Medical School of Saarland, Kirrberger Straße, 66421, Homburg, Saar, Germany.

Objective: To evaluate the potential impact of body mass index (BMI), smoking habit, alcohol consumption, physical activity and parity on disease course of women with triple-negative breast cancer (TNBC).

Material And Methods: This was a retrospective chart analysis of patients with TNBC. Primary target parameters were overall survival (OS) and disease-free survival (DFS) depending on BMI, smoking habit, alcohol consumption, physical activity and parity. Results were descriptively evaluated and plotted as Kaplan-Meier curves. The null hypothesis was tested using the non-parametric log-rank test. All patients were treated at the University Medical School of Saarland, Dept of Gynecology, Obstetrics and Reproductive Medicine.

Results: A total of 197 patients were analyzed. More than 50% of women were 40-60 years old (mean 57 years) and had a normal BMI. More than 88% of patients had either a T1 or T2 tumor, 64% were N0 and 66.5% had a G3 cancer. Thirty-four of 84 patients (40.38%) on neo-adjuvant chemotherapy reached a pathology-confirmed complete remission. During the follow-up (median 41.43 months), 34 (17.3%) patients had recurrent disease and 51 (25.9%) suffered from metastases. A total of 51 (25.9%) finally deceased. OS and DFS were not significantly impacted by BMI (OS: p = 0.4720; DFS: p = 0.2272), smoking habit (p = 0.9892; p = 0.6040), alcohol consumption (p = 0.6515; p = 0.7460), physical activity (p = 0.3320; p = 0.5991) or parity (p = 0.5929; 0.1417).

Conclusion: BMI, smoking habit, alcohol consumption, physical activity and parity had no impact on OS or DFS in women with TNBC.
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http://dx.doi.org/10.1007/s00404-019-05413-4DOI Listing
February 2020

Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides.

Science 2019 10;366(6461):76-82

Center for Integrated Protein Science, Department of Chemistry, LMU München, Butenandtstrasse 5-13, 81377 München, Germany.

Theories about the origin of life require chemical pathways that allow formation of life's key building blocks under prebiotically plausible conditions. Complex molecules like RNA must have originated from small molecules whose reactivity was guided by physico-chemical processes. RNA is constructed from purine and pyrimidine nucleosides, both of which are required for accurate information transfer, and thus Darwinian evolution. Separate pathways to purines and pyrimidines have been reported, but their concurrent syntheses remain a challenge. We report the synthesis of the pyrimidine nucleosides from small molecules and ribose, driven solely by wet-dry cycles. In the presence of phosphate-containing minerals, 5'-mono- and diphosphates also form selectively in one-pot reactions. The pathway is compatible with purine synthesis, allowing the concurrent formation of all Watson-Crick bases.
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http://dx.doi.org/10.1126/science.aax2747DOI Listing
October 2019

Thyroid hemiagenesis is combined with a variety of thyroid disorders.

Nuklearmedizin 2019 Jun 11;58(3):265-271. Epub 2019 Apr 11.

Department of Nuclear Medicine, University Hospital of Cologne.

Aim: Thyroid hemiagenesis (TH) is a rare congenital anomaly in which one thyroid lobe fails to develop. We describe our experience with at least 13 patients presenting with TH at our department.

Methods: We retrospectively analysed patients with TH, who had been referred primarily to our clinic between 2004 and 2010. In patients with TH, thyroid function parameters and thyroid autoantibodies were examined. Tc-pertechnetate thyroid scintigraphy and sonography were performed in all patients and confirmed the diagnosis of TH.

Results: We identified 13 patients (11 women, 2 men) with TH in our patient collective and calculated an estimated prevalence of TH of 0.08 %.We found TH to occur more frequently in the left lobe and also more frequently in females than in males. 9 patients presented with a total absence of one thyroid lobe and 4 patients presented with severe hypoplasia of one thyroid lobe with an isthmus appearing as a "hockey stick sign" on scintigraphic imaging. Associated thyroid diseases could be observed in the remaining lobe in all patients and included hyperthyroidism, hypothyroidism, nodular goiter, toxic goiter, hypofunctioning nodules, Graves' disease and Hashimoto-thyroiditis. The most frequent thyroid disease in our patients with TH was nodular goiter. We did not find any association of TH with malignancy.

Conclusion: TH is mostly detected incidentally as the prevalence of TH is extraordinary low. The fact that all of our patients with TH were also affected by other forms of thyroid disease is reasonable since the patients were not referred to the diagnostic centre due to TH but rather due to the associated thyroid disease. Possibly there are different groups of TH: the symptomatic hypothyroid children, the lifelong euthyroid adults who are diagnosed incidentally through another thyroid disease and the patients with a molecular failure of proper thyroid development.
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http://dx.doi.org/10.1055/a-0830-4425DOI Listing
June 2019

Publisher Correction: Non-canonical nucleosides and chemistry of the emergence of life.

Nat Commun 2019 01 15;10(1):325. Epub 2019 Jan 15.

Department of Chemistry at the Ludwig-Maximilians Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.

The original version of this Article contained errors in the citations in the second, third and fourth sentences of the first paragraph of the 'Life and LUCA' section, which incorrectly read 'Its development is explained by Darwinian evolution, which must have begun with rudimentary "living" vesicles that at some point transitioned into what we call the last universal common ancestor (LUCA). LUCA is a hypothetical life form obtained from phylogenetic analysis from which all three kingdoms of life originated. To our understanding, LUCA already possessed the capacity to synthesize specific building blocks such as amino acids, nucleotides and lipids.' The correct version states '(LUCA)' in place of '(LUCA)', 'originated' instead of 'originated' and 'lipids' rather than 'lipids'. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-08340-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333768PMC
January 2019

Non-canonical nucleosides and chemistry of the emergence of life.

Nat Commun 2018 12 12;9(1):5174. Epub 2018 Dec 12.

Department of Chemistry at the Ludwig-Maximilians Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.

Prebiotic chemistry, driven by changing environmental parameters provides canonical and a multitude of non-canonical nucleosides. This suggests that Watson-Crick base pairs were selected from a diverse pool of nucleosides in a pre-Darwinian chemical evolution process.
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http://dx.doi.org/10.1038/s41467-018-07222-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289997PMC
December 2018

Efficacy of low-temperature plasma-activated gas disinfection against biofilm on contaminated GI endoscope channels.

Gastrointest Endosc 2019 01 16;89(1):105-114. Epub 2018 Aug 16.

Center for Bioelectrics, Old Dominion University, Norfolk, Virginia, USA; Department of Electrical and Computer Engineering, Norfolk, Virginia, USA.

Background And Aims: It has been increasingly recognized that the safety of GI endoscopes needs to be improved by addressing the small margin of safety of high-level disinfectants (HLDs) and the failure of HLDs to clear multidrug-resistant organisms and biofilms. There is also an unmet need for effective low-temperature sterilization techniques that have a clear pathway for U.S. Food and Drug Administration clearance. Here, we report the results of our investigation of a novel argon plasma-activated gas (PAG) for disinfection and potentially sterilization of biofilm-contaminated endoscopic channels.

Methods: Test polytetrafluoroethylene channel segments were contaminated with 4-, 24- and 48-hour luminal biofilms of methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, or Escherichia coli and were treated by PAG flowing for up to 9 minutes. After PAG treatment, inactivation and dispersal of luminal bacterial biofilms and their regrowth in 48 hours were evaluated. Reactive species induced by PAG were measured with colorimetric probes and electron spin resonance spectrometry. Surface morphology and elemental composition of PAG-treated channel material were analyzed with scanning electron microscopy.

Results: PAG treatment for 9 minutes led to more than 8 log reduction of viable cells and dispersal of 24- and 48-hour luminal biofilms of all 3 bacteria and to suppression of their regrowth, whereas it resulted in little morphologic abnormalities in channel material. Ozone concentration of PAG fell to below .01 ppm within 30 seconds of switching off the plasma. PAG-treated deionized water was acidified with numerous types of reactive species, each with a concentration some 3 orders of magnitude or more below its bacterial inhibition concentration.

Conclusions: PAG is capable of effectively and rapidly disinfecting luminal bacterial biofilms and offers an alternative to the step of HLDs and/or ethylene oxide in the endoscope reprocessing procedure with safety to personnel and environment.
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http://dx.doi.org/10.1016/j.gie.2018.08.009DOI Listing
January 2019

Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth-Generation by Prebiotic Methylations and Carbamoylations.

Angew Chem Int Ed Engl 2018 05 17;57(20):5943-5946. Epub 2018 Apr 17.

Center for Integrated Protein Science (CiPSM) at the Department, of Chemistry, LMU München, Butenandtstrasse 5-13, 81377, München, Germany.

The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth.
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http://dx.doi.org/10.1002/anie.201801919DOI Listing
May 2018

Wet-dry cycles enable the parallel origin of canonical and non-canonical nucleosides by continuous synthesis.

Nat Commun 2018 01 11;9(1):163. Epub 2018 Jan 11.

Center for Integrated Protein Science Munich CiPSM at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.

The molecules of life were created by a continuous physicochemical process on an early Earth. In this hadean environment, chemical transformations were driven by fluctuations of the naturally given physical parameters established for example by wet-dry cycles. These conditions might have allowed for the formation of (self)-replicating RNA as the fundamental biopolymer during chemical evolution. The question of how a complex multistep chemical synthesis of RNA building blocks was possible in such an environment remains unanswered. Here we report that geothermal fields could provide the right setup for establishing wet-dry cycles that allow for the synthesis of RNA nucleosides by continuous synthesis. Our model provides both the canonical and many ubiquitous non-canonical purine nucleosides in parallel by simple changes of physical parameters such as temperature, pH and concentration. The data show that modified nucleosides were potentially formed as competitor molecules. They could in this sense be considered as molecular fossils.
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http://dx.doi.org/10.1038/s41467-017-02639-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765019PMC
January 2018

Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions.

Chemistry 2017 Nov 17;23(63):15945-15956. Epub 2017 Oct 17.

Universität Heidelberg, Anorganisch-Chemisches Institut and Interdisciplinary Center for Scientific Computing, INF 270, D-, 69120, Heidelberg, Germany.

The synthesis of the octadentate bispidine ligand bearing two picolinic acid pendant arms (H bispa ), and its coordination chemistry with radionuclides relevant for nuclear medicine, namely indium(III) ( In), lutetium(III) ( Lu), and lanthanum(III) (as surrogate for Ac), are reported. The non-radioactive metal complexes of the N O -type bispa ligand were characterized by H and C NMR spectroscopy, elemental analysis, mass spectrometry and single-crystal X-ray analysis. Experimental structural data, computational analysis, complex stabilities determined by potentiometric titration, and "radiostabilities" determined by competition studies in the presence of human serum reveal complex stabilities of H bispa comparable to those of the macrocyclic "gold standard" DOTA. After an incubation time of 1 day, 86 and 87 % of [ Lu(bispa )] and [ Lu(DOTA)] , respectively, remain intact. Importantly, unlike DOTA, H bispa is radiolabeled quantitatively with In and Ac under ambient conditions, which is an essential aspect when working with heat-sensitive antibodies as targeting vectors. In the case of In , room temperature radiolabeling of H bispa yields molar activities as high as 70 MBq nmol within 10 minutes. These are promising results for radiopharmaceutical applications of H bispa .
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http://dx.doi.org/10.1002/chem.201702284DOI Listing
November 2017

Stable Isotope-Assisted Evaluation of Different Extraction Solvents for Untargeted Metabolomics of Plants.

Int J Mol Sci 2016 Jun 28;17(7). Epub 2016 Jun 28.

Center for Analytical Chemistry, Department of Agrobiotechnology (IFA-Tulln), University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad-Lorenz-Strasse 20, 3430 Tulln, Austria.

The evaluation of extraction protocols for untargeted metabolomics approaches is still difficult. We have applied a novel stable isotope-assisted workflow for untargeted LC-HRMS-based plant metabolomics , which allows for the first time every detected feature to be considered for method evaluation. The efficiency and complementarity of commonly used extraction solvents, namely 1 + 3 (v/v) mixtures of water and selected organic solvents (methanol, acetonitrile or methanol/acetonitrile 1 + 1 (v/v)), with and without the addition of 0.1% (v/v) formic acid were compared. Four different wheat organs were sampled, extracted and analysed by LC-HRMS. Data evaluation was performed with the in-house-developed MetExtract II software and R. With all tested solvents a total of 871 metabolites were extracted in ear, 785 in stem, 733 in leaf and 517 in root samples, respectively. Between 48% (stem) and 57% (ear) of the metabolites detected in a particular organ were found with all extraction mixtures, and 127 of 996 metabolites were consistently shared between all extraction agent/organ combinations. In aqueous methanol, acidification with formic acid led to pronounced pH dependency regarding the precision of metabolite abundance and the number of detectable metabolites, whereas extracts of acetonitrile-containing mixtures were less affected. Moreover, methanol and acetonitrile have been found to be complementary with respect to extraction efficiency. Interestingly, the beneficial properties of both solvents can be combined by the use of a water-methanol-acetonitrile mixture for global metabolite extraction instead of aqueous methanol or aqueous acetonitrile alone.
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http://dx.doi.org/10.3390/ijms17071017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964393PMC
June 2016

Dataset from proteomic analysis of rat, mouse, and human liver microsomes and S9 fractions.

Data Brief 2015 Jun 24;3:95-8. Epub 2015 Feb 24.

Université du Québec à Montréal (UQÀM), Chemistry Department/Pharmaqam, Montréal, Que., Canada.

Rat, mouse and human liver microsomes and S9 fractions were analyzed using an optimized method combining ion exchange fractionation of digested peptides, and ultra-high performance liquid chromatography (UHPLC) coupled to high resolution tandem mass spectrometry (HR-MS/MS). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the PRIDE partner repository (Vizcaíno et al., 2013 [1]) with the dataset identifiers PXD000717, PXD000720, PXD000721, PXD000731, PXD000733 and PXD000734. Data related to the peptides (trypsin digests only) were also uploaded to Peptide Atlas (Farrah et al., 2013 [2]) and are available with the dataset identifiers PASS00407, PASS00409, PASS00411, PASS00412, PASS00413 and PASS00414. The present dataset is associated with a research article published in EuPA Open Proteomics [3].
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http://dx.doi.org/10.1016/j.dib.2015.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510096PMC
June 2015

A Novel Xanthomonas sp. Causes Bacterial Spot of Rose (Rosa spp.).

Plant Dis 2013 Oct;97(10):1301-1307

Mid-Florida Research and Education Center, University of Florida, IFAS, Apopka 32703.

A bacterial spot of rose (Rosa spp.) caused by a xanthomonad was observed in Florida and Texas. Ten representative strains collected from the two states between 2004 and 2010 were used to determine the taxonomic position of this rose pathogen. Fatty acid methyl ester analysis was performed and a nearly 2-kb 16S-23S rRNA intergenic spacer along with flanking portions of the 16S and 23S rRNA genes were sequenced for selected strains, showing that they were members of the genus Xanthomonas. Multilocus sequence typing and analysis (MLST/MLSA) and pathogenicity tests were conducted to further characterize the Xanthomonas strains. The MLSA, based on six gene fragments-fusA, gapA, gltA, gyrB, lacF, and lepA-showed that the rose strains fell into Xanthomonas axonopodis subgroup 9.2 and shared the highest similarity values (98.8 to 99.7%) with X. alfalfae subsp. citrumelonis of the subgroup. However, principal coordinate analysis grouped the rose strains into a unique cluster distinct from other members of the subgroup according to virulence phenotypes on 11 plant species belonging to five plant families (Araceae, Euphorbiaceae, Rosaceae, Rutaceae, and Solanaceae). Moreover, the rose strains were aggressive on rose and Indian Hawthorn (Rhaphiolepsis indica). On the basis of the MLSA and virulence phenotypes, the pathovar epithet rosa is proposed.
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http://dx.doi.org/10.1094/PDIS-09-12-0851-REDOI Listing
October 2013

A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT.

Blood 2013 Aug 3;122(7):1312-5. Epub 2013 Jun 3.

Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany.

To ascertain the genetic basis of a paroxysmal nocturnal hemoglobinuria (PNH) case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8-MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI anchor synthesis, whereas PIGT is essential for attachment of the preassembled GPI anchor to proteins. Although a single mutation event in the X-chromosomal gene PIGA is known to cause GPI-anchored protein deficiency, 2 such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells.
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http://dx.doi.org/10.1182/blood-2013-01-481499DOI Listing
August 2013

Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study.

J Clin Oncol 2013 Mar 22;31(7):944-51. Epub 2013 Jan 22.

University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.

Purpose: Radioiodinated metaiodobenzylguanidine ((123)I-mIBG) scintigraphy is an established imaging method in neuroblastoma. Semiquantitative scoring systems have been developed to assess the extent of disease and response to chemotherapy. We present the results of the comparison between the SIOPEN [International Society of Pediatric Oncology Europe Neuroblastoma Group] score and the modified Curie score.

Patients And Methods: We retrospectively analyzed 147 mIBG scans of 58 patients older than 1 year of age with stage 4 neuroblastoma from German Neuroblastoma Trial NB97 that were assessed according to the SIOPEN and the Curie scoring method. mIBG examinations were performed at diagnosis and after four and six cycles of chemotherapy.

Results: Scoring results were highly correlated between both methods, and interobserver reliability was excellent. A Curie score ≤ 2 and a SIOPEN score ≤ 4 (best cutoff) at diagnosis were correlated to significantly better event-free and overall survival compared with higher scores. After four cycles of chemotherapy, overall survival was significantly better for mIBG-negative patients compared with those with any residual mIBG-positive metastases. After six cycles of chemotherapy, there was no difference in survival between mIBG-negative patients and patients with residual mIBG-positive metastases. Patients without mIBG-positive metastases after four and six cycles of chemotherapy had a better overall survival, but late clearance of mIBG-positive metastases did not improve outcome.

Conclusion: Higher mIBG scores at diagnosis and occurrence of any residual mIBG-positive metastases after four cycles of chemotherapy predicted unfavorable outcome for patients with stage 4 neuroblastoma. Later clearance of metastases did not improve prognosis. The Curie and the SIOPEN score were equally reliable and predictive.
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http://dx.doi.org/10.1200/JCO.2012.45.8794DOI Listing
March 2013

68Ga-DOTATATE-PET/CT positive metastatic lymph node in a 69-year-old woman with Merkel cell carcinoma.

Clin Nucl Med 2012 Nov;37(11):1108-11

Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany.

We report the case of a 69-year-old woman with a Merkel cell carcinoma (MCC) in whom subsequent lymph node metastasis was first diagnosed by 68Ga-Dotatate-PET/CT followed by histopathological confirmation. MCC is an extraordinarily rare and aggressive neuroendocrine tumor of dermal origin with a high rate of postoperative recurrence. Owing to its rarity, the diagnosis of MCC remains a significant challenge. In our case, 68Ga-Dotatate-PET/CT proved clinically useful for diagnosing the lymph node metastasis of a MCC.
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http://dx.doi.org/10.1097/RLU.0b013e318266d3b3DOI Listing
November 2012

Acute hypoxia modifies regulation of neuroglobin in the neonatal mouse brain.

Exp Neurol 2012 Jul 19;236(1):112-21. Epub 2012 Apr 19.

Department of Pediatrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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.
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http://dx.doi.org/10.1016/j.expneurol.2012.04.006DOI Listing
July 2012

Development of hypothyroidism during long-term follow-up of patients with toxic nodular goitre after radioiodine therapy.

Clin Endocrinol (Oxf) 2012 Feb;76(2):297-303

Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany.

Objective: To investigate the cure rate and incidence of hypothyroidism of radioiodine treatment with a calculated dose regimen and an intended thyroid dose of 150 Gy in patients with toxic nodular goitre during long-term follow-up.

Patients: A total of 265 consecutive patients with toxic nodular goitre were treated between March 2003 and August 2004 at our institute and followed up for a maximum of 8 years. Preliminary radioiodine testing with volumetric measurement of the thyroid by ultrasound as well as individual thyroidal radioiodine uptake and half-life measurements were performed before radioiodine therapy. The estimated radiation dose to the thyroid was 150 Gy.

Measurements: Follow-up controls with respect to success of therapy and development of hypothyroidism were performed 3 months, 1 and up to 8 years after radioiodine treatment. The relation of the achieved thyroid dose to the success rate of treatment and to the incidence of hypothyroidism was analysed.

Results: The cure rates were 85% at 3 months, 98% at 1 year and 98% at the end of follow-up. Above an achieved thyroid dose of more than 120 Gy, there was no significant association between the dose achieved in the thyroid and the cure rate on follow-up. The incidences of hypothyroidism at 3 months, at 1 year and at the end of follow-up were 32%, 55% and 73%, respectively.

Conclusions: Radioiodine treatment with a calculated dose regimen is a highly effective treatment option in patients with toxic goitre with an overall success rate of 98%. However, radioiodine treatment with an intended thyroid dose of 150 Gy leads to a high incidence of hypothyroidism on long-term follow-up. This finding supports the suggestion that in future intended thyroid doses could be lowered in patients treated with a calculated dose regimen for toxic nodular goitre.
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http://dx.doi.org/10.1111/j.1365-2265.2011.04204.xDOI Listing
February 2012

Systemic hypoxia differentially affects neurogenesis during early mouse brain maturation.

Brain Dev 2012 Apr 6;34(4):261-73. Epub 2011 Aug 6.

Department of Pediatrics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.braindev.2011.07.006DOI Listing
April 2012

Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain.

Am J Physiol Regul Integr Comp Physiol 2010 Dec 6;299(6):R1489-99. Epub 2010 Oct 6.

Department of Pediatrics, University of Erlangen, Erlangen, Germany.

Late-gestational intrauterine hypoxia represents a well-known risk factor of acquired perinatal brain injury. Cell type and age-specific sensitivity of hypoxia-responsive genes to low-oxygen partial pressure is to be considered in the screening for early indicators of fetoplacental tissue hypoxia. To identify early hypoxia-induced alterations in gene expression during late-gestational hypoxia (6% O(2), 6 h; gestational day 20) we compared primary mouse placenta and brain transcriptomes using high-density oligonucleotide microarrays. Upregulation of candidate marker genes for hypoxia was confirmed by quantitative RT-PCR and immunohistochemistry. Both developing brain and placenta were highly responsive to systemic hypoxia at the level of gene expression involving hypoxia-inducible transcription factor (HIF)-dependent genes and immediate early genes (IEG) (Fos, Jun, Egr1, Bhlhb2), apoptosis-promoting factors (Bnip3, Dusp1, Ier3) that were all upregulated, and genes modulating RNA binding and translation (Rbm3, Thap2, Lig4, Rbm12b) that mainly were downregulated. Functional activity of the HIF system was obvious from elevated expression of various known HIF target genes (Adm, Vegf, Hk2, Pdk1, Bnip3, Ier3, Dusp-1), indicating immediate availability among early response to acute hypoxia. In addition, genes not yet described as being hypoxia related were identified that are involved in angiogenesis/cell differentiation (Gna13, Gab2), mRNA processing, and embryonic development. RT-PCR of placenta and brain tissues confirmed upregulation of selected HIF target genes and IEG. These data indicate that the early hypoxia-induced genomic response of the placenta mirrors that of developing brain in a temporally parallel manner. Our observations implicate future diagnostic options to identify fetal and cerebral tissue hypoxia.
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http://dx.doi.org/10.1152/ajpregu.00697.2009DOI Listing
December 2010

Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain.

Brain Res 2009 Jul 18;1280:43-51. Epub 2009 May 18.

Department of Pediatrics, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.

Hypoxia-inducible transcription factors (HIFs) are crucially involved in brain development and cellular adaptation to hypoxia and ischemia. Degradation of HIF is regulated under normoxia by oxygen-dependent hydroxylation of specific prolyl residues on the labile alpha-subunit by HIF prolyl hydroxylases (PHD). Prolyl-4-hydroxylase inhibitors (PHI) have shown protective effects in vitro and in vivo in adult kidney and brain. The aim of the present study was to investigate in vivo short-term effects of a novel low molecular weight PHI, FG-4497, on HIF-regulated cytotrophic and vasoactive factors in developing mouse brain. Neonatal (P7, n=26) C57/BL6 mice were treated with PHI FG-4497 (30-100 mg/kg, i.p., duration 6 h). Gene expression was analyzed by TaqMan RT-PCR in kidney and developing brain in comparison to controls (NaCl 0.9% and non-treated animals). HIF-1alpha protein was quantified by Western blot analysis. Dose-response studies revealed prominent effects of FG-4497 at a dose of 100 mg/kg as assessed by significant up-regulation of mRNA in both kidney and brain of the following HIF-dependent genes: vascular endothelial growth factor, adrenomedullin and erythropoietin. Organ-specific transcriptional regulation was evident from analysis of hexokinase 2, inducible NO synthase and PHD3 mRNA concentrations. In the brain, HIF-1alpha and HIF-2alpha protein markedly accumulated in response to FG-4497. Besides vasoactive factors, PHI significantly increased cerebral chemokine receptor CXCR-4 mRNA levels. In conclusion, the novel PHI FG-4497 activates HIFs at an early stage of brain maturation and modulates neurotrophic processes known to be crucially involved in brain development and hypoxia-induced brain pathology.
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http://dx.doi.org/10.1016/j.brainres.2009.05.023DOI Listing
July 2009