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Vumma, Ravi
Publications (10 of 11) Show all publications
Pernow, Y., Shahror, R., Acharya, S., Jahnson, L., Vumma, R. & Venizelos, N. (2018). Aberrant tryptophan transport in cultured fibroblast from patients with Male Idiopathic Osteoporosis: an in vitro study. Bone Reports, 8, 25-28
Open this publication in new window or tab >>Aberrant tryptophan transport in cultured fibroblast from patients with Male Idiopathic Osteoporosis: an in vitro study
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2018 (English)In: Bone Reports, ISSN 2352-1872, Vol. 8, p. 25-28Article in journal (Refereed) Published
Abstract [en]

It has been demonstrated, that long-term chronic tryptophan deficiency, results in decreased serotonin synthesis, which may lead to low bone mass and low bone formation. Findings from studies in male patients with idiopathic osteoporosis suggested a decreased transport of tryptophan in erythrocytes of osteoporotic patients, indicating that serotonin system defects may be involved in the etiology of low bone mass. Tryptophan is the precursor of serotonin, and a disturbed transport of tryptophan is implicated in altered serotonin synthesis. However, no study has investigated the tryptophan transport kinetics in MIO patients. The aim of this study is to investigate the kinetic parameters of tryptophan transport in fibroblasts derived from MIO patients compared to age and sex matched controls.

Fibroblast cells were cultured from skin biopsies obtained from 14 patients diagnosed with Male Idiopathic Osteoporosis and from 13 healthy age-sex matched controls, without a diagnosis of osteoporosis. Transport of the amino acid tryptophan across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax) and affinity constant (Km) were determined by using the Lineweaver-Burke plot equation.

The results of this study have shown a significantly lower mean value for Vmax (p = 0.0138) and lower Km mean value (p = 0.0009) of tryptophan transport in fibroblasts of MIO patients compared to the control group. A lower Vmax implied a decreased tryptophan transport availability in MIO patients.

In conclusion, reduced cellular tryptophan availability in MIO patients might result in reduced brain serotonin synthesis and its endogenous levels in peripheral tissues, and this may contribute to low bone mass/formation. The findings of the present study could contribute to the etiology of idiopathic osteoporosis and for the development of novel approaches for diagnosis, treatment and management strategies of MIO.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Amino acid transport, Fibroblasts, Male Idiopathic Osteoporosis, Serotonin, Tryptophan
National Category
Rheumatology and Autoimmunity
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-71433 (URN)10.1016/j.bonr.2018.01.002 (DOI)29379847 (PubMedID)
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-11-01Bibliographically approved
Wall, R., Marques, T., Edebol-Carlman, H., Sundin, J., Vumma, R., Rangel, I. & Brummer, R. (2017). Altered expression of membrane transporters in colonic mucosa of patients with Irritable Bowel Syndrome (IBS) and Post-infectious (PI)-IBS compared to healthy subjects. Paper presented at NeuroGASTRO 2017 Congress, 24-26 August 2017, Cork, Ireland. Neurogastroenterology and Motility, 29(Supplement 2), 107-108, Article ID 219.
Open this publication in new window or tab >>Altered expression of membrane transporters in colonic mucosa of patients with Irritable Bowel Syndrome (IBS) and Post-infectious (PI)-IBS compared to healthy subjects
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2017 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no Supplement 2, p. 107-108, article id 219Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Wiley-Blackwell, 2017
National Category
Gastroenterology and Hepatology
Research subject
Natural Science, Medicine
Identifiers
urn:nbn:se:lnu:diva-67846 (URN)000407643600220 ()
Conference
NeuroGASTRO 2017 Congress, 24-26 August 2017, Cork, Ireland
Available from: 2017-09-07 Created: 2017-09-07 Last updated: 2017-09-07Bibliographically approved
Vumma, R., Johansson, J. & Venizelos, N. (2017). Proinflammatory cytokines and oxidative stress decrease the transport of dopamine precursor tyrosine in human fibroblasts. Neuropsychobiology, 75(4), 178-184
Open this publication in new window or tab >>Proinflammatory cytokines and oxidative stress decrease the transport of dopamine precursor tyrosine in human fibroblasts
2017 (English)In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 75, no 4, p. 178-184Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated.

AIMS: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts.

METHODS: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of 14C-tyrosine compared to untreated controls.

RESULTS AND CONCLUSION: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.

Place, publisher, year, edition, pages
S. Karger, 2017
Keywords
Dopamine precursor, Human fibroblasts, Neuropsychiatric disorders, Oxidative stress, Proinflammatory cytokines, Tyrosine transport
National Category
Psychiatry
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-71432 (URN)10.1159/000485130 (DOI)000431062500004 ()29339668 (PubMedID)
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-07-11Bibliographically approved
Vumma, R., Bang, C. S., Kruse, R., Johansson, K. & Persson, K. (2016). Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization: a comparison with nitrofurantoin. Journal of antibiotics (Tokyo. 1968), 69(3), 183-186
Open this publication in new window or tab >>Antibacterial effects of nitric oxide on uropathogenic Escherichia coli during bladder epithelial cell colonization: a comparison with nitrofurantoin
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2016 (English)In: Journal of antibiotics (Tokyo. 1968), ISSN 0021-8820, E-ISSN 1881-1469, Vol. 69, no 3, p. 183-186Article in journal (Refereed) Published
Abstract [en]

Uropathogenic Escherichia coli (UPEC) is the predominant causative organism of urinary tract infections (UTI) with a high recurrence rate.1 Recurrence of UTI may involve intracellular localization of bacterial colonies within the bladder mucosa, a process that could benefit the bacteria in terms of protection against antibiotics and host immune cells.2, 3 Once internalized, UPEC may multiply and form intracellular bacterial communities with biofilm-like properties4 and/or enter a non-replicating stable and quiescent state that may serve as a source for recurrent UTI.2, 5, 6 A wide range of antimicrobial agents is used for the treatment of UTI but many antibiotics are unable to penetrate biofilm matrix or inhibit bacteria in a metabolically quiescent state. A recent study demonstrated that of seven different functional classes of antibiotics only a few, including nitrofurantoin and some fluoroquinolones, were able to eliminate internalized UPEC within bladder epithelial cells. Nitric oxide (NO) is a small hydrophobic molecule with antibacterial properties that readily diffuses through lipid bilayer membranes. During infection various host cells produce NO enzymatically from inducible nitric oxide synthase and NO has a key role in the innate immune response. It has been shown previously that NO has antibacterial activity against UPEC isolates, including multidrug-resistant extended spectrum beta-lactamase-producing isolates. Although NO can interact directly with bacteria, it can also be oxidized to reactive nitrogen species.

National Category
Pharmacology and Toxicology
Research subject
Biomedical Sciences, Pharmacology
Identifiers
urn:nbn:se:lnu:diva-52187 (URN)10.1038/ja.2015.112 (DOI)26531685 (PubMedID)
Available from: 2016-04-22 Created: 2016-04-22 Last updated: 2018-01-10Bibliographically approved
Comasco, E., Vumma, R., Toffoletto, S., Johansson, J., Flyckt, L., Lewander, T., . . . Venizelos, N. (2016). Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia.. Neuropsychobiology, 74(2), 96-103
Open this publication in new window or tab >>Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia.
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2016 (English)In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 74, no 2, p. 96-103Article in journal (Refereed) Published
Abstract [en]

Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.

National Category
Cell and Molecular Biology
Research subject
Natural Science, Medicine
Identifiers
urn:nbn:se:lnu:diva-60933 (URN)10.1159/000455234 (DOI)000399488600008 ()28190014 (PubMedID)
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-01-13Bibliographically approved
Demirel, I., Vumma, R., Mohlin, C., Svensson, L., Säve, S. & Persson, K. (2012). Nitric Oxide Activates IL-6 Production and Expression in Human Renal Epithelial Cells. American Journal of Nephrology, 36(6), 524-530
Open this publication in new window or tab >>Nitric Oxide Activates IL-6 Production and Expression in Human Renal Epithelial Cells
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2012 (English)In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 36, no 6, p. 524-530Article in journal (Refereed) Published
Abstract [en]

Background/Aims: Increased nitric oxide (NO) production or inducible form of NO synthase activity have been documented in patients suffering from urinary tract infection (UTI), but the role of NO in this infection is unclear. We investigated whether NO can affect the host response in human renal epithelial cells by modulating IL-6 production and mRNA expression. Methods: The human renal epithelial cell line A498 was infected with a uropathogenic Escherichia coli (UPEC) strain and/or the NO donor DETA/NO. The IL-6 production and mRNA expression were evaluated by ELISA and real-time RT-PCR. IL-6 mRNA stability was evaluated by analyzing mRNA degradation by real-time RT-PCR. Results: DETA/NO caused a significant (p < 0.05) increase in IL-6 production. Inhibitors of p38 MAPK and ERK1/2 signaling, but not JNK, were shown to significantly suppress DETA/NO-induced IL-6 production. UPEC-induced IL-6 production was further increased (by 73 +/- 23%, p < 0.05) in the presence of DETA/NO. The IL-6 mRNA expression increased 2.1 +/- 0.17-fold in response to DETA/NO, while the UPEC-evoked increase was pronounced (20 +/- 4.5-fold). A synergistic effect of DETA/NO on UPEC-induced IL-6 expression was found (33 +/- 7.2-fold increase). The IL-6 mRNA stability studies showed that DETA/NO partially attenuated UPEC-induced degradation of IL-6 mRNA. Conclusions: NO was found to stimulate IL-6 in renal epithelial cells through p38 MAPK and ERK1/2 signaling pathways and also to increase IL-6 mRNA stability in UPEC-infected cells. This study proposes a new role for NO in the host response during UTI by modulating the transcription and production of the cytokine IL-6. Copyright (C) 2012 S. Karger AG, Basel

Keywords
Nitric oxide, Urinary tract infections, IL-6, MAPK signaling, Renal epithelial cells
National Category
Urology and Nephrology Immunology in the medical area
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-24513 (URN)10.1159/000345351 (DOI)000312916200004 ()2-s2.0-84869889861 (Scopus ID)
Available from: 2013-02-22 Created: 2013-02-22 Last updated: 2018-01-11Bibliographically approved
Säve, S., Mohlin, C., Vumma, R. & Persson, K. (2011). Activation of Adenosine A(2A) Receptors Inhibits Neutrophil Transuroepithelial Migration. Infection and Immunity, 79(8), 3431-3437
Open this publication in new window or tab >>Activation of Adenosine A(2A) Receptors Inhibits Neutrophil Transuroepithelial Migration
2011 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 79, no 8, p. 3431-3437Article in journal (Refereed) Published
Abstract [en]

Adenosine has been identified as a significant inhibitor of inflammation by acting on adenosine A(2A) receptors. In this study, we examined the role of adenosine and A(2A) receptors in the transmigration of human neutrophils across an in vitro model of the transitional bladder urothelium. Human uroepithelial cells (UROtsa) were grown on transwell inserts; uropathogenic Escherichia coli (UPEC) and neutrophils were added to the transwell system; and the number of migrating neutrophils was evaluated. Reverse transcription-PCR (RT-PCR), immunohistochemistry, and flow cytometry were used to investigate the expression of adenosine receptors, the epithelial adhesion molecule ICAM-1, and the neutrophil integrin CD11b. Levels of proinflammatory interleukin-8 (IL-8) and phosphorylated I kappa B alpha were measured by enzyme-linked immunosorbent assays (ELISA) and Luminex assays, respectively. The neutrophils expressed all four adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3) receptors), but A(3) receptors were not expressed by UROtsa cells. UPEC stimulated neutrophil transuroepithelial migration, which was significantly decreased in response to the specific A(2A) receptor agonist CGS 21680. The inhibitory effect of CGS 21680 on neutrophil migration was reversed by the A(2A) receptor antagonist SCH 58261. The production of chemotactic IL-8 and the expression of the adhesion molecule ICAM-1 or CD11b were not significantly affected by CGS 21680. However, a significant decrease in the level of phosporylated I kappa B alpha was revealed in response to CGS 21680. In conclusion, UPEC infection in vitro evoked neutrophil migration through a multilayered human uroepithelium. The UPEC-evoked neutrophil transmigration decreased in response to A(2A) receptor activation, possibly through inhibition of NF-kappa B signaling pathways.

National Category
Medical and Health Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-16180 (URN)10.1128/IAI.05005-11 (DOI)000292770300047 ()2-s2.0-79961106306 (Scopus ID)
Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2017-12-08Bibliographically approved
Johansson, J., Landgren, M., Fernell, E., Vumma, R., Åhlin, A., Bjerkenstedt, L. & Venizelos, N. (2011). Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study. Behavioral and Brain Functions, 7(40)
Open this publication in new window or tab >>Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study
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2011 (English)In: Behavioral and Brain Functions, ISSN 1744-9081, E-ISSN 1744-9081, Vol. 7, no 40Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport.

METHODS: Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (V(max)) and affinity constant (K(m)) were determined. Any difference between the two groups was analyzed by Student's unpaired t-test or the Mann Whitney U test.

RESULTS: The ADHD group had significantly decreased V(max) (p = 0.039) and K(m) (increased affinity) (p = 0.010) of tryptophan transport in comparison to controls. They also had a significantly higher V(max)of alanine transport (p = 0.031), but the Km of alanine transport did not differ significantly. There were no significant differences in any of the kinetic parameters regarding tyrosine transport in fibroblasts for the ADHD group.

CONCLUSIONS: Tryptophan uses the same transport systems in both fibroblasts and at the blood brain barrier (BBB). Hence, a decreased transport capacity of tryptophan implies that less tryptophan is being transported across the BBB in the ADHD group. This could lead to deficient serotonin access in the brain that might cause disturbances in both the serotonergic and the catecholaminergic neurotransmitter systems, since these systems are highly interconnected. The physiological importance of an elevated transport capacity of alanine to the brain is not known to date.

National Category
Neurosciences
Research subject
Natural Science
Identifiers
urn:nbn:se:lnu:diva-52190 (URN)10.1186/1744-9081-7-40 (DOI)21942982 (PubMedID)
Available from: 2016-04-22 Created: 2016-04-22 Last updated: 2018-01-10Bibliographically approved
Vumma, R., Johansson, J., Lewander, T. & Venizelos, N. (2011). Tryptophan transport in human fibroblast cells-a functional characterization.. International Journal of Tryptophan Research, 4, 19-27
Open this publication in new window or tab >>Tryptophan transport in human fibroblast cells-a functional characterization.
2011 (English)In: International Journal of Tryptophan Research, ISSN 1178-6469, Vol. 4, p. 19-27Article in journal (Refereed) Published
Abstract [en]

There are indications that serotonergic neurotransmission is disturbed in several psychiatric disorders. One explanation may be disturbed transport of tryptophan (precursor for serotonin synthesis) across cell membranes. Human fibroblast cells offer an advantageous model to study the transport of amino acids across cell membranes, since they are easy to propagate and the environmental factors can be controlled. The aim of this study was to functionally characterize tryptophan transport and to identify the main transporters of tryptophan in fibroblast cell lines from healthy controls.Tryptophan kinetic parameters (V(max) and K(m)) at low and high concentrations were measured in fibroblasts using the cluster tray method. Uptake of (3)H (5)-L-tryptophan at different concentrations in the presence and absence of excess concentrations of inhibitors or combinations of inhibitors of amino acid transporters were also measured. Tryptophan transport at high concentration (0.5 mM) had low affinity and high V(max) and the LAT1 isoform of system-L was responsible for approximately 40% of the total uptake of tryptophan. In comparison, tryptophan transport at low concentration (50 nM) had higher affinity, lower V(max) and approximately 80% of tryptophan uptake was transported by system-L with LAT1 as the major isoform. The uptake of tryptophan at the low concentration was mainly sodium (Na(+)) dependent, while uptake at high substrate concentration was mainly Na(+) independent. A series of different transporter inhibitors had varying inhibitory effects on tryptophan uptake.This study indicates that tryptophan is transported by multiple transporters that are active at different substrate concentrations in human fibroblast cells. The tryptophan transport trough system-L was mainly facilitated by the LAT1 isoform, at both low and high substrate concentrations of tryptophan.

National Category
Neurosciences
Research subject
Chemistry, Biochemistry
Identifiers
urn:nbn:se:lnu:diva-52189 (URN)10.4137/IJTR.S6913 (DOI)22084600 (PubMedID)
Available from: 2016-04-22 Created: 2016-04-22 Last updated: 2018-01-10Bibliographically approved
Persson, M., Johansson, J., Vumma, R., Raita, J., Bjerkenstedt, L., Wiesel, F. & Venizelos, N. (2009). Aberrant amino acid transport in fibroblasts from patients with bipolar disorder. Neuroscience Letters, 457(1), 49-52, Article ID 19429160.
Open this publication in new window or tab >>Aberrant amino acid transport in fibroblasts from patients with bipolar disorder
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2009 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 457, no 1, p. 49-52, article id 19429160Article in journal (Refereed) Published
Abstract [en]

Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n=10) and healthy controls (n=10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (V(max)) and affinity constant (K(m)) were determined. A significantly lower V(max) for tyrosine (p=0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K(m) for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V(max)) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.

Place, publisher, year, edition, pages
Elsevier, 2009
National Category
Neurosciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
urn:nbn:se:lnu:diva-62512 (URN)10.1016/j.neulet.2009.03.095 (DOI)
Available from: 2017-04-19 Created: 2017-04-19 Last updated: 2018-01-13Bibliographically approved
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