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Wang, Mingde
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Turkmen, S., Bixo, M., Hedström, H., Gideonsson, I., Nyberg, S., Wang, M. & Bäckström, T. (2016). The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome [Letter to the editor]. Clinical Endocrinology, 85(1), 152-154
Open this publication in new window or tab >>The author's reply: Blood allopregnanolone levels in women with polycystic ovary syndrome
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2016 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 85, no 1, p. 152-154Article in journal, Letter (Refereed) Published
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-124215 (URN)10.1111/cen.13079 (DOI)000378512100023 ()27061597 (PubMedID)
Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2018-06-07Bibliographically approved
Hedström, H., Bäckström, T., Bixo, M., Nyberg, S., Wang, M., Gideonsson, I. & Turkmen, S. (2015). Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone. Clinical Endocrinology, 83(5), 643-650
Open this publication in new window or tab >>Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA A receptor sensitivity to allopregnanolone
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2015 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 5, p. 643-650Article in journal (Refereed) Published
Abstract [en]

ObjectiveSeveral studies have reported that -aminobutyric acid (GABA) ergic circuits are involved in the pathophysiology of polycystic ovary syndrome (PCOS). The progesterone metabolite allopregnanolone is a potent GABA(A)-receptor-modulating steroid, and patients may have increased concentrations of allopregnanolone or altered GABA(A) receptor sensitivity. We investigated both of these possibilities in this study. PatientsWe enrolled 9 women with PCOS and 24 age-matched eumenorrhoeic controls, who were divided into two groups by body mass index (BMI) (16 normal weight and 8 overweight). MeasurementsWe investigated the effects of allopregnanolone injection on GABA(A) receptor sensitivity in both groups of women. All women received a single intravenous dose of allopregnanolone (0050mg/kg). GABA(A) receptor sensitivity was assessed with the saccadic eye velocity (SEV) over 30 degrees (SEV30 degrees), the SEV30 degrees/allopregnanolone concentration ([Allo]) ratio, and sedation, which were measured together with serum allopregnanolone at intervals for 180min after injection. The controls were tested in the follicular phase of the menstrual cycle. ResultsBaseline allopregnanolone concentrations were higher in the PCOS women than in the normal-weight (P=0034) and overweight controls (P=0004). The allopregnanolone concentrations after injection were higher in the PCOS women (P=0006) and overweight controls (P=0037) than in the normal-weight controls. All groups showed a decline in the SEV30 degrees/[Allo] ratio after injection. Allopregnanolone had a smaller effect on the SEV30 degrees/[Allo] ratio in the overweight women (PCOS, P=0032; controls, P=0007) than in the normal-weight controls. The sedation score after allopregnanolone injection was lower in the PCOS patients than in the controls, but was not different between the two control groups. ConclusionsPCOS women had elevated baseline allopregnanolone concentrations compared with follicular-phase controls. All overweight women (PCOS and controls) were less sensitive to allopregnanolone than normal-weight controls.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-111462 (URN)10.1111/cen.12809 (DOI)000363267400008 ()25929428 (PubMedID)
Available from: 2015-12-01 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Bengtsson, S. K., Johansson, M., Bäckström, T., Nitsch, R. M. & Wang, M. (2013). Brief but Chronic Increase in Allopregnanolone Cause Accelerated AD Pathology Differently in Two Mouse Models. Current Alzheimer Research, 10(1), 38-47
Open this publication in new window or tab >>Brief but Chronic Increase in Allopregnanolone Cause Accelerated AD Pathology Differently in Two Mouse Models
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2013 (English)In: Current Alzheimer Research, ISSN 1567-2050, Vol. 10, no 1, p. 38-47Article in journal (Refereed) Published
Abstract [en]

Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABA(A) receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABA(A) receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer's disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble A beta in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased A beta-levels caused by mildly elevated ALLO-levels.

Place, publisher, year, edition, pages
Bentham Science Publishers, 2013
Keywords
Allopregnanolone, Alzheimer's disease, beta-amyloid(1-42), beta-amyloid(1-40), cognition, physiological stress, transgenic
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-70364 (URN)10.2174/156720513804871363 (DOI)000317271800006 ()
Available from: 2013-05-16 Created: 2013-05-14 Last updated: 2018-06-08Bibliographically approved
Bengtsson, S., Johansson, M., Bäckström, T., Nitsch, R. & Wang, M. (2013). Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models. Current Alzheimer Research, 10(1), 38-47
Open this publication in new window or tab >>Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
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2013 (English)In: Current Alzheimer Research, ISSN 1567-2050, Vol. 10, no 1, p. 38-47Article in journal (Refereed) Published
Abstract [en]

Abstract: Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels. learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Ab in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.

Place, publisher, year, edition, pages
Bentham Science Publishers, 2013
Keywords
Alzheimer's disease, beta-amyloid proteins, allopregnanolone, chronic stress, transgenic mouse models, synaptophysin, amyloid plaques
National Category
Neurosciences
Research subject
Obstetrics and Gynaecology; Neurology; Medical Pharmacology; Geriatrics
Identifiers
urn:nbn:se:umu:diva-66571 (URN)
Funder
Swedish Research Council, 4x-11198
Available from: 2013-02-28 Created: 2013-02-25 Last updated: 2018-06-08Bibliographically approved
Bengtsson, S. K., Johansson, M., Bäckström, T. & Wang, M. (2012). Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice. Journal of Alzheimer's Disease, 31(1), 71-84
Open this publication in new window or tab >>Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
2012 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 1, p. 71-84Article in journal (Refereed) Published
Abstract [en]

The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABA(A) receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-beta (A beta) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular A beta. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic A beta PP(Swe)PSEN1(Delta E9) mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble A beta in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism.

Keywords
Allopregnanolone, Alzheimer's disease, amyloid-beta, amyloid-beta(1-40), amyloid-beta(1-42), cognition, physiological stress
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-57556 (URN)10.3233/JAD-2012-120268 (DOI)000306122900009 ()
Available from: 2012-08-13 Created: 2012-08-06 Last updated: 2018-06-08Bibliographically approved
Wang, M. (2011). Neurosteroids and GABA-A receptor function. Frontiers in Neuroendocrine science, 2(44), 1-23
Open this publication in new window or tab >>Neurosteroids and GABA-A receptor function
2011 (English)In: Frontiers in Neuroendocrine science, Vol. 2, no 44, p. 1-23Article in journal (Refereed) Published
Abstract [en]

Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α, 17α-diol (Adiol), and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) enhance the GABA-mediated Cl- currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABAA-receptor function and activate δ-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnane steroids and pregnenolone sulfate (PS) are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions.

Keywords
allopregnanolone, THDOC, pregnenolone sulfate, GABAA-receptor, premenstrual dysphoric disorder, mood, cognition
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-55123 (URN)10.3389/fendo.2011.00044 (DOI)
Available from: 2012-05-08 Created: 2012-05-08 Last updated: 2018-06-08Bibliographically approved
Wang, M.-D., Rahman, M., Johansson, I.-M. & Bäckström, T. (2010). Agonist function of the recombinant alpha 4 beta 3 delta GABAA receptor is dependent on the human and rat variants of the alpha 4-subunit. Clinical and experimental pharmacology & physiology, 37(7), 662-669
Open this publication in new window or tab >>Agonist function of the recombinant alpha 4 beta 3 delta GABAA receptor is dependent on the human and rat variants of the alpha 4-subunit
2010 (English)In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 37, no 7, p. 662-669Article in journal (Refereed) Published
Abstract [en]

1. It is known that the alpha(4)-subunit is likely to occur in the brain predominantly in alpha(4)beta(3)delta receptors at extrasynaptic sites. Recent studies have revealed that the alpha(1)-, alpha(4)-, gamma(2)- and delta-subunits may colocalize extrasynaptically in dentate granule cells of the hippocampus. In the present study, we characterized a series of recombinant GABA(A) receptors containing human (H) and rat (R) alpha(1)/alpha(4)-, beta(2)/beta(3)- and gamma(2S)/delta-subunits in Xenopus oocytes using the two-electrode voltage-clamp technique. 2. Both H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) receptors were sensitive to activation by GABA and pentobarbital. Contrary to earlier findings that the alpha(4)beta(3)delta combination was more sensitive to agonist action than the alpha(4)beta(3)gamma(2S) receptor, we observed extremely small GABA- and pentobarbital-activated currents at the wild-type H alpha(4)beta(3)delta receptor. However, GABA and pentobarbital activated the wild-type R alpha(4)beta(3)delta receptor with high potency (EC(50) = 0.5 +/- 0.7 and 294 +/- 5 micromol/L, respectively). 3. Substituting the H alpha(4) subunit with R alpha(4) conferred a significant increase in activation on the GABA and pentobarbital site in terms of reduced EC(50) and increased I(max). When the H alpha(4) subunit was combined with the R beta(3) and R delta subunit in a heteropentameric form, the amplitude of GABA- and pentobarbital-activated currents increased significantly compared with the wild-type H alpha(4)beta(3)delta receptor. 4. Thus, the results indicate that the R alpha(4)beta(3)delta, H alpha(1)beta(3)delta and H alpha(4)beta(3)gamma(2S) combinations may contribute to functions of extrasynaptic GABA(A) receptors. The presence of the R alpha(4) subunit at recombinant GABA(A) receptors containing the delta-subunit is a strong determinant of agonist action. The recombinant H alpha(4)beta(3)delta receptor is a less sensitive subunit composition in terms of agonist activation.

Place, publisher, year, edition, pages
Blackwell Publishing, 2010
Keywords
α4-subunit, β3-subunit, δ-subunit, GABA, GABAA
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-36800 (URN)10.1111/j.1440-1681.2010.05374.x (DOI)000278917600004 ()20337660 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2018-06-08Bibliographically approved
Strömberg, J., Lundgren, P., Taube, M., Bäckström, T., Wang, M. & Haage, D. (2009). The effect of the neuroactive steroid 5β-pregnane-3β, 20(R)-diol on the time course of GABA evoked currents is different to that of pregnenolone sulphate. European Journal of Pharmacology, 605(1-3), 78-86
Open this publication in new window or tab >>The effect of the neuroactive steroid 5β-pregnane-3β, 20(R)-diol on the time course of GABA evoked currents is different to that of pregnenolone sulphate
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2009 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 605, no 1-3, p. 78-86Article in journal (Refereed) Published
Abstract [en]

The endogenous progesterone metabolite allopregnanolone has a number of properties including anesthetic, sedative, antiepileptic, anxiolytic, impaired memory function and negative mood symptoms. Allopregnanolone is a potent positive GABA(A) receptor function modulators. In contrast, 3beta-hydroxy-steroids (3beta-steroids) usually modulate the GABA(A) receptor negatively. They have attracted some interest for their possible use as therapeutic agents that could counteract the negative symptoms induced by allopregnanolone. Two hypotheses for the action of 3beta-steroids have been proposed: 1) 3beta-steroids act in a similar way to pregnenolone sulphate, which non-competitively reduces GABA(A) receptor activity. 2) 3beta-steroids specifically antagonize the effect of allopregnanolone. We have therefore tried to clarify this issue by comparing the effect of pregnenolone sulphate and 5beta-pregnane-3beta, 20(R)-diol on the GABA-evoked currents by the patch clamp technique on neurons from the medial preoptic nucleus. Both pregnenolone sulphate and 5beta-pregnane-3beta, 20(R)-diol increase the desensitization rate of the current response evoked by a 2 s GABA application. However, their effects on other parameters of the GABA evoked currents differed in degree and sometimes even in direction. The actions of pregnenolone sulphate and 5beta-pregnane-3beta, 20(R)-diol were not altered in the presence of allopregnanolone, which indicates that they do not directly interact with allopregnanolone. In addition, when 5beta-pregnane-3beta, 20(R)-diol was tested on spontaneous inhibitory postsynaptic currents (sIPSCs), it dramatically reduced the allopregnanolone-induced prolongation of the decay time constant but it had no effect on the decay under control conditions. In conclusion, the effect of 5beta-pregnane-3beta, 20(R)-diol on GABA-evoked currents is different to that of pregnenolone sulphate in medial preoptic nucleus neurons.

Keywords
Patch clamp; sIPSCs; Tau decay; Desensitization; (Rat)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-36809 (URN)10.1016/j.ejphar.2008.12.038 (DOI)19168059 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2018-06-08Bibliographically approved
Rahman, M., Borra, V. B., Isaksson, M., Johansson, I.-M., Ragagnin, G., Bäckström, T. & Wang, M.-D. (2008). A comparison of the pharmacological properties of recombinant human and rat α1β2γ2L GABAA receptors in Xenopus oocytes. Clinical and experimental pharmacology & physiology, 35(9), 1002-1011
Open this publication in new window or tab >>A comparison of the pharmacological properties of recombinant human and rat α1β2γ2L GABAA receptors in Xenopus oocytes
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2008 (English)In: Clinical and experimental pharmacology & physiology, ISSN 0305-1870, E-ISSN 1440-1681, Vol. 35, no 9, p. 1002-1011Article in journal (Refereed) Published
Abstract [en]

In the present study, we compared the pharmacology, particularly neurosteroid modulation of the GABA(A) receptor, between human and rat alpha(1)beta(2)gamma(2)(L) GABA(A) receptors and between human receptors containing the long (L) and short (S) forms of the gamma(2)-subunit. We observed that maximum responses to GABA were significantly higher with the human alpha(1)beta(2)gamma(2)(L) receptor compared with the rat receptor. In terms of neurosteroid modulation, increases in the EC(15) response to GABA induced by 3alpha-OH-5beta-pregnan-20-one (3alpha5betaP), 5alpha-androstane-3alpha,17beta-diol (3alpha5alphaADL) and 5alpha-pregnane-3alpha,20beta-diol (3alpha5alpha-diol) were significantly greater for the rat compared with the human receptor. Responses to 30 micromol/L GABA were inhibited by 3beta-OH-5alpha-pregnan-20-one (UC1010) and 5beta-pregnan-3beta,20(R)-diol (UC1020) to a greater degree for human and rat receptors, respectively. Responses to GABA + 3alpha5alphaTHDOC were inhibited by 5alpha-pregnan-3beta,20(S)-diol (UC1019) and pregnenolone sulphate to a greater degree for human and rat receptors, respectively. The GABA dose-response curves for human alpha(1)beta(2)gamma(2)(S) and alpha(1)beta(2)gamma(2)(L) receptors were identical. However, the maximum GABA-evoked current, the direct gating effect of pentobarbital and the allosteric potentiation of the GABA EC(15) response by 3alpha5alphaTHDOC and 3alpha5betaP were significantly higher with alpha(1)beta(2)gamma(2)(S) than alpha(1)beta(2)gamma(2)(L) receptors. Inhibition of the response to 30 micromol/L GABA by UC1010 and UC1020 was greater for a(1)beta(2)gamma(2)(L) and alpha(1)beta(2)gamma(2)(S) receptors, respectively. Inhibition of responses to 3alpha5alphaTHDOC + GABA by UC1019 and UC1010 was significantly higher for alpha(1)beta(2)gamma(2)(L) receptors. In conclusion, the site of activation by GABA and neurosteroid modulation differ between human and rat alpha(1)beta(2)gamma(2)(L) receptors, as well as between human receptors containing the L and S splice variants of the gamma(2)-subunit.

Keywords
g2L and g2S isoforms;GABA;human and rat a1b2g2L receptors;neurosteroids
Identifiers
urn:nbn:se:umu:diva-36818 (URN)10.1111/j.1440-1681.2008.04946.x (DOI)18430052 (PubMedID)
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2018-06-08Bibliographically approved
Wang, M.-D., Borra, V. B., Strömberg, J., Lundgren, P., Haage, D. & Bäckström, T. (2008). Neurosteroids 3beta, 20 (R/S)-pregnandiols decrease offset rate of the GABA-site activation at the recombinant GABA(A) receptor.. Eur J Pharmacol, 586(1-3), 67-73
Open this publication in new window or tab >>Neurosteroids 3beta, 20 (R/S)-pregnandiols decrease offset rate of the GABA-site activation at the recombinant GABA(A) receptor.
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2008 (English)In: Eur J Pharmacol, ISSN 0014-2999, Vol. 586, no 1-3, p. 67-73Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-9998 (URN)18374329 (PubMedID)
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2018-06-09Bibliographically approved
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