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Lindblad, Charlotte
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Publications (10 of 11) Show all publications
Loizou, C., Laurell, G., Lindquist, D., Öfverman, C., Stefansson, K., Nylander, K. & Olofsson, K. (2015). Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus. Oncology Letters, 10(6), 3565-3572.
Open this publication in new window or tab >>Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus
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2015 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 10, no 6, 3565-3572 p.Article in journal (Refereed) Published
Abstract [en]

The incidence rate of tonsillar cancer is increasing worldwide. The current study identifies a parallel increase in the incidence of tonsillar cancer, human papilloma virus (HPV) and p16 expression among a population from northern Sweden, a sparsely populated area, confirming the strong association between p16 and HPV infection in tonsillar tissue. Data from the Swedish Cancer Registry was assessed to identify cases of tonsillar cancer in the northern territorial area of Sweden. HPV DNA was extracted from paraffin embedded diagnostic biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of p16 was identified by immunochemistry. Patients were grouped into urban or rural residence categories. A total of 214 cases were identified, comprising 155 (72.4%) men and 59 (27.6%) women, and 65 of these patients, who presented between 2000 and 2012, were analyzed. The overall median age for the analyzed patients was 58 years; 48 (74%) were males (median age, 57.5 years) and 17 (26%) were females (median age, 65 years). Of the 65 specimens, 59 (91%) were positive for HPV, and 62 (95%) expressed p16. The incidence of tonsillar cancer in the cohort demonstrated a 2-fold increase between 1990 and 2013; specifically, a 2.7-fold increase was observed in men whilst the female group exhibited only a small increase. These findings demonstrate a strong association between p16 expression and HPV infection in tonsillar malignancies. The incidence of HPV-positive tonsillar cancer has increased in recent years, even in sparsely populated regions, as demonstrated in northern Sweden.

Place, publisher, year, edition, pages
Spandidos Publications, 2015
Keyword
head and neck cancer, human papilloma virus, immunohistochemistry, incidence, p16, tonsillar cancer
National Category
Cancer and Oncology Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-114586 (URN)10.3892/ol.2015.3775 (DOI)000367232600038 ()
Available from: 2016-02-16 Created: 2016-01-25 Last updated: 2017-11-30Bibliographically approved
Stefansson, K., Oda, H., Öfverman, C., Lundin, E., Hedman, H. & Lindquist, D. (2015). LRIG protein expression and HPV prevalence in vulvar cancer patients in northern Sweden. International Journal of Gynecological Cancer, 25(9), 684-684.
Open this publication in new window or tab >>LRIG protein expression and HPV prevalence in vulvar cancer patients in northern Sweden
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2015 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, 684-684 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-123480 (URN)000377145702004 ()
Available from: 2016-07-06 Created: 2016-07-04 Last updated: 2017-11-28Bibliographically approved
Lindquist, D., Öfverman, C., Stefansson, K. & Aglund, K. (2015). Survival-data for endometrial cancer patients in northern Sweden 2010-2011. International Journal of Gynecological Cancer, 25(9), 1100-1100.
Open this publication in new window or tab >>Survival-data for endometrial cancer patients in northern Sweden 2010-2011
2015 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, 1100-1100 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-123479 (URN)000377145703060 ()
Available from: 2016-07-06 Created: 2016-07-04 Last updated: 2017-11-28Bibliographically approved
Öfverman, C. (2009). Progesterone metabolites: learning, tolerance, antagonism & metabolism. (Doctoral dissertation). Umeå: Umeå university.
Open this publication in new window or tab >>Progesterone metabolites: learning, tolerance, antagonism & metabolism
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Progesterone metabolites as allopregnanolone, isoallopregnanolone and tetrahydrodeoxy-corticosterone (THDOC) are increased in the luteal phase of the menstrual cycle, throughout pregnancy and during stress. Allopregnanolone and THDOC are neurosteroids with 3α-hydroxy, 5α-configurations and positive modulating effect on the GABAA receptor. They have similar properties and effect, and share the same binding sites on the GABAA receptor. Isoallopregnanolone has a 3β-hydroxy, 5α-configuration and a diverse effect as a proposed antagonist to both allopregnanolone and THDOC. Neurosteroids are thought to exert their effect predominantly at extrasynaptic GABAA receptors, containing for example α4- or α5-subunits. Such receptors are involved in the tonic response. Different subunits have diverse distribution pattern in the brain and are involved in different functions. The α5-subunit, mainly expressed in the hippocampus, is involved in learning, while α4 is more widespread and involved in e.g. anxiety and anaesthesia.

The aim of the present thesis was to contribute to the knowledge about selected progesterone metabolites and their effects on learning and tolerance development, as well as their metabolism. Also basic characteristics between different α-subunits of the GABAA receptor were evaluated.

The thesis shows that the effect of bicuculline and pentobarbital is not dependent on the α-subunit isoform of the GABAA receptor expressed in oocytes. Acute tolerance developed after allopregnanolone-induced anaesthesia with a decrease at both mRNA and protein levels of the GABAA receptor α4-subunit in the thalamus VPM nucleus. A negative correlation between the α4 mRNA and the increased dose of allopregnanolone needed to maintain the anaesthesia level was also shown. In addition, allopregnanolone induces a learning impairment in the Morris water maze test, when high concentrations of allopregnanolone are present in the brain. This impairment is not possible to reverse by isoallopregnanolone. In α5β3γ2L-transfected HEK-293 cells THDOC induces a baseline shift of its own and also potentiate the GABA-current. Neither of those THDOC effects can be inhibited by isoallopregnanolone. Instead isoallopregnanolone shows an agonistic effect on the THDOC-potentiation of the GABA-response. The main allopregnanolone metabolites identified, 5α-DHP and isoallopregnanolone, as well as allopregnanolone itself are mainly localized to the brain after an i.v. injection. After an isoallopregnanolone injection there is a more even distribution of the given steroid and the metabolites between plasma and brain. There is an epimerisation between isoallopregnanolone and allopregnanolone and vice versa.

In conclusion, the present thesis shows that the α4-subunit in the thalamus VPM nucleus is likely to be involved in the acute tolerance development against allopregnanolone and that allopregnanolone-induced learning impairment is likely to be hippocampus dependent. The lack of antagonistic effect of isoallopregnanolone on the THDOC-induced α5β3γ2L-GABAA response, together with epimerisation of isoallopregnanolone to allopregnanolone, could explain why isoallopregnanolone does not work as an antagonist to the allopregnanolone-induced learning impairment in a hippocampus dependent learning task.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 73 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1306
Keyword
allopregnanolone, isoallopregnanolone, THDOC, learning, tolerance, antagonism, inhibition, patch clamp, Morris water maze, metabolism, epimerization
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-27064 (URN)978-91-7264-888-3 (ISBN)
Public defence
2009-12-05, Sal 914, By 1, 9 tr, NUS, Norrlands Universitetssjukhus, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2009-11-16 Created: 2009-11-09 Last updated: 2010-01-18Bibliographically approved
Birzniece, V., Türkmen, S., Lindblad, C., Zhu, D., Johansson, I.-M., Bäckström, T. & Wahlström, G. (2006). GABA(A) receptor changes in acute allopregnanolone tolerance. European Journal of Pharmacology, 535(1-3), 125-134.
Open this publication in new window or tab >>GABA(A) receptor changes in acute allopregnanolone tolerance
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2006 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 535, no 1-3, 125-134 p.Article in journal (Refereed) Published
Abstract [en]

To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

Keyword
Anesthetics/administration & dosage/blood/pharmacokinetics, Animals, Brain/*drug effects/metabolism, Brain Chemistry/drug effects, Dentate Gyrus/chemistry/drug effects/metabolism, Dose-Response Relationship; Drug, Drug Tolerance, Gene Expression/drug effects, Immunohistochemistry, In Situ Hybridization, Infusions; Intravenous, Male, Pregnanolone/*administration & dosage/blood/pharmacokinetics, Protein Subunits/analysis/genetics, RNA; Messenger/genetics/metabolism, Rats, Rats; Sprague-Dawley, Receptors; GABA-A/analysis/*genetics, Receptors; GABA-B/analysis/genetics, Ventral Thalamic Nuclei/chemistry/drug effects/metabolism
Identifiers
urn:nbn:se:umu:diva-16927 (URN)10.1016/j.ejphar.2006.01.059 (DOI)16513107 (PubMedID)
Available from: 2007-12-02 Created: 2007-12-02 Last updated: 2017-12-14Bibliographically approved
Birzniece, V., Bäckström, T., Johansson, I.-M., Lindblad, C., Lundgren, P., Löfgren, M., . . . Zhu, D. (2006). Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.. Brain Research Reviews, 51(2), 212-239.
Open this publication in new window or tab >>Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.
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2006 (English)In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 51, no 2, 212-239 p.Article in journal (Refereed) Published
Keyword
Animals, Brain/drug effects/*metabolism/physiopathology, Cognition/drug effects, Cognition Disorders/chemically induced/*metabolism/physiopathology, Gonadal Steroid Hormones/adverse effects/*metabolism, Humans, Learning/drug effects, Neural Pathways/drug effects/metabolism/physiopathology, Receptors; GABA-A/metabolism, Serotonin/*metabolism, gamma-Aminobutyric Acid/*metabolism
Identifiers
urn:nbn:se:umu:diva-15313 (URN)doi:10.1016/j.brainresrev.2005.11.001 (DOI)16368148 (PubMedID)
Available from: 2008-01-04 Created: 2008-01-04 Last updated: 2017-12-14Bibliographically approved
Rahman, M., Lindblad, C., Johansson, I.-M., Bäckström, T. & Wang, M.-D. (2006). Neurosteroid modulation of recombinant rat alpha5beta2gamma2L and alpha1beta2gamma2L GABA(A) receptors in Xenopus oocyte.. Eur J Pharmacol, 547(1-3), 37-44.
Open this publication in new window or tab >>Neurosteroid modulation of recombinant rat alpha5beta2gamma2L and alpha1beta2gamma2L GABA(A) receptors in Xenopus oocyte.
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2006 (English)In: Eur J Pharmacol, ISSN 0014-2999, Vol. 547, no 1-3, 37-44 p.Article in journal (Refereed) Published
Keyword
Androstane-3;17-diol/pharmacology, Animals, Desoxycorticosterone/analogs & derivatives/pharmacology, Dose-Response Relationship; Drug, Female, GABA Agonists/pharmacology, GABA Antagonists/pharmacology, GABA Modulators/*pharmacology, Male, Membrane Potentials/drug effects, Microinjections, Oocytes/*drug effects/metabolism/physiology, Patch-Clamp Techniques/instrumentation/methods, Pregnanediol/pharmacology, Pregnanes/pharmacology, Pregnenolone/pharmacology, Protein Subunits/genetics/physiology, Pyridines/pharmacology, RNA; Messenger/administration & dosage/genetics, Rats, Rats; Wistar, Receptors; GABA-A/genetics/*physiology, Steroids/*pharmacology, Xenopus laevis, gamma-Aminobutyric Acid/pharmacology
Identifiers
urn:nbn:se:umu:diva-16917 (URN)10.1016/j.ejphar.2006.07.039 (DOI)16934248 (PubMedID)
Available from: 2007-10-19 Created: 2007-10-19 Last updated: 2011-04-12Bibliographically approved
Bäckström, T., Andersson, A., Andreén, L., Birzniece, V., Bixo, M., Björn, I., . . . Zingmark, E. (2003). Pathogenesis in menstrual cycle-linked CNS disorders.. Annals of the New York Academy of Sciences, 1007, 42-53.
Open this publication in new window or tab >>Pathogenesis in menstrual cycle-linked CNS disorders.
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2003 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1007, 42-53 p.Article, review/survey (Other academic) Published
Keyword
Affect/physiology, Animals, Female, Humans, Menstrual Cycle/*physiology, Mood Disorders/*etiology/physiopathology/psychology, Pregnanolone/physiology, Premenstrual Syndrome/*etiology/physiopathology/psychology, Receptors; GABA-A/physiology
Identifiers
urn:nbn:se:umu:diva-16450 (URN)10.1196/annals.1286.005 (DOI)14993039 (PubMedID)
Available from: 2007-09-28 Created: 2007-09-28 Last updated: 2017-12-14Bibliographically approved
Johansson, I.-M., Birzniece, V., Lindblad, C., Olsson, T. & Bäckström, T. (2002). Allopregnanolone inhibits learning in the Morris water maze. Brain Research, 934(2), 125-131.
Open this publication in new window or tab >>Allopregnanolone inhibits learning in the Morris water maze
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2002 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 934, no 2, 125-131 p.Article in journal (Refereed) Published
Abstract [en]

The progesterone metabolite allopregnanolone (3alpha-OH-5alpha-pregnane-20-one) inhibits neural functions, enhancing the GABA induced GABA(A) receptor activation. This effect is benzodiazepine like and benzodiazepines are known to impair memory. Acute effects of allopregnanolone on the hippocampus dependent spatial learning in the Morris water maze have not been studied. Adult male Wistar rats where injected (i.v.) with allopregnanolone (2 mg/kg), or vehicle, daily for 11 days. At 8 or 20 min after each injection, studies of place navigation were performed in the Morris water maze. Allopregnanolone concentrations in plasma and in nine different brain areas where analyzed by radioimmunoassay. The latency to find the platform was increased 8 min after the allopregnanolone injection, while normal learning was seen after 20 min. Swim speed did not differ between groups. A higher number of rats were swimming close to the pool wall (thigmotaxis) in the 8 min allopregnanolone group compared to the other groups. Allopregnanolone concentrations in the brain tissue at 8 min were 1.5 to 2.5 times higher then at 20 min after the allopregnanolone injections. After vehicle injections the brain concentrations of allopregnanolone were at control levels. Plasma concentrations of allopregnanolone followed the same pattern as in the brain, with the exception of an increase 8 min after vehicle injections. The natural progesterone metabolite allopregnanolone can inhibit learning in the Morris water maze, an effect not caused by motor impairment. The learning impairment might be due to a combination of changed swimming behavior and difficulties in navigation.

Identifiers
urn:nbn:se:umu:diva-4031 (URN)10.1016/S0006-8993(02)02414-9 (DOI)11955475 (PubMedID)
Available from: 2004-08-11 Created: 2004-08-11 Last updated: 2017-12-14Bibliographically approved
Öfverman, C., Hill, M., Bäckström, T. & Johansson, I.-M.Neurosteroid metabolism: identification of allopregnanolone and isoallopregnanolone metabolites in rat brain and plasma. .
Open this publication in new window or tab >>Neurosteroid metabolism: identification of allopregnanolone and isoallopregnanolone metabolites in rat brain and plasma
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Metabolism of progesterone produces steroids that by themselves have other functional properties than the hormone. The most prominent metabolite, allopregnanolone (3α-OH-5α-pregnane-20-one), has a strong GABAA receptor agonistic activity. Isoallopregnanolone (3β-OH-5α-pregnane-20-one) is also formed from progesterone; this allopregnanolone epimer can in certain situations function as an antagonist to effects induced by allopregnanolone.

This study was designed to further evaluate the metabolism of allopregnanolone and isoallopregnanolone in the rat. This was done by intravenous injections of either steroid and analyses of selected possible metabolites within the brain as well as in plasma, eight minutes after the injection. Analyses were performed with GC-MS.

It was found that the main metabolites accumulated after the allopregnanolone treatment was the precursor 5α-dihydroprogesterone, followed by isoallopregnanolone. The injected allopregnanolone, as well as the two major metabolites formed, were mainly present in the brain. When isoallopregnanolone was injected, the main metabolites formed were allopregnanolone and 6α-hydroxylated isoallopregnanolone, followed by the precursor 5α-dihydroprogesterone. Interestingly, the metabolites formed after isoallopregnanolone injections were more evenly distributed between the analyzed brain areas and the plasma. After both treatments a high proportion of conjugation (typically around 50%), was in plasma found for both the injected and the produced steroids.

With the high amounts of metabolites found in the brain, there might be a high converting capacity within the brain for these kinds of steroids. This suggests that interchange between the studied epimers is of physiological nature. One may then speculate that the brain uses the conversion between allopregnanolone and isoallopregnanolone to regulate the GABAergic inhibition. If this is the case, a dysregulation of this metabolism might cause symptoms and/or CNS disorders. 

Identifiers
urn:nbn:se:umu:diva-27071 (URN)
Available from: 2009-11-10 Created: 2009-11-10 Last updated: 2011-04-12Bibliographically approved
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