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Article ; Online: HERV-W envelope expression in blood leukocytes as a marker of disease severity of COVID-19.

Garcia-Montojo, Marta / Nath, Avindra

2021 Volume 67, Page(s) 103363

MeSH term(s)	Biomarkers/blood ; COVID-19/virology ; Gene Products, env ; Humans ; Leukocytes/virology ; Pregnancy Proteins ; SARS-CoV-2/genetics ; Viral Envelope Proteins/genetics
Chemical Substances	Biomarkers ; Gene Products, env ; Pregnancy Proteins ; Viral Envelope Proteins ; syncytin
Language	English
Publishing date	2021-05-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2021.103363
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Article ; Online: HERV-W envelope expression in blood leukocytes as a marker of disease severity of COVID-19

Marta Garcia-Montojo / Avindra Nath

EBioMedicine, Vol 67, Iss , Pp 103363- (2021)

2021

Keywords	Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Technical considerations in detection of HERV-K in amyotrophic lateral sclerosis: selection of controls and the perils of qPCR.

Garcia-Montojo, Marta / Li, Wenxue / Nath, Avindra

Acta neuropathologica communications

2019 Volume 7, Issue 1, Page(s) 101

MeSH term(s)	Amyotrophic Lateral Sclerosis ; Endogenous Retroviruses ; Humans ; Motor Cortex ; RNA ; Real-Time Polymerase Chain Reaction
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2019-07-03
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-019-0753-z
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Article ; Online: Retroviral Elements in Pathophysiology and as Therapeutic Targets for Amyotrophic Lateral Sclerosis.

Li, Wenxue / Pandya, Darshan / Pasternack, Nicholas / Garcia-Montojo, Marta / Henderson, Lisa / Kozak, Christine A / Nath, Avindra

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

2022 Volume 19, Issue 4, Page(s) 1085–1101

Abstract: The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical ... ...

Abstract	The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs.
MeSH term(s)	Humans ; Animals ; Mice ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/therapy ; DNA Transposable Elements ; Macaca mulatta/genetics ; Macaca mulatta/metabolism ; RNA, Small Interfering ; Endogenous Retroviruses/genetics ; Endogenous Retroviruses/metabolism ; HIV Infections/drug therapy ; HIV Infections/genetics ; Oligonucleotides, Antisense ; RNA-Directed DNA Polymerase/genetics ; RNA-Directed DNA Polymerase/metabolism
Chemical Substances	DNA Transposable Elements ; RNA, Small Interfering ; Oligonucleotides, Antisense ; RNA-Directed DNA Polymerase (EC 2.7.7.49)
Language	English
Publishing date	2022-04-12
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Intramural
ZDB-ID	2316693-9
ISSN	1878-7479 ; 1933-7213
ISSN (online)	1878-7479
ISSN	1933-7213
DOI	10.1007/s13311-022-01233-8
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Article ; Online: Antibody Response to HML-2 May Be Protective in Amyotrophic Lateral Sclerosis.

Garcia-Montojo, Marta / Simula, Elena Rita / Fathi, Saeed / McMahan, Cynthia / Ghosal, Anubrata / Berry, James D / Cudkowicz, Merit / Elkahloun, Abdel / Johnson, Kory / Norato, Gina / Jensen, Peter / James, Tony / Sechi, Leonardo A / Nath, Avindra

Annals of neurology

2022 Volume 92, Issue 5, Page(s) 782–792

Abstract: Objectives: Reactivation of HERV-K(HML-2) has been found in subsets of individuals with amyotrophic lateral sclerosis (ALS). This study examines the antibody response against HML-2 in ALS and analyzes its clinical relevance.: Methods: Antibodies to ... ...

Abstract	Objectives: Reactivation of HERV-K(HML-2) has been found in subsets of individuals with amyotrophic lateral sclerosis (ALS). This study examines the antibody response against HML-2 in ALS and analyzes its clinical relevance. Methods: Antibodies to HML-2 envelope (env) were analyzed using a peptide array for epitope mapping and by a peptide enzyme-linked immunosorbent assay (ELISA) in 242 healthy donors, and 243 ALS and 85 multiple sclerosis (MS) individuals. Extracellular levels of HML-2 were analyzed by digital polymerase chain reaction (PCR). Results: Antibodies in the sera of ALS individuals recognized more HML-2 env peptides compared to healthy controls (p < 0.0001). ALS individuals had higher levels of HML-2 than healthy donors (p = 0.02) and higher antibody levels against a select HML-2 env peptide compared to healthy donors or individuals with multiple sclerosis (p < 0.0001). 55.14% of ALS compared to 21.16% of healthy donors and 13.10% of MS individuals had antibodies against the HML-2 peptide (AUC = 0.769, p < 0.0001). Levels of extracellular HML-2 DNA in serum (p = 0.02) and the number of HML-2 env peptides recognized by ALS sera (p = 0.02) correlated with disease duration. Among ALS individuals, lower levels of HML-2 antibodies were associated with a definite diagnosis per EL Escorial criteria (p = 0.03), and with a lower predicted (p = 0.02) and observed survival (p = 0.03). Interpretation: There is a differential antibody response against specific epitopes of HML-2 env in ALS and controls, suggesting epitope spreading, likely due to persistent antigenic exposure following reactivation of the viral genes. Low levels of antibodies to HML-2 env in ALS are associated with poor prognosis and decreased survival probability. ANN NEUROL 2022;92:782-792.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/genetics ; Antibody Formation ; Epitopes ; Peptides ; Multiple Sclerosis
Chemical Substances	Epitopes ; Peptides
Language	English
Publishing date	2022-08-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.26466
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Article: Human endogenous retrovirus-K (HML-2): a comprehensive review

Garcia-Montojo, Marta / Doucet-O’Hare, Tara / Henderson, Lisa / Nath, Avindra

Critical reviews in microbiology. 2018 Nov. 2, v. 44, no. 6

2018

Abstract: The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically ... ...

Abstract	The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered “junk DNA” and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.
Keywords	Primates ; Retroviridae ; adults ; embryogenesis ; epigenetics ; genome ; human physiology ; humans ; neoplasms ; neurodegenerative diseases ; open reading frames ; pathogenesis ; phylogeny ; therapeutics ; transcription (genetics) ; translation (genetics) ; viruses
Language	English
Dates of publication	2018-1102
Size	p. 715-738.
Publishing place	Taylor & Francis
Document type	Article
ZDB-ID	1053620-6
ISSN	1549-7828 ; 1040-841X
ISSN (online)	1549-7828
ISSN	1040-841X
DOI	10.1080/1040841X.2018.1501345
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Article ; Online: Human endogenous retrovirus-K (HML-2): a comprehensive review.

Garcia-Montojo, Marta / Doucet-O'Hare, Tara / Henderson, Lisa / Nath, Avindra

Critical reviews in microbiology

2018 Volume 44, Issue 6, Page(s) 715–738

Abstract	The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered "junk DNA" and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.
MeSH term(s)	Animals ; Endogenous Retroviruses/classification ; Endogenous Retroviruses/genetics ; Endogenous Retroviruses/isolation & purification ; Endogenous Retroviruses/physiology ; Genome, Human ; Humans ; Retroviridae/classification ; Retroviridae/genetics ; Retroviridae/isolation & purification ; Retroviridae/physiology ; Retroviridae Infections/virology ; Virus Replication
Language	English
Publishing date	2018-10-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1053620-6
ISSN	1549-7828 ; 1040-841X
ISSN (online)	1549-7828
ISSN	1040-841X
DOI	10.1080/1040841X.2018.1501345
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Article ; Online: Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic.

Annals of neurology

2022 Volume 92, Issue 4, Page(s) 545–561

Abstract: Objective: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and ... ...

Abstract	Objective: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env. Methods: Env neurotoxicity was detected in ALS cerebrospinal fluid and confirmed using recombinant Env protein in a cell-based assay and a mouse model. The mechanism of neurotoxicity was assessed with immunoprecipitation followed by mass spectrometry and Western blot, and by screening a panel of inhibitors. Results: We observed that recombinant HML-2 Env protein caused neurotoxicity resulting in neuronal cell death, retraction of neurites, and decreased neuronal electrical activity. Injection of the Env protein into the brains of mice also resulted in neuronal cell death. HML-2 Env protein was also found in the cerebrospinal fluid of patients with sporadic ALS. The neurotoxic properties of the Env and the cerebrospinal fluid could be rescued with the anti-Env antibody. The Env was found to bind to CD98HC complexed to β1 integrin on the neuronal cell surface. Using a panel of compounds to screen for their ability to block Env-induced neurotoxicity, we found that several compounds were protective and are linked to the β1 integrin pathway. Interpretation: HERV-K Env is released extracellularly in ALS and causes neurotoxicity via a novel mechanism. Present results pave the way for new treatment strategies in sporadic ALS. ANN NEUROL 2022;92:545-561.
MeSH term(s)	Amyotrophic Lateral Sclerosis/genetics ; Animals ; Endogenous Retroviruses ; Gene Products, env ; Humans ; Integrin beta1 ; Mice ; Mice, Transgenic
Chemical Substances	Gene Products, env ; Integrin beta1
Language	English
Publishing date	2022-07-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	80362-5
ISSN	1531-8249 ; 0364-5134
ISSN (online)	1531-8249
ISSN	0364-5134
DOI	10.1002/ana.26452
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Article ; Online: Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma.

Shah, Ashish H / Rivas, Sarah R / Doucet-O'Hare, Tara T / Govindarajan, Vaidya / DeMarino, Catherine / Wang, Tongguang / Ampie, Leonel / Zhang, Yong / Banasavadi-Siddegowda, Yeshavanth Kumar / Walbridge, Stuart / Maric, Dragan / Garcia-Montojo, Marta / Suter, Robert K / Lee, Myoung-Hwa / Zaghloul, Kareem A / Steiner, Joseph / Elkahloun, Abdel G / Chandar, Jay / Seetharam, Deepa /

Desgraves, Jelisah / Li, Wenxue / Johnson, Kory / Ivan, Michael E / Komotar, Ricardo J / Gilbert, Mark R / Heiss, John D / Nath, Avindra

The Journal of clinical investigation

2023 Volume 133, Issue 13

Abstract: Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report ... ...

Abstract	Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor-like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models. Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2-specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.
MeSH term(s)	Humans ; Animals ; Mice ; Endogenous Retroviruses/genetics ; Glioblastoma/genetics ; Stem Cell Niche ; Proviruses/genetics
Language	English
Publishing date	2023-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI167929
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Article ; Online: Fingolimod Use for the Treatment of Multiple Sclerosis in a Clinical Practice Setting in Madrid.

Galán Sánchez-Seco, Victoria / Casanova-Peño, Ignacio / Álvarez-Lafuente, Roberto / Sánchez-Jiménez, Mónica / García-Martínez, Ángel / Domínguez-Mozo, María Inmaculada / Arias-Leal, Ana María / García-Montojo, Marta / Arroyo-González, Rafael

Clinical neuropharmacology

2017 Volume 40, Issue 1, Page(s) 29–33

Abstract: Objective: To assess the effectiveness and safety of fingolimod use in a Spanish clinical practice setting.: Methods: Retrospective study with multiple sclerosis patients who received at least 1 fingolimod dose between January 2004 and January 2015. ... ...

Abstract	Objective: To assess the effectiveness and safety of fingolimod use in a Spanish clinical practice setting. Methods: Retrospective study with multiple sclerosis patients who received at least 1 fingolimod dose between January 2004 and January 2015. Effectiveness and safety data were collected during the entire treatment of each patient. Analysis was performed for the total population and stratified according to prior treatment, sex, and age at treatment initiation. Results: A total of 167 patients were included, 50.9% had prior immunomodulator use, 33.5% natalizumab use, and 15.6% were naive patients. The annual relapse rate (ARR) decreased for the total population at month 12 (62%) and month 24 (84%) (P < 0.0001, in both cases); for naive patients (P < 0.05) and patients with prior immunomodulator use (P < 0.0001); for patients with prior natalizumab use, the ARR kept low after treatment initiation (0.23). After 24 months, the proportion of relapse-free patients was 70% or greater and disability progression-free patients was 80% or greater. No significant differences were observed when the results were compared by prior treatment, sex, or age. Thirty-two patients (19.2%) reported adverse drug reactions and 9.6% discontinued: 4.8% due to adverse drug reactions and 4.8% for lack of effectiveness. Conclusions: The results support fingolimod use due to clinical effectiveness, tolerability, and ease of administration.
MeSH term(s)	Adult ; Disability Evaluation ; Female ; Fingolimod Hydrochloride/therapeutic use ; Humans ; Immunosuppressive Agents/therapeutic use ; Male ; Middle Aged ; Multiple Sclerosis/drug therapy ; Recurrence ; Retrospective Studies ; Spain ; Time Factors ; Treatment Outcome
Chemical Substances	Immunosuppressive Agents ; Fingolimod Hydrochloride (G926EC510T)
Language	English
Publishing date	2017-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	199293-4
ISSN	1537-162X ; 0362-5664
ISSN (online)	1537-162X
ISSN	0362-5664
DOI	10.1097/WNF.0000000000000196
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