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Article: Subcortical and default mode network connectivity is impaired in myalgic encephalomyelitis/chronic fatigue syndrome.

Inderyas, Maira / Thapaliya, Kiran / Marshall-Gradisnik, Sonya / Barth, Markus / Barnden, Leighton

2024 Volume 17, Page(s) 1318094

Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic condition with core symptoms of fatigue and cognitive dysfunction, suggesting a key role for the central nervous system in the pathophysiology of this disease. Several ... ...

Abstract	Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic condition with core symptoms of fatigue and cognitive dysfunction, suggesting a key role for the central nervous system in the pathophysiology of this disease. Several studies have reported altered functional connectivity (FC) related to motor and cognitive deficits in ME/CFS patients. In this study, we compared functional connectivity differences between 31 ME/CFS and 15 healthy controls (HCs) using 7 Tesla MRI. Functional scans were acquired during a cognitive Stroop color-word task, and blood oxygen level-dependent (BOLD) time series were computed for 27 regions of interest (ROIs) in the cerebellum, brainstem, and salience and default mode networks. A region-based comparison detected reduced FC between the pontine nucleus and cerebellum vermis IX (
Language	English
Publishing date	2024-01-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1318094
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Article ; Online: Imbalanced Brain Neurochemicals in Long COVID and ME/CFS: A Preliminary Study Using MRI.

Thapaliya, Kiran / Marshall-Gradisnik, Sonya / Eaton-Fitch, Natalie / Eftekhari, Zeinab / Inderyas, Maira / Barnden, Leighton

The American journal of medicine

2024

Abstract: Purpose: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long ... ...

Abstract	Purpose: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures. Methods: Magnetic resonance spectroscopy data were acquired with a 3T Prisma magnetic resonance imaging scanner (Siemens Healthcare, Erlangen, Germany). We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n = 17), ME/CFS (n = 17), and healthy controls (n = 10) using Osprey software. The statistical analyses were performed using SPSS version 29 (IBM, Armonk, NY). Age and sex were included as nuisance covariates. Results: Glutamate levels were significantly higher in patients with long COVID (P = .02) and ME/CFS (P = .017) than in healthy controls. No significant difference was found between the 2 patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (P = .012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS. Conclusion: Our study identified significantly elevated glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the 2 patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.
Language	English
Publishing date	2024-04-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2024.04.007
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Article ; Online: Understanding myalgic encephalomyelitis.

Marshall-Gradisnik, Sonya / Eaton-Fitch, Natalie

Science (New York, N.Y.)

2022 Volume 377, Issue 6611, Page(s) 1150–1151

Abstract: Myalgic encephalomyelitis and Long Covid have overlapping presentation. ...

Abstract	Myalgic encephalomyelitis and Long Covid have overlapping presentation.
MeSH term(s)	COVID-19/complications ; Fatigue Syndrome, Chronic/diagnosis ; Fatigue Syndrome, Chronic/virology ; Humans
Language	English
Publishing date	2022-09-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abo1261
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Article ; Online: Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review.

Maksoud, Rebekah / Magawa, Chandi / Eaton-Fitch, Natalie / Thapaliya, Kiran / Marshall-Gradisnik, Sonya

BMC medicine

2023 Volume 21, Issue 1, Page(s) 189

Abstract: Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case ... ...

Abstract	Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case criteria following exclusion of any other potential medical conditions. While there are some studies that report potential biomarkers for ME/CFS, their efficacy has not been validated. The aim of this systematic review is to collate and appraise literature pertaining to a potential biomarker(s) which may effectively differentiate ME/CFS patients from healthy controls. Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane review guidelines. PubMed, Embase and Scopus were systematically searched for articles containing "biomarker" and "ME/CFS" keywords in the abstract or title and if they included the following criteria: (1) were observational studies published between December 1994 and April 2022; (2) involved adult human participants; (3) full text is available in English (4) original research; (5) diagnosis of ME/CFS patients made according to the Fukuda criteria (1994), Canadian Consensus Criteria (2003), International Consensus Criteria (2011) or Institute of Medicine Criteria (2015); (6) study investigated potential biomarkers of ME/CFS compared to healthy controls. Quality and Bias were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. Results: A total of 101 publications were included in this systematic review. Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%), endovascular/circulatory (17.82%), neurological (7.92%), ion channel (8.91%) and physical dysfunction biomarkers (8.91%). Most of the potential biomarkers reported were blood-based (79.2%). Use of lymphocytes as a model to investigate ME/CFS pathology was prominent among immune-based biomarkers. Most biomarkers had secondary (43.56%) or tertiary (54.47%) selectivity, which is the ability for the biomarker to identify a disease-causing agent, and a moderate (59.40%) to complex (39.60%) ease-of-detection, including the requirement of specialised equipment. Conclusions: All potential ME/CFS biomarkers differed in efficiency, quality, and translatability as a diagnostic marker. Reproducibility of findings between the included publications were limited, however, several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness. The heterogeneity shown across many of the included studies highlights the need for multidisciplinary research and uniform protocols in ME/CFS biomarker research.
MeSH term(s)	United States ; Adult ; Humans ; Canada ; Fatigue Syndrome, Chronic/diagnosis ; Reproducibility of Results ; Academies and Institutes ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-05-24
Publishing country	England
Document type	Systematic Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2131669-7
ISSN	1741-7015 ; 1741-7015
ISSN (online)	1741-7015
ISSN	1741-7015
DOI	10.1186/s12916-023-02893-9
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Article: Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients.

Thapaliya, Kiran / Marshall-Gradisnik, Sonya / Barth, Markus / Eaton-Fitch, Natalie / Barnden, Leighton

Frontiers in neuroscience

2023 Volume 17, Page(s) 1125208

Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID ( ... ...

Abstract	Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID (WHO Delphi consensus), and 10 healthy control (HC) subjects on 3D, T1-weighted MRI images acquired using sub-millimeter isotropic resolution using an ultra-high field strength of 7 Tesla. Group comparisons with HC detected significantly larger volumes in ME/CFS for pons (
Language	English
Publishing date	2023-03-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1125208
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Article: Altered brain connectivity in Long Covid during cognitive exertion: a pilot study.

Barnden, Leighton / Thapaliya, Kiran / Eaton-Fitch, Natalie / Barth, Markus / Marshall-Gradisnik, Sonya

Frontiers in neuroscience

2023 Volume 17, Page(s) 1182607

Abstract: Introduction: Debilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection.: Methods: Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) ... ...

Abstract	Introduction: Debilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection. Methods: Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to-ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores. Results: Two ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI. Discussion: Multiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep-wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov.
Language	English
Publishing date	2023-06-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1182607
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Article ; Online: Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Du Preez, Stanley / Eaton-Fitch, Natalie / Smith, Peter K / Marshall-Gradisnik, Sonya

Biomolecules

2023 Volume 13, Issue 7

Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. ... ...

Abstract	Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca
MeSH term(s)	Humans ; Fatigue Syndrome, Chronic ; Calcium/metabolism ; TRPM Cation Channels ; Killer Cells, Natural/metabolism ; Transient Receptor Potential Channels ; Protein Serine-Threonine Kinases
Chemical Substances	Calcium (SY7Q814VUP) ; TRPM Cation Channels ; Transient Receptor Potential Channels ; TRPM7 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-06-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13071039
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Article ; Online: A systematic review and meta-analysis of urinary biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Taccori, Asher / Maksoud, Rebekah / Eaton-Fitch, Natalie / Patel, Maharshi / Marshall-Gradisnik, Sonya

Journal of translational medicine

2023 Volume 21, Issue 1, Page(s) 440

Abstract: Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic ... ...

Abstract	Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness that affects many body systems including the immune, nervous, endocrine, cardiovascular, and urinary systems. There is currently no universal diagnostic marker or targeted treatment for ME/CFS. Urine is a non-invasive sample that provides biomarkers that may have the potential to be used in a diagnostic capacity for ME/CFS. While there are several studies investigating urine-based biomarkers for ME/CFS, there are no published systematic reviews to summarise existing evidence of these markers. The aim of this systematic review was to compile and appraise literature on urinary-based biomarkers in ME/CFS patients compared with healthy controls. Methods: Three databases: Embase, PubMed, and Scopus were searched for articles pertaining to urinary biomarkers for ME/CFS compared with healthy controls published between December 1994 to December 2022. The final articles included in this review were determined through application of specific inclusion and exclusion criteria. Quality and bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. A meta-analysis according to Cochrane guidelines was conducted on select studies, in particular, those that investigate urinary free cortisol levels in ME/CFS patients compared to healthy controls using the program STATA 17. Results: Twenty-one studies were included in this review. All of the studies investigated urinary-based markers in ME/CFS patients compared with healthy controls. The reported changes in urinary outputs include urinary free cortisol (38.10%), carnitine (28.6%), iodine (4.76%), and the metabolome (42.86%). In most cases, there was minimal overlap in the main outcomes measured across the studies, however, differences in urinary free cortisol between ME/CFS patients and healthy controls were commonly reported. Seven studies investigating urinary free cortisol were included in the meta-analysis. While there were significant differences found in urinary free cortisol levels in ME/CFS patients, there was also substantial heterogeneity across the included studies that makes drawing conclusions difficult. Conclusions: There is limited evidence suggesting a consistent and specific potential urinary-based biomarker for ME/CFS. Further investigations using more standardised methodologies and more stringent case criteria may be able to identify pathophysiological differences with diagnostic potential in ME/CFS patients compared with healthy controls.
MeSH term(s)	Humans ; Biomarkers/urine ; Fatigue Syndrome, Chronic/complications ; Fatigue Syndrome, Chronic/diagnosis ; Fatigue Syndrome, Chronic/urine ; Hydrocortisone/urine
Chemical Substances	Biomarkers ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2023-07-05
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Review ; Systematic Review
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-023-04295-0
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Article ; Online: Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target.

Sasso, Etianne Martini / Muraki, Katsuhiko / Eaton-Fitch, Natalie / Smith, Peter / Jeremijenko, Andrew / Griffin, Paul / Marshall-Gradisnik, Sonya

Frontiers in immunology

2024 Volume 15, Page(s) 1264702

Abstract: Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/ ... ...

Abstract	Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells. This research aimed to: i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS; and ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients. Methods: Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition ( Results: This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients. Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC. Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX. Discussion: Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients. This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after
MeSH term(s)	Humans ; TRPM Cation Channels/metabolism ; COVID-19/immunology ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Adult ; Male ; Middle Aged ; Female ; Naltrexone/pharmacology ; Naltrexone/therapeutic use ; SARS-CoV-2/physiology ; Fatigue Syndrome, Chronic/drug therapy ; Fatigue Syndrome, Chronic/immunology ; Patch-Clamp Techniques ; COVID-19 Drug Treatment
Chemical Substances	TRPM3 protein, human
Language	English
Publishing date	2024-05-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1264702
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Article ; Online: Health-related quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndrome: an Australian cross-sectional study.

Eaton-Fitch, N / Johnston, S C / Zalewski, P / Staines, D / Marshall-Gradisnik, S

Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation

2020 Volume 29, Issue 6, Page(s) 1521–1531

Abstract: Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient ... ...

Abstract	Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS. Methods: Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL. Results: Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties. Conclusion: This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.
MeSH term(s)	Australia ; Cross-Sectional Studies ; Fatigue Syndrome, Chronic/psychology ; Female ; Humans ; Male ; Middle Aged ; Quality of Life/psychology
Language	English
Publishing date	2020-01-22
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1161148-0
ISSN	1573-2649 ; 0962-9343
ISSN (online)	1573-2649
ISSN	0962-9343
DOI	10.1007/s11136-019-02411-6
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