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| 2. |
- Pettersson-Pablo, Paul, 1986-, et al.
(författare)
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Body fat percentage and CRP correlates with a composite score of vascular risk markers in healthy, young adults : The Lifestyle, Biomarkers, and Atherosclerosis (LBA) study
- 2020
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Ingår i: BMC Cardiovascular Disorders. - : BioMed Central. - 1471-2261 .- 1471-2261. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Identification of early signs of atherosclerosis in young adults have the potential to guide early interventions to prevent later cardiovascular disease. We therefore analyzed measures of vascular structure and function and biomarkers of cardiovascular risk in a sample of young healthy adults.METHODS: Pulse-wave velocity (PWV), carotid-intima media thickness (cIMT) and augmentation index (AIX) were measured in 834 healthy non-smokers (ages 18.0-25.9). Emphasis was put on discriminating between individuals having a vascular structure and function associated with a higher or lower risk, and cluster analysis algorithms were employed to assign the subjects into groups based on these vascular measurements. In addition, a vascular status score (VSS) was calculated by summarizing the results according to quintiles of the vascular measurements. The associations between VSS and cardiovascular biomarkers were examined by regression analyses.RESULTS: The cluster analyses did not yield sufficiently distinct clustering (groups of individuals that could be categorized unequivocally as having either a vascular structure and function associated with a higher or lower CVD risk). VSS proved a better classificatory variable. The associations between VSS and biomarkers of cardiovascular risk were analyzed by univariable and multivariable regressions. Only body fat percentage and C-reactive protein (CRP) were independently associated with VSS.CONCLUSIONS: A VSS calculation, which integrates PWV, cIMT, and AIX measurements is better suited for cardiovascular risk evaluation in young adults than cluster analyses. The independent associations of VSS with body fat percentage and CRP highlight the decisive role of adiposity and systemic inflammation in early atherosclerotic progression and suggests a subordinate role of insulin and lipid metabolism in this age span.
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| 3. |
- Bengtsson, Sara, 1978-, et al.
(författare)
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GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?
- 2020
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Ingår i: Neurobiology of stress. - : Elsevier. - 2352-2895. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A receptor modulating steroid allopregnanolone (APa), it's role in underlying mechanisms for impaired cognition and of AD, and to determine options for therapy of AD. On one hand, APa given intermittently promotes neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of APa impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups to analyze the mechanisms underlying the difference. We conclude that the effects of APa depend on administration pattern and that chronic slightly increased APa exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pathology. These collaborative assessments provide insights for the therapeutic development of APa and APa antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials.
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| 4. |
- Bengtsson, Sara K. S., 1978-, et al.
(författare)
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Extra-synaptic GABAA receptor potentiation and neurosteroid-induced learning deficits are inhibited by GR3027, a GABAA modulating steroid antagonist
- 2023
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABAA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01–3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1–3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABAA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP’s negative effects on LoR and learning in the MWM.
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| 5. |
- Berin, Emilia, 1992-
(författare)
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Resistance Training and Physical Activity in Postmenopausal Women : Effects on Vasomotor Symptoms, Quality of Life and Microcirculation
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Menopause is a physiological event, but is associated with bothersome symptoms as well as physical changes that affect women’s health. About 75 % of women experience vasomotor symptoms (hot flushes and night sweats) related to menopause that often reduce quality of life. The vasomotor symptoms may be attributed to dysfunctional temperature regulation centrally in the hypothalamus and peripherally in the skin’s circulation. The most effective treatment for vasomotor symptoms is menopausal hormone therapy, but not all women are able to, or want to, use it. In addition to the impact on quality of life, studies have associated vasomotor symptoms and menopause with macrovascular endothelial dysfunction. Previous studies on the association of these factors with the skin’s microcirculatory function are small and few. Observational studies have associated physical activity and exercise with less vasomotor symptoms, but the evidence from intervention trials is of low quality and the results are ambiguous. Physical activity has established general health effects, and could potentially decrease vasomotor symptoms by effects on endogenous opioids centrally, and by more efficient thermoregulation peripherally. The aim of this thesis was to investigate the effect of resistance training on vasomotor symptoms and health-related quality of life in postmenopausal women, and to explore the women’s experiences of the training to find barriers and facilitators. We also aimed to investigate whether the skin’s microcirculatory function differed between women regarding menopausal status, vasomotor symptoms, menopausal hormone therapy, and physical activity. Material and methods The first study was an open randomized controlled trial including 65 postmenopausal women with moderate to severe vasomotor symptoms and low physical activity levels. We randomized the women to 15 weeks of resistance training (intervention) or unchanged physical activity (control). The participants registered vasomotor symptoms daily in a diary, and answered health-related quality of life questionnaires at baseline and at 15 weeks. The first 15 women to finish the intervention were recruited to a qualitative study. The women’s experiences of the resistance training intervention were explored in individual interviews after the intervention period, and all were followed-up with telephone interviews after one year. The third study was cross-sectional, including 1148 women from Linköping, 50-64 years old, who participated in the Swedish CArdioPulmonary bioImage Study (SCAPIS). These women answered a questionnaire about menopausal status, vasomotor symptoms and menopausal hormone therapy use, and wore accelerometers for seven days to assess physical activity. The skin’s microcirculation was assessed at rest and during post-occlusive reactive hyperemia. Results Moderate to severe vasomotor symptoms per 24 hours decreased significantly more in the group of women randomized to resistance training compared with the control group (mean difference -2.7, 95% CI -4.2 to -1.3). The resistance training group improved in domains of menopause-specific health-related quality of life compared with the control group but there was little impact on generic health-related quality of life. In the qualitative study we found that the vasomotor symptoms acted as a “trigger” for the women to become motivated to exercise. Their motivation then evolved from being driven by hopes of symptom relief into being driven by a wish for general well-being, which was still a driving force after one year. Microvascular function did not differ between postmenopausal and premenopausal women, or between women with or without vasomotor symptoms or menopausal hormone therapy. Women with higher levels of objectively measured and self-reported physical activity had a better reactivity of the skin’s microcirculation. The differences remained significant after adjusting for BMI, smoking, hypertension, diabetes, and education. Conclusions Resistance training could be effective for decreasing vasomotor symptoms and improving some aspects of health-related quality of life in motivated postmenopausal women. The vasomotor symptoms themselves spurred motivation to exercise, indicating they present an opportunity to increase physical activity. When a woman seeks medical advice for vasomotor symptoms, this could be a chance for health care professionals to help her initiate or increase exercise. Women who performed more physical activity and exercise had better skin microvascular function, but no association with VMS was found. Future studies are needed to investigate what type and dose of exercise is the most effective to reduce vasomotor symptoms and whether there is a way to predict for whom exercise will or will not be an effective intervention.
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| 7. |
- Bäckström, Torbjörn, et al.
(författare)
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A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 133
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Tidskriftsartikel (refereegranskat)abstract
- Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms related to the increase in progesterone and the neuroactive steroid allopregnanolone. Our hypothesis is that allopregnanolone is the symptom provoking factor. The rationale for the present study was to treat PMDD patients with the GABAA receptor modulating steroid antagonist, sepranolone (isoallopregnanolone). Patients (n = 206) with PMDD from 12 European centers were randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg and 16 mg. Patients administered sepranolone subcutaneously every 48 h during the 14 premenstrual days of three consecutive menstrual cycles. After obtaining informed consent, the PMDD diagnosis was confirmed according to DSM-5 and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. Inclusion and exclusion criteria stipulated that the women should be essentially healthy, not pregnant, have no ongoing psychiatric disorder or take interfering medications, and have regular menstrual cycles. The study's primary endpoint was the Total symptom score (Sum21, the score for all 21 symptom questions in the DRSP). In the prespecified statistical analysis the average score of the 5 worst premenstrual days in treatment cycles 2 and 3 were subtracted from the corresponding average score in the two diagnostic cycles. The treatment effects were tested using analysis of variance in a hierarchal order starting with the combined active sepranolone treatments vs. placebo. The prespecified analysis of Sum21 showed a large treatment effect of all three treatments but no statistically significant difference to placebo. However, the ratings of distress showed a significant treatment effect of sepranolone compared to placebo (p = 0.037) and the ratings of impairment showed a trend to greater treatment effect of sepranolone compared to placebo. Many women with PMDD had symptoms during a longer period than the late luteal phase. It has previously been shown that 9 premenstrual days may be more representative for comparison of PMDD symptom periods than the 5 worst premenstrual days. A post hoc analysis was undertaken in the per protocol population investigating the treatment effect during 9 premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008). Similar significant treatment effects were found for the impairment and distress scores. A significantly larger number of individuals experienced no or minimal symptoms (Sum21 <42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020). The results indicate that there is an attenuating effect by sepranolone on symptoms, impairment, and distress in women with PMDD especially by the 10 mg dosage. Sepranolone was well tolerated, and no safety concerns were identified.
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| 8. |
- Bäckström, Torbjörn, et al.
(författare)
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Allopregnanolone and its antagonist modulate neuroinflammation and neurological impairment
- 2024
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Ingår i: Neuroscience and Biobehavioral Reviews. - : Elsevier. - 0149-7634 .- 1873-7528. ; 161
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Forskningsöversikt (refereegranskat)abstract
- Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
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| 9. |
- Bäckström, Torbjörn, et al.
(författare)
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Isoallopregnanolone inhibits estrus cycle-dependent aggressive behavior
- 2023
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Ingår i: Biomolecules. - : MDPI. - 2218-273X. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Among female rats, some individuals show estrus cycle-dependent irritability/aggressive behaviors, and these individual rats may be used as a model for premenstrual dysphoric disorder (PMDD). We wanted to investigate if these behaviors are related to the estrus cycle phase containing moderately increased levels of positive GABA-A receptor-modulating steroids (steroid-PAM), especially allopregnanolone (ALLO), and if the adverse behavior can be antagonized. The electrophysiology studies in this paper show that isoallopregnanolone (ISO) is a GABA-A-modulating steroid antagonist (GAMSA), meaning that ISO can antagonize the agonistic effects of positive GABA-A receptor-modulating steroids in both α1β2γ2L and α4β3δ GABA-A receptor subtypes. In this study, we also investigated whether ISO could antagonize the estrus cycle-dependent aggressive behaviors in female Wistar rats using a resident–intruder test. Our results confirmed previous reports of estrus cycle-dependent behaviors in that 42% of the tested rats showed higher levels of irritability/aggression at diestrus compared to those at estrus. Furthermore, we found that, during the treatment with ISO, the aggressive behavior at diestrus was alleviated to a level comparable to that of estrus. We noticed an 89% reduction in the increase in aggressive behavior at diestrus compared to that at estrus. Vehicle treatment in the same animals showed a minimal effect on the diestrus-related aggressive behavior. In conclusion, we showed that ISO can antagonize Steroid-PAM both in α1β2γ2L and α4β3δ GABA-A receptor subtypes and inhibit estrus cycle-dependent aggressive behavior.
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| 10. |
- Bäckström, Torbjörn
(författare)
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Menstruationscykelbundna tillstånd
- 2022. - 3
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Ingår i: Gynekologi. - Lund : Studentlitteratur AB. - 9789144144191 ; , s. 89-96
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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