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Article: The bioactive dietary polyphenol preparation alleviates depression and anxiety-like behaviors by modulating the regional heterogeneity of microglia morphology.

Yang, Eun-Jeong / Frolinger, Tal / Westfall, Susan / Iqbal, Umar Haris / Murrough, James / Pasinetti, Giulio M

bioRxiv : the preprint server for biology

2023

Abstract: Scope: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and ... ...

Abstract	Scope: The goal of this study is to investigate the effects of a bioactive dietary polyphenol preparation (BDPP), which is made up of grape-derived polyphenols, on microglial responses, as well as the underlying molecular mechanisms in depression and anxiety-like behaviors. Methods and results: We find that treatment with BDPP significantly decreased depression-like and anxiety-like behaviors induced by chronic stress in mice, while leaving their locomotor activity unaffected. We also find that BDPP treatment reversed microglia activation in the amygdala and hippocampal formation, regions of the brain involved in emotional regulation, from an amoeboid shape to ramified shape. Additionally, BDPP treatment modulates the release of pro-inflammatory cytokines such as interleukin-6 via high mobility box 1 protein and the receptor for advanced glycation end products (HMGB1-RAGE) signaling pathway in activated microglia induced by chronic stress. Conclusion: Our findings suggest regional heterogeneity in microglial responses following chronic stress in subregions of the corticolimbic circuit. Specifically, activation of the immune-inflammatory HMGB1-RAGE pathway might provide a new avenue for therapeutic intervention in stress-induced anxiety- and depression-like behavior, using bioactive and bioavailable polyphenols.
Language	English
Publishing date	2023-03-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.30.534961
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Article: The Gut Microbiota Links Dietary Polyphenols With Management of Psychiatric Mood Disorders.

Westfall, Susan / Pasinetti, Giulio Maria

Frontiers in neuroscience

2019 Volume 13, Page(s) 1196

Abstract: The pathophysiology of depression is multifactorial yet generally aggravated by stress and its associated physiological consequences. To effectively treat these diverse risk factors, a broad acting strategy is required and is has been suggested that gut- ... ...

Abstract	The pathophysiology of depression is multifactorial yet generally aggravated by stress and its associated physiological consequences. To effectively treat these diverse risk factors, a broad acting strategy is required and is has been suggested that gut-brain-axis signaling may play a pinnacle role in promoting resilience to several of these stress-induced changes including pathogenic load, inflammation, HPA-axis activation, oxidative stress and neurotransmitter imbalances. The gut microbiota also manages the bioaccessibility of phenolic metabolites from dietary polyphenols whose multiple beneficial properties have known therapeutic efficacy against depression. Although several potential therapeutic mechanisms of dietary polyphenols toward establishing cognitive resilience to neuropsychiatric disorders have been established, only a handful of studies have systematically identified how the interaction of the gut microbiota with dietary polyphenols can synergistically alleviate the biological signatures of depression. The current review investigates several of these potential mechanisms and how synbiotics, that combine probiotics with dietary polyphenols, may provide a novel therapeutic strategy for depression. In particular, synbiotics have the potential to alleviate neuroinflammation by modulating microglial and inflammasome activation, reduce oxidative stress and balance serotonin metabolism therefore simultaneously targeting several of the major pathological risk factors of depression. Overall, synbiotics may act as a novel therapeutic paradigm for neuropsychiatric disorders and further understanding the fundamental mechanisms of gut-brain-axis signaling will allow full utilization of the gut microbiota's as a therapeutic tool.
Language	English
Publishing date	2019-11-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2019.01196
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Article: Design of a Novel Synbiotic Formulation to Optimize Gut-derived Phenolic Acid Mediated Gut-brain Axis Signals for the Treatment of Stress-induced Depression and Anxiety (OR23-03-19)

Westfall, Susan / Pasinetti, Giulio

Current developments in nutrition. 2019 June 13, v. 3, no. Supplement_1

2019

Abstract: Synbiotics, the combination of probiotics and prebiotics, may optimize the production of polyphenolic metabolites, and act as therapeutic agents for inflammation-induced depression. Recent evidence suggests that dysregulated immune activity increases ... ...

Abstract	Synbiotics, the combination of probiotics and prebiotics, may optimize the production of polyphenolic metabolites, and act as therapeutic agents for inflammation-induced depression. Recent evidence suggests that dysregulated immune activity increases susceptibility to depression and that bioactive polyphenolic metabolites can effectively reduce that inflammation. The problem remains that bioactive metabolite production is dependent on the gut microbiota, leading to significant interpersonal variation in the metabolites’ therapeutic efficacy. The hypothesis of the study is that the synbiotic will standardize production and bioavailability of bioactive metabolites capable of suppressing innate immune biological signatures of depression. To standardize the production of bioactive metabolites, the synbiotic will be designed in an innovative in vitro model of the human gastrointestinal tract using a multivariate regression algorithm to predict which probiotic formulation produces the most effective bioactive metabolites. Following in vivo bioavailability and toxicity testing, the synbiotic's therapeutic efficacy was tested in a chronic unpredictable stress (CUS) mouse model of depression by measuring specific behaviors and changes to the gut microbiota populations. These changes were correlated to biological markers of depression modulated by the synbiotic-derived metabolites including neurobiological markers of depression and variations in innate immune markers, including interleukin-1β (IL-1β). In this study, we show that a synbiotic combining a dietary polyphenolic preparation with L. plantarum and B. longum can potentiate the reduction in anxiety and depression in male mice subjected to a 28 day CUS protocol, as compared to polyphenolic treatment alone. Interestingly, we found that the synbiotic may mediate microglia inflammasome activation. This finding was reflected by inhibition of NLRP3-mediated generation of IL-1β in microglia. Collectively, these results support the potential role of a synbiotic in the potentiation of attenuation of psychological impairment in a model of depression through mechanisms that involved innate immune NLRP3 inflammation mediation in microglia. This project was funding a P50 CARBON Center grant from the NCCIH/ODS (Pasinetti, PD/PI).
Keywords	algorithms ; animal models ; anxiety ; bioavailability ; biomarkers ; gastrointestinal system ; inflammasomes ; inflammation ; interleukin-1beta ; intestinal microorganisms ; males ; metabolites ; mice ; neuroglia ; phenolic acids ; prebiotics ; probiotics ; therapeutics ; toxicity testing
Language	English
Dates of publication	2019-0613
Publishing place	Oxford University Press
Document type	Article
ISSN	2475-2991
DOI	10.1093/cdn/nzz040.OR23-03-19
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Investigation of Potential Brain Microbiome in Alzheimer's Disease: Implications of Study Bias.

Westfall, Susan / Dinh, Duy M / Pasinetti, Giulio Maria

Journal of Alzheimer's disease : JAD

2020 Volume 75, Issue 2, Page(s) 559–570

Abstract: Background: Dysbiotic microbiota in the gastrointestinal tract promotes and aggravates neurodegenerative disorders. Alzheimer's disease (AD) has been shown to correlate to dysbiotic bacteria and the immune, metabolic, and endocrine abnormalities ... ...

Abstract	Background: Dysbiotic microbiota in the gastrointestinal tract promotes and aggravates neurodegenerative disorders. Alzheimer's disease (AD) has been shown to correlate to dysbiotic bacteria and the immune, metabolic, and endocrine abnormalities associated with abnormal gut-brain-axis signaling. Recent reports also indicate that brain dysbacteriosis may play a role in AD pathogenesis. Objective: To evaluate the presence and differences of brain-region dependent microbiomes in control and AD subjects and the contribution of study bias. Methods: Two independent cohorts of postmortem AD brain samples were collected from separate locations, processed with different extraction protocols and investigated for the presence of bacterial DNA indicative of a brain microbiome with V4 16S next generation sequencing. Results: In both cohorts, few differences between the control and AD groups were observed in terms of alpha and beta diversities, phyla and genera proportions. Independent of study in both AD and control subjects the most abundant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Variations in beta diversity between hippocampal and cerebellum samples were observed indicating an impact of brain region on the presence of microbial DNA. Importantly, differences in alpha and beta diversities between the two independent cohorts were found indicating a significant cohort- and processing-dependent effect on the microbiome. Finally, there were cohort-specific correlations between the gut microbiome and subject demographics indicate that postmortem interval may have a significant impact on brain microbiome determination. Conclusions: Regardless of the study bias, this study concludes that bacterial DNA can be isolated from the human brain suggesting that a brain microbiome may exist; however, more studies are required to understand the variation in AD.
MeSH term(s)	Alzheimer Disease/microbiology ; Brain/microbiology ; Dysbiosis/microbiology ; Female ; Humans ; Male ; Microbiota ; Nerve Degeneration/microbiology
Language	English
Publishing date	2020-04-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-191328
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Article ; Online: Synthesis and characterization of peptide conjugated human serum albumin nanoparticles for targeted cardiac uptake and drug delivery.

Lomis, Nikita / Westfall, Susan / Shum-Tim, Dominique / Prakash, Satya

PloS one

2021 Volume 16, Issue 9, Page(s) e0254305

Abstract: Congestive heart failure, a prominent cardiovascular disease results primarily from myocardial infarction or ischemia. Milrinone (MRN), a widely used clinical drug for heart failure, improves myocardial contractility and cardiac function through its ... ...

Abstract	Congestive heart failure, a prominent cardiovascular disease results primarily from myocardial infarction or ischemia. Milrinone (MRN), a widely used clinical drug for heart failure, improves myocardial contractility and cardiac function through its inotropic and vasodilatory effects. However, lacking target specificity, it exhibits low bioavailability and lower body retention time. Therefore, in this study, angiotensin II (AT1) peptide conjugated human serum albumin nanoparticles (AT1-HSA-MRN-NPs) have been synthesized for targeted delivery of MRN to the myocardium, overexpressing AT1 receptors under heart failure. The NPs were surface functionalized through a covalent conjugation reaction between HSA and AT1. Nanoparticle size was 215.2±4.7 nm and zeta potential -28.8±2.7 mV and cumulative release of MRN was ~72% over 24 hrs. The intracellular uptake of nanoparticles and cell viability was studied in H9c2 cells treated with AT1-MRN-HSA-NPs vs the control non-targeted drug, MRN Lactate under normal, hypoxic and hypertrophic conditions. The uptake of AT1-HSA-MRN-NPs in H9c2 cells was significantly higher as compared to non-targeted nanoparticles, and the viability of H9c2 cells treated with AT1-MRN-HSA-NPs vs MRN Lactate was 73.4±1.4% vs 44.9±1.4%, respectively. Therefore, AT1-HSA-MRN-NPs are safe for in vivo use and exhibit superior targeting and drug delivery characteristics for treatment of heart failure.
MeSH term(s)	Animals ; Biological Transport ; Cardiotonic Agents/chemistry ; Cardiotonic Agents/pharmacology ; Cell Survival ; Drug Carriers ; Drug Delivery Systems ; Humans ; Milrinone/chemistry ; Milrinone/pharmacology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Peptide Fragments/chemistry ; Peptide Fragments/pharmacology ; Rats ; Serum Albumin, Human/chemistry
Chemical Substances	Cardiotonic Agents ; Drug Carriers ; Peptide Fragments ; Milrinone (JU9YAX04C7) ; Serum Albumin, Human (ZIF514RVZR)
Language	English
Publishing date	2021-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0254305
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Article ; Online: One year of COVID: primary care learning experiences in a health system.

Erickson, Rodney / Westfall, Erin / Chavez, Augustine / Laabs, Susan / Thacher, Thomas / DeJesus, Ramona

Annals of family medicine

2022 , Issue 20 Suppl 1

Abstract: Context: Patients and communities consider their primary care clinicians (PCC's) to be their most trusted source of information. During the first 12 months of the COVID pandemic, initially reliable, accurate information was scare, evolving, and at times ... ...

Abstract	Context: Patients and communities consider their primary care clinicians (PCC's) to be their most trusted source of information. During the first 12 months of the COVID pandemic, initially reliable, accurate information was scare, evolving, and at times conflicting. From testing, public health prevention, treatment, and vaccinations clinicians had to learn, apply, and convey this information honestly and openly. Objective: This was a survey of a health system's PCC's after the first year of the pandemic. The objective was to determine the clinical, educational, and advisory roles performed by PCC's and the sources of from which PCC's obtained the information necessary to fulfill these roles. Study Design: An intranet survey was sent to members of the system's primary care learning collaborative. Questions were multiple answer with options for open-ended answers. Setting: Large health system. Population: Learning collaborative membership consisting of physicians, nurse practitioners (NP), and physician assistants (PA). Instrument: Brief intranet survey. Outcome measures: Identify clinical and educational roles for PCC. Results: 192 surveys were sent; 109 responses; 72% physicians, 28% NP/PA. 25 unique clinical roles were identified. Most common: discuss vaccine (94%), work excuse/return to work (88%), outpatient care (87%), virtual assessment for COVID (74%). 14 unique educational or advisory roles were identified; the most common being teaching residents (45%) or students (42%), lecture/discussion on COVID (20%) or vaccines (22%) or advising community groups (18%). Sources of information related to COVID were diverse. When asked to identify the three most relied on sources, system (internal COVID website or disseminated by system) (83%), colleagues (34%), and consultants (33%), were the most common source. CME was the least relied upon (7%). Frequently the system utilized information from CDC, state/local health department information along with national organizations. Conclusions: During the pandemic, primary care clinicians provided a broad array of clinical services, and are a source of information for colleagues, patients, and communities. They rely on a broad array of sources for reliable information, mostly relationship-based, not formal CME. The trusted relationships primary care clinicians have with others throughout their communities was essential in promulgating accurate reliable information during the first year of the pandemic.
MeSH term(s)	Humans ; COVID-19/epidemiology ; COVID-19/prevention & control ; Learning ; Delivery of Health Care ; Vaccination ; Primary Health Care
Language	English
Publishing date	2022-04-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2171425-3
ISSN	1544-1717 ; 1544-1709
ISSN (online)	1544-1717
ISSN	1544-1709
DOI	10.1370/afm.20.s1.2780
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Article ; Online: A novel synbiotic delays Alzheimer's disease onset via combinatorial gut-brain-axis signaling in Drosophila melanogaster.

Westfall, Susan / Lomis, Nikita / Prakash, Satya

PloS one

2019 Volume 14, Issue 4, Page(s) e0214985

Abstract: The gut-brain-axis (GBA) describing the bidirectional communication between the gut microbiota and brain was recently implicated in Alzheimer's disease (AD). The current study describes a novel synbiotic containing three metabolically active probiotics ... ...

Abstract	The gut-brain-axis (GBA) describing the bidirectional communication between the gut microbiota and brain was recently implicated in Alzheimer's disease (AD). The current study describes a novel synbiotic containing three metabolically active probiotics and a novel polyphenol-rich prebiotic which has beneficial impacts on the onset and progression of AD. In a transgenic humanized Drosophila melanogaster model of AD, the synbiotic increased survivability and motility and rescued amyloid beta deposition and acetylcholinesterase activity. Such drastic effects were due to the synbiotic's combinatorial action on GBA signaling pathways including metabolic stability, immune signaling, oxidative and mitochondrial stress possibly through pathways implicating PPARγ. Overall, this study shows that the therapeutic potential of GBA signaling is best harnessed in a synbiotic that simultaneously targets multiple risk factors of AD.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/microbiology ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Animals ; Animals, Genetically Modified ; Brain/metabolism ; Brain/pathology ; Disease Models, Animal ; Drosophila melanogaster ; Gastrointestinal Tract/metabolism ; Gastrointestinal Tract/microbiology ; Gastrointestinal Tract/pathology ; Humans ; Prebiotics ; Probiotics/pharmacology ; Signal Transduction
Chemical Substances	Amyloid beta-Peptides ; Prebiotics
Language	English
Publishing date	2019-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0214985
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Article ; Online: PaCE Builds on the Tradition of Responsible Research Within NAPCRG.

Haeme, Raymond / Felzien, Maret / Kelly, Kirk / Lowe, Susan / Martinez-Guijosa, Arturo / Mason, Kirk / Kaplan, David / LeMaster, Joseph / Westfall, John M / Pavilanis, Alan / Templeton, Anna / Haddad, Leyla / Ramsden, Vivian R

Annals of family medicine

2023 Volume 21, Issue 6, Page(s) 562–563

MeSH term(s)	Humans ; Family Practice ; Primary Health Care
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2171425-3
ISSN	1544-1717 ; 1544-1709
ISSN (online)	1544-1717
ISSN	1544-1709
DOI	10.1370/afm.3063
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Article ; Online: Synthesis and characterization of peptide conjugated human serum albumin nanoparticles for targeted cardiac uptake and drug delivery.

Nikita Lomis / Susan Westfall / Dominique Shum-Tim / Satya Prakash

PLoS ONE, Vol 16, Iss 9, p e

2021 Volume 0254305

Abstract	Congestive heart failure, a prominent cardiovascular disease results primarily from myocardial infarction or ischemia. Milrinone (MRN), a widely used clinical drug for heart failure, improves myocardial contractility and cardiac function through its inotropic and vasodilatory effects. However, lacking target specificity, it exhibits low bioavailability and lower body retention time. Therefore, in this study, angiotensin II (AT1) peptide conjugated human serum albumin nanoparticles (AT1-HSA-MRN-NPs) have been synthesized for targeted delivery of MRN to the myocardium, overexpressing AT1 receptors under heart failure. The NPs were surface functionalized through a covalent conjugation reaction between HSA and AT1. Nanoparticle size was 215.2±4.7 nm and zeta potential -28.8±2.7 mV and cumulative release of MRN was ~72% over 24 hrs. The intracellular uptake of nanoparticles and cell viability was studied in H9c2 cells treated with AT1-MRN-HSA-NPs vs the control non-targeted drug, MRN Lactate under normal, hypoxic and hypertrophic conditions. The uptake of AT1-HSA-MRN-NPs in H9c2 cells was significantly higher as compared to non-targeted nanoparticles, and the viability of H9c2 cells treated with AT1-MRN-HSA-NPs vs MRN Lactate was 73.4±1.4% vs 44.9±1.4%, respectively. Therefore, AT1-HSA-MRN-NPs are safe for in vivo use and exhibit superior targeting and drug delivery characteristics for treatment of heart failure.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Albumin Nanoparticle Formulation for Heart-Targeted Drug Delivery: In Vivo Assessment of Congestive Heart Failure.

Lomis, Nikita / Sarfaraz, Ziyab K / Alruwaih, Aiman / Westfall, Susan / Shum-Tim, Dominique / Prakash, Satya

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 7

Abstract: Congestive heart failure is a fatal cardiovascular disease resulting in tissue necrosis and loss of cardiac contractile function. Inotropic drugs such as milrinone are commonly used to improve the myocardial contractility and heart function. However, ... ...

Abstract	Congestive heart failure is a fatal cardiovascular disease resulting in tissue necrosis and loss of cardiac contractile function. Inotropic drugs such as milrinone are commonly used to improve the myocardial contractility and heart function. However, milrinone is associated with severe side effects and lower circulation time. In this article, a novel protein nanoparticle formulation for heart-targeted delivery of milrinone has been designed and tested. The formulation was prepared using albumin protein conjugated with the targeting ligand, angiotensin II peptide to form nanoparticles following the ethanol desolvation method. The formulation was characterized for size, charge, and morphology and tested in a rat model of congestive heart failure to study pharmacokinetics, biodistribution, and efficacy. The overall cardiac output parameters were evaluated comparing the formulation with the control non-targeted drug, milrinone lactate. This formulation exhibited improved pharmacokinetics with a mean retention time of 123.7 min, half-life of 101.3 min, and clearance rate of 0.24 L/(kg*h). The targeted formulation also significantly improved ejection fraction and fractional shortening parameters thus improving cardiac function. This study demonstrates a new approach in delivering inotropic drugs such as milrinone for superior treatment of congestive heart failure.
Language	English
Publishing date	2021-07-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14070697
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