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Article ; Online: Dexmedetomidine Protects Cerebellar Neurons against Hyperoxia-Induced Oxidative Stress and Apoptosis in the Juvenile Rat.

Puls, Robert / von Haefen, Clarissa / Bührer, Christoph / Endesfelder, Stefanie

International journal of molecular sciences

2023 Volume 24, Issue 9

Abstract: The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. ... ...

Abstract	The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development could be a crucial factor in neurodevelopmental disorders of prematurity. Recent studies have focused on dexmedetomidine (DEX), which has been associated with potential neuroprotective properties and is used as an off-label application in neonatal units. Wistar rats (P6) were exposed to 80% hyperoxia for 24 h and received as pretreatment a single dose of DEX (5µg/kg, i.p.). Analyses in the immature rat cerebellum immediately after hyperoxia (P7) and after recovery to room air (P9, P11, and P14) included examinations for cell death and inflammatory and oxidative responses. Acute exposure to high oxygen concentrations caused a significant oxidative stress response, with a return to normal levels by P14. A marked reduction of hyperoxia-mediated damage was demonstrated after DEX pretreatment. DEX produced a much earlier recovery than in controls, confirming a neuroprotective effect of DEX on alterations elicited by oxygen stress on the developing cerebellum.
MeSH term(s)	Infant, Newborn ; Animals ; Rats ; Humans ; Hyperoxia/complications ; Hyperoxia/drug therapy ; Rats, Wistar ; Animals, Newborn ; Dexmedetomidine/pharmacology ; Dexmedetomidine/therapeutic use ; Infant, Premature ; Apoptosis ; Oxidative Stress ; Oxygen/pharmacology ; Interneurons
Chemical Substances	Dexmedetomidine (67VB76HONO) ; Oxygen (S88TT14065)
Language	English
Publishing date	2023-04-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24097804
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat.

Puls, Robert / von Haefen, Clarissa / Bührer, Christoph / Endesfelder, Stefanie

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 4

Abstract: Impaired cerebellar development of premature infants and the associated impairment of cerebellar functions in cognitive development could be crucial factors for neurodevelopmental disorders. Anesthetic- and hyperoxia-induced neurotoxicity of the immature ...

Abstract	Impaired cerebellar development of premature infants and the associated impairment of cerebellar functions in cognitive development could be crucial factors for neurodevelopmental disorders. Anesthetic- and hyperoxia-induced neurotoxicity of the immature brain can lead to learning and behavioral disorders. Dexmedetomidine (DEX), which is associated with neuroprotective properties, is increasingly being studied for off-label use in the NICU. For this purpose, six-day-old Wistar rats (P6) were exposed to hyperoxia (80% O
Language	English
Publishing date	2023-04-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12040980
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Article: Cardioprotective Effects of Dexmedetomidine in an Oxidative-Stress In Vitro Model of Neonatal Rat Cardiomyocytes.

Borger, Moritz / von Haefen, Clarissa / Bührer, Christoph / Endesfelder, Stefanie

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 6

Abstract: Preterm birth is a risk factor for cardiometabolic disease. The preterm heart before terminal differentiation is in a phase that is crucial for the number and structure of cardiomyocytes in further development, with adverse effects of hypoxic and ... ...

Abstract	Preterm birth is a risk factor for cardiometabolic disease. The preterm heart before terminal differentiation is in a phase that is crucial for the number and structure of cardiomyocytes in further development, with adverse effects of hypoxic and hyperoxic events. Pharmacological intervention could attenuate the negative effects of oxygen. Dexmedetomidine (DEX) is an α2-adrenoceptor agonist and has been mentioned in connection with cardio-protective benefits. In this study, H9c2 myocytes and primary fetal rat cardiomyocytes (NRCM) were cultured for 24 h under hypoxic condition (5% O
Language	English
Publishing date	2023-06-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12061206
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Article ; Online: Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat

Puls, Robert / von Haefen, Clarissa / Bührer, Christoph / Endesfelder, Stefanie

Antioxidants. 2023 Apr. 21, v. 12, no. 4

2023

Abstract	Impaired cerebellar development of premature infants and the associated impairment of cerebellar functions in cognitive development could be crucial factors for neurodevelopmental disorders. Anesthetic- and hyperoxia-induced neurotoxicity of the immature brain can lead to learning and behavioral disorders. Dexmedetomidine (DEX), which is associated with neuroprotective properties, is increasingly being studied for off-label use in the NICU. For this purpose, six-day-old Wistar rats (P6) were exposed to hyperoxia (80% O₂) or normoxia (21% O₂) for 24 h after DEX (5 µg/kg, i.p.) or vehicle (0.9% NaCl) application. An initial detection in the immature rat cerebellum was performed after the termination of hyperoxia at P7 and then after recovery in room air at P9, P11, and P14. Hyperoxia reduced the proportion of Calb1+-Purkinje cells and affected the dendrite length at P7 and/or P9/P11. Proliferating Pax6+-granule progenitors remained reduced after hyperoxia and until P14. The expression of neurotrophins and neuronal transcription factors/markers of proliferation, migration, and survival were also reduced by oxidative stress in different manners. DEX demonstrated protective effects on hyperoxia-injured Purkinje cells, and DEX without hyperoxia modulated neuronal transcription in the short term without any effects at the cellular level. DEX protects hyperoxia-damaged Purkinje cells and appears to differentially affect cerebellar granular cell neurogenesis following oxidative stress.
Keywords	air ; cerebellum ; cognitive development ; dexmedetomidine ; hyperoxia ; juveniles ; neurodevelopment ; neurogenesis ; neurons ; neurotoxicity ; neurotrophins ; normoxia ; oxidative stress ; protective effect ; rats
Language	English
Dates of publication	2023-0421
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12040980
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cardioprotective Effects of Dexmedetomidine in an Oxidative-Stress In Vitro Model of Neonatal Rat Cardiomyocytes

Borger, Moritz / von Haefen, Clarissa / Bührer, Christoph / Endesfelder, Stefanie

Antioxidants. 2023 June 02, v. 12, no. 6

2023

Abstract	Preterm birth is a risk factor for cardiometabolic disease. The preterm heart before terminal differentiation is in a phase that is crucial for the number and structure of cardiomyocytes in further development, with adverse effects of hypoxic and hyperoxic events. Pharmacological intervention could attenuate the negative effects of oxygen. Dexmedetomidine (DEX) is an α2-adrenoceptor agonist and has been mentioned in connection with cardio-protective benefits. In this study, H9c2 myocytes and primary fetal rat cardiomyocytes (NRCM) were cultured for 24 h under hypoxic condition (5% O₂), corresponding to fetal physioxia (pO₂ 32–45 mmHg), ambient oxygen (21% O₂, pO₂ ~150 mmHg), or hyperoxic conditions (80% O₂, pO₂ ~300 mmHg). Subsequently, the effects of DEX preconditioning (0.1 µM, 1 µM, 10 µM) were analyzed. Modulated oxygen tension reduced both proliferating cardiomyocytes and transcripts (CycD2). High-oxygen tension induced hypertrophy in H9c2 cells. Cell-death-associated transcripts for caspase-dependent apoptosis (Casp3/8) increased, whereas caspase-independent transcripts (AIF) increased in H9c2 cells and decreased in NRCMs. Autophagy-related mediators (Atg5/12) were induced in H9c2 under both oxygen conditions, whereas they were downregulated in NRCMs. DEX preconditioning protected H9c2 and NRCMs from oxidative stress through inhibition of transcription of the oxidative stress marker GCLC, and inhibited the transcription of both the redox-sensitive transcription factors Nrf2 under hyperoxia and Hif1α under hypoxia. In addition, DEX normalized the gene expression of Hippo-pathway mediators (YAP1, Tead1, Lats2, Cul7) that exhibited abnormalities due to differential oxygen tensions compared with normoxia, suggesting that DEX modulates the activation of the Hippo pathway. This, in the context of the protective impact of redox-sensitive factors, may provide a possible rationale for the cardio-protective effects of DEX in oxygen-modulated requirements on survival-promoting transcripts of immortalized and fetal cardiomyocytes.
Keywords	agonists ; apoptosis ; cardiomyocytes ; dexmedetomidine ; gene expression ; hyperoxia ; hypertrophy ; hypoxia ; models ; normoxia ; oxidative stress ; oxygen ; premature birth ; rats ; risk factors
Language	English
Dates of publication	2023-0602
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12061206
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Withdrawal: p14

Normand, Guillaume / Hemmati, Philipp G / Verdoodt, Berlinda / von Haefen, Clarissa / Wendt, Jana / Güner, Dilek / May, Evelyne / Dörken, Bernd / Daniel, Peter T

The Journal of biological chemistry

2023 Volume 299, Issue 4, Page(s) 104673

Language	English
Publishing date	2023-04-11
Publishing country	United States
Document type	Journal Article ; Retraction of Publication
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.104673
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Article ; Online: In a secondary analysis from a randomised, double-blind placebo-controlled trial Dexmedetomidine blocks cholinergic dysregulation in delirium pathogenesis in patients with major surgery.

Jacob, Yanite / Schneider, Bill / Spies, Claudia / Heinrich, Maria / von Haefen, Clarissa / Kho, Widuri / Pohrt, Anne / Müller, Anika

Scientific reports

2023 Volume 13, Issue 1, Page(s) 3971

Abstract: Dexmedetomidine is an alpha-2 adrenoreceptor agonist with anti-inflammatory and anti-delirogenic properties. Pathogenesis of postoperative delirium (POD) includes cholinergic dysfunction and deregulated inflammatory response to surgical trauma. ... ...

Abstract	Dexmedetomidine is an alpha-2 adrenoreceptor agonist with anti-inflammatory and anti-delirogenic properties. Pathogenesis of postoperative delirium (POD) includes cholinergic dysfunction and deregulated inflammatory response to surgical trauma. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are discussed as biomarkers for both POD and severity in acute inflammation. To show whether there is a link between blood cholinesterase activities and dexmedetomidine, we performed a secondary analysis of a randomised, double-blind, placebo-controlled trial that recently showed a lower incidence of POD in the dexmedetomidine group. Abdominal or cardiac surgical patients aged ≥ 60 years were randomised to receive dexmedetomidine or placebo intra- and postoperatively in addition to standard general anaesthesia. We analysed the course of perioperative cholinesterase activities of 56 patients, measured preoperatively and twice postoperatively. Dexmedetomidine resulted in no change in AChE activity and caused a rapid recovery of BChE activity after an initial decrease, while placebo showed a significant decrease in both cholinesterase activities. There were no significant between-group differences at any point in time. From these data it can be assumed that dexmedetomidine could alleviate POD via altering the cholinergic anti-inflammatory pathway (CAIP). We advocate for further investigations to show the direct connection between dexmedetomidine and cholinesterase activity.
MeSH term(s)	Humans ; Dexmedetomidine/pharmacology ; Dexmedetomidine/therapeutic use ; Acetylcholinesterase ; Butyrylcholinesterase ; Delirium/drug therapy ; Delirium/etiology ; Emergence Delirium/drug therapy ; Double-Blind Method
Chemical Substances	Dexmedetomidine (67VB76HONO) ; Acetylcholinesterase (EC 3.1.1.7) ; Butyrylcholinesterase (EC 3.1.1.8)
Language	English
Publishing date	2023-03-09
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-30756-z
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Article ; Online: Perioperative Levels of IL8 and IL18, but not IL6, are Associated with Nucleus Basalis Magnocellularis Atrophy Three Months after Surgery.

Heinrich, Maria / Spies, Claudia / Borchers, Friedrich / Feinkohl, Insa / Pischon, Tobias / Slooter, Arjen J C / von Haefen, Clarissa / Zacharias, Norman / Winterer, Georg / Lammers-Lietz, Florian

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

2024 Volume 19, Issue 1, Page(s) 10

Abstract: Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in ... ...

Abstract	Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).
MeSH term(s)	Humans ; Atrophy/pathology ; Basal Nucleus of Meynert/pathology ; Basal Nucleus of Meynert/physiology ; Inflammation/pathology ; Interleukin-18 ; Interleukin-8 ; Aged
Chemical Substances	Interleukin-18 ; Interleukin-8
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2227405-4
ISSN	1557-1904 ; 1557-1890
ISSN (online)	1557-1904
ISSN	1557-1890
DOI	10.1007/s11481-024-10110-4
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Article: Perioperative advanced haemodynamic monitoring of patients undergoing multivisceral debulking surgery: an observational pilot study.

Middel, Charlotte / Stetzuhn, Matthias / Sander, Nadine / Kalkbrenner, Björn / Tigges, Timo / Pielmus, Alexandru-Gabriel / Spies, Claudia / Pietzner, Klaus / Klum, Michael / von Haefen, Clarissa / Hunsicker, Oliver / Sehouli, Jalid / Konietschke, Frank / Feldheiser, Aarne

Intensive care medicine experimental

2023 Volume 11, Issue 1, Page(s) 61

Abstract: Background: Patients undergoing high-risk surgery show haemodynamic instability and an increased risk of morbidity. However, most of the available data concentrate on the intraoperative period. This study aims to characterise patients with advanced ... ...

Abstract	Background: Patients undergoing high-risk surgery show haemodynamic instability and an increased risk of morbidity. However, most of the available data concentrate on the intraoperative period. This study aims to characterise patients with advanced haemodynamic monitoring throughout the whole perioperative period using electrical cardiometry. Methods: In a prospective, observational, monocentric pilot study, electrical cardiometry measurements were obtained using an Osypka ICON™ monitor before surgery, during surgery, and repeatedly throughout the hospital stay for 30 patients with primary ovarian cancer undergoing multivisceral cytoreductive surgery. Severe postoperative complications according to the Clavien-Dindo classification were used as a grouping criterion. Results: The relative change from the baseline to the first intraoperative timepoint showed a reduced heart rate (HR, median - 19 [25-quartile - 26%; 75-quartile - 10%]%, p < 0.0001), stroke volume index (SVI, - 9.5 [- 15.3; 3.2]%, p = 0.0038), cardiac index (CI, - 24.5 [- 32; - 13]%, p < 0.0001) and index of contractility (- 17.5 [- 35.3; - 0.8]%, p < 0.0001). Throughout the perioperative course, patients had intraoperatively a reduced HR and CI (both p < 0.0001) and postoperatively an increased HR (p < 0.0001) and CI (p = 0.016), whereas SVI was unchanged. Thoracic fluid volume increased continuously versus preoperative values and did not normalise up to the day of discharge. Patients having postoperative complications showed a lower index of contractility (p = 0.0435) and a higher systolic time ratio (p = 0.0008) over the perioperative course in comparison to patients without complications, whereas the CI (p = 0.3337) was comparable between groups. One patient had to be excluded from data analysis for not receiving the planned surgery. Conclusions: Substantial decreases in HR, SVI, CI, and index of contractility occurred from the day before surgery to the first intraoperative timepoint. HR and CI were altered throughout the perioperative course. Patients with postoperative complications differed from patients without complications in the markers of cardiac function, a lower index of contractility and a lower SVI. The analyses of trends over the whole perioperative time course by using non-invasive technologies like EC seem to be useful to identify patients with altered haemodynamic parameters and therefore at an increased risk for postoperative complications after major surgery.
Language	English
Publishing date	2023-09-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2740385-3
ISSN	2197-425X
ISSN	2197-425X
DOI	10.1186/s40635-023-00543-1
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Article ; Online: Preoperative hypoalbuminaemia in liver surgery: an observational study at a university medical centre.

Kuhlmann, Anna Dorothea / Spies, Claudia / Schulte, Erika / Jara, Maximilian / von Haefen, Clarissa / Mertens, Mandy / Süß, Laura Anouk / Winkler, Nathalie / Lachmann, Gunnar / Lachmann, Cornelia

BMJ open

2023 Volume 13, Issue 5, Page(s) e068405

Abstract: Objectives: Preoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and orthopaedic surgery. However, much less is known about the association between ... ...

Abstract	Objectives: Preoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and orthopaedic surgery. However, much less is known about the association between preoperative serum albumin and clinical outcomes after liver surgery. In this study, we sought to determine whether hypoalbuminaemia before partial hepatectomy is associated with a worse postoperative outcome. Design: Observational study. Setting: University Medical Centre in Germany. Participants: We analysed 154 patients enrolled in the perioperative PHYsostigmine prophylaxis for liver resection patients at risk for DELIrium and postOperative cognitive dysfunction (PHYDELIO) trial with a preoperative serum albumin assessment. Hypoalbuminaemia was defined as serum albumin <35 g/L. Subgroups classified as hypoalbuminaemia and non-hypoalbuminaemia consisted of 32 (20.8%) and 122 (79.2%) patients, respectively. Outcome measures: The outcome parameters of interest were postoperative complications according to Clavien (moderate: I, II; major: ≥III), length of intensive care unit (ICU) stay, length of hospital stay and survival rates 1 year after surgery. Results: Preoperative hypoalbuminaemia was associated with the occurrence of major postoperative complications (OR 3.051 (95% CI 1.197 to 7.775); p=0.019) after adjusting for age, sex, randomisation, American Society of Anesthesiologists physical status, preoperative diagnosis and Child-Pugh class. Both ICU and hospital lengths of stay were significantly prolonged in patients with preoperative hypoalbuminaemia (OR 2.573 (95% CI 1.015 to 6.524); p=0.047 and OR 1.296 (95% CI 0.254 to 3.009); p=0.012, respectively). One-year survival was comparable between patients with and without hypoalbuminaemia. Conclusions: We found that low serum albumin before surgery was associated with a worse short-term outcome after partial hepatectomy, which strengthens the prognostic value of serum albumin in the setting of liver surgery. Trial registration numbers: ISRCTN18978802 and EudraCT 2008-007237-47.
MeSH term(s)	Humans ; Risk Factors ; Hypoalbuminemia/epidemiology ; Postoperative Complications/epidemiology ; Serum Albumin ; Liver ; Academic Medical Centers
Chemical Substances	Serum Albumin
Language	English
Publishing date	2023-05-18
Publishing country	England
Document type	Observational Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2022-068405
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