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  • 1.
    Affatato, Oreste
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Beating of hammers2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    I've been investigating the connection between migraine and depression—two debilitating disorders with high comorbidity. My overarching goal is to unravel their pathophysiology and pinpoint associated risk factors to pave the way for more effective therapeutic interventions. The fruits of my labor is discussed in the introductory part of the thesis and comprises four first-author publications in international peer-reviewed journals.

    In the first two projects, I worked mostly on the comorbid aspects of migraine and depression. I conducted a meta-analysis on the efficacy of onabotulinumtoxinA injections as a treatment for those grappling with both migraine and depression. The findings were promising, showing not only the treatment's safety and effectiveness but also hinting at a shared pathophysiology between the two conditions. The second project delved into the structural brain anatomy, utilizing voxel-based magnetic resonance imaging measures to explore subcortical volumes in migraine and depression patients. The distinct patterns observed suggest a nuanced relationship at the subcortical level.

    Expanding beyond comorbidity, my research ventured into the occupational determinants of migraine, scrutinizing the impact of job-related factors on migraine prevalence. Leveraging data from the UK Biobank, the third project identified strong associations between migraine and specific job categories, setting the stage for future interventions and policies to enhance workers' well-being. Additionally, my exploration into the role of the cerebellum and brainstem in migraine pathophysiology, using the UK Biobank data, unveiled larger gray matter volumes in multiple cerebellar regions in individuals with migraines. This sheds light on potential mechanisms underlying migraine attacks, contributing significantly to our understanding and potential treatments for these challenging disorders.

    List of papers
    1. High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis
    Open this publication in new window or tab >>High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis
    Show others...
    2021 (English)In: Journal of Translational Medicine, E-ISSN 1479-5876, Vol. 19, no 1, article id 133Article, review/survey (Refereed) Published
    Abstract [en]

    Background: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression.

    Methods: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October 30th, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random- effects empirical Bayes model.

    Results: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of - 8.94 points (CI [ - 10.04,- 7.84], p < 0.01) in the BDI scale, of - 5.90 points (CI [ - 9.92,- 1.88], p < 0.01) in the BDI-II scale and of - 6.19 points (CI [ - 9.52,- 2.86], p < 0.01) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of - 4.10 (CI [ - 7.31,- 0.89], p = 0.01) points in the HIT6 scale, - 32.05 (CI [ - 55.96,- 8.14], p = 0.01) in the MIDAS scale, - 1.7 (CI [ - 3.27,- 0.13], p = 0.03) points in the VAS scale and of - 6.27 (CI [ - 8.48,- 4.07], p < 0.01) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores.

    Conclusion: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2021
    Keywords
    OnabotulinumtoxinA, Botox, Migraine, Depression, Meta-analysis
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-442250 (URN)10.1186/s12967-021-02801-w (DOI)000636462700003 ()33789668 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2021-05-17 Created: 2021-05-17 Last updated: 2024-07-04Bibliographically approved
    2. Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank
    Open this publication in new window or tab >>Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank
    2021 (English)In: Journal of Headache and Pain, ISSN 1129-2369, E-ISSN 1129-2377, Vol. 22, no 1, article id 145Article in journal (Refereed) Published
    Abstract [en]

    Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.

    Place, publisher, year, edition, pages
    Springer NatureSpringer Nature, 2021
    Keywords
    Migraine, Occupation, Work, Job, Sex differences
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-461712 (URN)10.1186/s10194-021-01356-x (DOI)000726269000002 ()34863088 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2022-01-31 Created: 2022-01-31 Last updated: 2024-04-11Bibliographically approved
    3. Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study
    Open this publication in new window or tab >>Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study
    Show others...
    2023 (English)In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 284Article in journal (Refereed) Published
    Abstract [en]

    Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

    Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

    Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

    Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

    Place, publisher, year, edition, pages
    BioMed Central (BMC)BMC, 2023
    Keywords
    Migraine, Depression, Structural brain MRI, UK Biobank
    National Category
    Neurosciences Neurology
    Identifiers
    urn:nbn:se:uu:diva-509232 (URN)10.1186/s12883-023-03336-x (DOI)001040412700002 ()37507671 (PubMedID)
    Available from: 2023-08-22 Created: 2023-08-22 Last updated: 2024-12-03Bibliographically approved
    4. Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study
    Open this publication in new window or tab >>Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study
    2023 (English)In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 9, article id 2528Article in journal (Refereed) Published
    Abstract [en]

    Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

    Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

    Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

    Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

    Place, publisher, year, edition, pages
    MDPI, 2023
    Keywords
    migraine, cerebellum, brainstem, structural MRI, UK Biobank
    National Category
    Neurology Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-514061 (URN)10.3390/biomedicines11092528 (DOI)001071288700001 ()37760969 (PubMedID)
    Available from: 2023-10-16 Created: 2023-10-16 Last updated: 2024-04-11Bibliographically approved
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  • 2.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dahlén, Amelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Assessing volumetric brain differences in migraine and depression patients: a UK Biobank study2023In: BMC Neurology, E-ISSN 1471-2377, Vol. 23, no 1, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.

    Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.

    Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).

    Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.

    Download full text (pdf)
    FULLTEXT01
  • 3.
    Affatato, Oreste
    et al.
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Mwinyi, Jessica
    Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study2023In: Biomedicines, E-ISSN 2227-9059, Vol. 11, no 9, article id 2528Article in journal (Refereed)
    Abstract [en]

    Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas.

    Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions.

    Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]).

    Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine.

    Download full text (pdf)
    FULLTEXT01
  • 4.
    Aguggia, Julieta P.
    et al.
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cornejo, Maria P.
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Fernandez, Gimena
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    De Francesco, Pablo N.
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Mani, Bharath K.
    UT Southwestern Med Ctr, Ctr Hypothalam Res, Dept Internal Med, Dallas, TX USA..
    Cassano, Daniela
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cabral, Agustina
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Valdivia, Spring
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Garcia Romero, Guadalupe
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Reynaldo, Mirta
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Fehrentz, Jean-Alain
    Univ Montpellier, Fac Pharm, Inst Biomol Max Mousseron, UMR 5247 CNRS,ENSCM, Montpellier, France..
    Zigman, Jeffrey M.
    UT Southwestern Med Ctr, Ctr Hypothalam Res, Dept Internal Med, Dallas, TX USA..
    Perello, Mario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Growth hormone secretagogue receptor signaling in the supramammillary nucleus targets nitric oxide-producing neurons and controls recognition memory in mice2022In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 139, article id 105716Article in journal (Refereed)
    Abstract [en]

    Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.

  • 5.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ammar, Nourhane
    Korzh, Stanislava
    Alsehli, Ahmed M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Faculty of Medicine, King Abdulaziz University and Hospital, Al Ehtifalat St., 21589, Jeddah, Saudi Arabia.
    Hosseini, Kimia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Boukhatmi, Hadi
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Fluvastatin-induced myofibrillar damage is associated with elevated ROS, and impaired fatty acid oxidation, and is preceded by mitochondrial morphological changes2024In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, no 1, article id 3338Article in journal (Refereed)
    Abstract [en]

    Previously, we showed that fluvastatin treatment induces myofibrillar damage and mitochondrial phenotypes in the skeletal muscles of Drosophila. However, the sequential occurrence of mitochondrial phenotypes and myofibril damage remains elusive. To address this, we treated flies with fluvastatin for two and five days and examined their thorax flight muscles using confocal microscopy. In the two-day fluvastatin group, compared to the control, thorax flight muscles exhibited mitochondrial morphological changes, including fragmentation, rounding up and reduced content, while myofibrils remained organized in parallel. In the five-day fluvastatin treatment, not only did mitochondrial morphological changes become more pronounced, but myofibrils became severely disorganized with significantly increased thickness and spacing, along with myofilament abnormalities, suggesting myofibril damage. These findings suggest that fluvastatin-induced mitochondrial changes precede myofibril damage. Moreover, in the five-day fluvastatin group, the mitochondria demonstrated elevated H2O2 and impaired fatty acid oxidation compared to the control group, indicating potential mitochondrial dysfunction. Surprisingly, knocking down Hmgcr (Drosophila homolog of HMGCR) showed normal mitochondrial respiration in all parameters compared to controls or five-day fluvastatin treatment, which suggests that fluvastatin-induced mitochondrial dysfunction might be independent of Hmgcr inhibition. These results provide insights into the sequential occurrence of mitochondria and myofibril damage in statin-induced myopathy for future studies.

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    fulltext
  • 6.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Behare, Neha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Alsehli, Ahmed M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. King Abdulaziz Univ & Hosp, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia.
    Berkins, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Arora, Aadeya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Antoniou, Eirini
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Moysiadou, Eleni I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Anantha-Krishnan, Sowmya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Cosmen, Patricia D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Vikner, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Moulin, Thiago C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Lund Univ, Fac Med, Dept Expt Med Sci, Solvegatan 19,BMC F10, S-22184 Lund, Sweden.
    Ammar, Nourhene
    Univ Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France..
    Boukhatmi, Hadi
    Univ Rennes, Inst Genet & Dev Rennes IGDR, UMR6290, CNRS, F-35065 Rennes, France..
    Clemensson, Laura E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 22, article id 3528Article in journal (Refereed)
    Abstract [en]

    The underlying mechanisms for statin-induced myopathy (SIM) are still equivocal. In this study, we employ Drosophila melanogaster to dissect possible underlying mechanisms for SIM. We observe that chronic fluvastatin treatment causes reduced general locomotion activity and climbing ability. In addition, transmission microscopy of dissected skeletal muscles of fluvastatin-treated flies reveals strong myofibrillar damage, including increased sarcomere lengths and Z-line streaming, which are reminiscent of myopathy, along with fragmented mitochondria of larger sizes, most of which are round-like shapes. Furthermore, chronic fluvastatin treatment is associated with impaired lipid metabolism and insulin signalling. Mechanistically, knockdown of the statin-target Hmgcr in the skeletal muscles recapitulates fluvastatin-induced mitochondrial phenotypes and lowered general locomotion activity; however, it was not sufficient to alter sarcomere length or elicit myofibrillar damage compared to controls or fluvastatin treatment. Moreover, we found that fluvastatin treatment was associated with reduced expression of the skeletal muscle chloride channel, C1C-a (Drosophila homolog of CLCN1), while selective knockdown of skeletal muscle C1C-a also recapitulated fluvastatin-induced myofibril damage and increased sarcomere lengths. Surprisingly, exercising fluvastatin-treated flies restored C1C-a expression and normalized sarcomere lengths, suggesting that fluvastatin-induced myofibrillar phenotypes could be linked to lowered C1C-a expression. Taken together, these results may indicate the potential role of C1C-a inhibition in statinassociated muscular phenotypes. This study underlines the importance of Drosophila melanogaster as a powerful model system for elucidating the locomotion and muscular phenotypes, promoting a better understanding of the molecular mechanisms underlying SIM.

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  • 7.
    Al-Sabri, Mohamed H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Nikpour, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Department of Medical Sciences, Uppsala University, BMC, Husargatan 3, 750 03, Uppsala, Sweden.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems: insights on its signalling pathway, linked disorders and theragnostic potential2022In: Cell & Bioscience, ISSN 2045-3701, Vol. 12, no 1, article id 151Article, review/survey (Refereed)
    Abstract [en]

    Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.

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  • 8.
    Andreoli, María F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Instituto de Desarrollo e Investigaciones Pediátricas (IDIP), HIAEP Sor María Ludovica de la Plata, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC-PBA), Calle 63 # 1069, La Plata, Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), La Plata, Argentina. mfandreoli@fbcb.unl.edu.ar..
    Fittipaldi, Antonela S
    Castrogiovanni, Daniel
    De Francesco, Pablo N
    Valdivia, Spring
    Heredia, Florencia
    Ribet-Travers, Carole
    Mendez, Ignacio
    Fasano, María V
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Doi, Suhail A
    Habib, Abdella M
    Perello, Mario
    Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner.2023In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations.

    METHODS: We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB).

    RESULTS: Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (β: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (β: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (β: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (β: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner.

    CONCLUSIONS: LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans.

    TRIAL REGISTRATION: The study was retrospectively registered in clinicaltrials.gov (April 2023).

    CLINICALTRIALS: gov Identifier: NCT05815641.

  • 9.
    Andreoli, María F.
    et al.
    Instituto de Desarrollo e Investigaciones Pediátricas (IDIP), Children's Hospital HIAEP “Sor María Ludovica” La Plata‐Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC‐PBA) La Plata Argentina;CONICET La Plata La Plata Argentina;Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University Uppsala Sweden.
    Kruger, Ana Luz
    Instituto de Desarrollo e Investigaciones Pediátricas (IDIP), Children's Hospital HIAEP “Sor María Ludovica” La Plata‐Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC‐PBA) La Plata Argentina;CONICET La Plata La Plata Argentina.
    Sokolov, Aleksandr V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University Uppsala Sweden.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University Uppsala Sweden.
    De Francesco, Pablo N.
    Neurophysiology Group, Instituto Multidisciplinario de Biología Celular (IMBICE) (UNLP‐CIC‐PBA‐Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)) La Plata Argentina.
    Perello, Mario
    Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University Uppsala Sweden;Neurophysiology Group, Instituto Multidisciplinario de Biología Celular (IMBICE) (UNLP‐CIC‐PBA‐Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)) La Plata Argentina.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Department of Surgical Sciences, Functional Pharmacology and Neuroscience Uppsala University Uppsala Sweden.
    LEAP2 is associated with impulsivity and reward sensitivity depending on the nutritional status and decreases with protein intake in humans2024In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326Article in journal (Refereed)
  • 10.
    Andreoli, María Florencia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Inst Desarrollo & Invest Pediat IDIP, HIAEP Sor Maria Ludov La Plata, Comis Invest Cient Prov Buenos Aires CIC PBA, La Plata, Argentina.;Consejo Nacl Invest Cient & Tecn CONICET, La Plata, Argentina..
    Gentreau, Mélissa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Perelló, Mario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Univ Nacl La Plata UNLP, Consejo Nacl Invest Cient & Tecn CONICET, Grp Neurofisiol, Inst Multidisciplinario Biol Celular IMBICE, La Plata, Argentina.;CIC La PBA, La Plata, Argentina.;Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, Calle 526 e-10 & 11, La Plata, Buenos Aires, Argentina..
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Genetic variants of LEAP2 are associated with anthropometric traits and circulating insulin-like growth factor-1 concentration: A UK Biobank study2024In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 26, no 9, p. 3565-3575Article in journal (Refereed)
    Abstract [en]

    Aim: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity.

    Methods: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRSLEAP2) using linear and logistic regression models. Sex-stratified analyses were also conducted.

    Results: Five SNPs showed positive associations with obesity-related traits. rs57880964 was associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF-1 concentrations in both men and women. GRSLEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF-1 concentration in both sexes.

    Conclusions: These findings reveal sex-specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF-1 concentration.

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  • 11.
    Bai, Mingxin
    et al.
    Sichuan Univ, West China Hosp, Diabetic Foot Care Ctr, Dept Endocrinol & Metab, Chengdu, Sichuan, Peoples R China..
    Sun, Xiaodong
    Weifang Med Univ, Affiliated Hosp, Dept Endocrinol & Metab, Weifang, Peoples R China..
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Karolinska Inst, Dept Clin Neurosci, Solna, Sweden..
    Gao, Yun
    Sichuan Univ, West China Hosp, Diabetic Foot Care Ctr, Dept Endocrinol & Metab, Chengdu, Sichuan, Peoples R China..
    Editorial: Metabolic diseases and healthy aging: prevention and public health policy based on risk factors2024In: Frontiers in Public Health, E-ISSN 2296-2565, Vol. 12, article id 1502564Article in journal (Other academic)
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  • 12.
    Barrile, Franco
    et al.
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cassano, Daniela
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Fernandez, Gimena
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    De Francesco, Pablo N.
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Reynaldo, Mirta
    Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cantel, Sonia
    Univ Montpellier, Inst Biomol Max Mousseron, CNRS, ENSCM, Montpellier, France..
    Fehrentz, Jean-Alain
    Univ Montpellier, Inst Biomol Max Mousseron, CNRS, ENSCM, Montpellier, France..
    Donato Jr, Jose
    Univ Sao Paulo, Inst Ciencias Biomed, Dept Physiol & Biophys, Sao Paulo, Brazil..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Zigman, Jeffrey M.
    UT Southwestern Med Ctr, Ctr Hypothalam Res, Dept Internal Med, Dallas, TX USA..
    Perello, Mario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Natl Univ La Plata, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.;Multidisciplinary Inst Cell Biol, Lab Neurophysiol, Calle 526 S-N Entre 10 & 11, RA-1900 La Plata, Buenos Aires, Argentina..
    Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation2023In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 156, article id 106333Article in journal (Refereed)
    Abstract [en]

    Objective: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin receptor (a.k.a. growth hormone secretagogue receptor, GHSR) in the mouse LHA (LHAGHSR neurons), its physiological implications and the neuronal circuit recruited by local ghrelin action.Methods: We investigated the distribution of LHAGHSR neurons using different histologic strategies, including the use of a reporter mice expressing enhanced green fluorescent protein under the control of the GHSR promoter. Also, we investigated the physiological implications of local injections of ghrelin within the LHA, and the extent to which the orexigenic effect of intra-LHA-injected ghrelin involves the arcuate nucleus (ARH) and orexin neurons of the LHA (LHAorexin neurons)Results: We found that: 1) LHAGHSR neurons are homogeneously distributed throughout the entire LHA; 2) intraLHA injections of ghrelin transiently increase food intake and locomotor activity; 3) ghrelin's orexigenic effect in the LHA involves the indirect recruitment of LHAorexin neurons and the activation of ARH neurons; and 4) LHAGHSR neurons are not targeted by plasma ghrelin.Conclusions: We provide a compelling neuroanatomical and functional characterization of LHAGHSR neurons in male mice that indicates that LHAGHSR cells are part of a hypothalamic neuronal circuit that potently induces food intake.

  • 13.
    Belyaeva, Irina I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Subbotina, Anna G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Eremenko, Ivan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Pharmacogenetics in Primary Headache Disorders2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 820214Article, review/survey (Refereed)
    Abstract [en]

    Primary headache disorders, such as migraine, tension-type headache (TTH), and cluster headache, belong to the most common neurological disorders affecting a high percentage of people worldwide. Headache induces a high burden for the affected individuals on the personal level, with a strong impact on life quality, daily life management, and causes immense costs for the healthcare systems. Although a relatively broad spectrum of different pharmacological classes for the treatment of headache disorders are available, treatment effectiveness is often limited by high variances in therapy responses. Genetic variants can influence the individual treatment success by influencing pharmacokinetics or pharmacodynamics of the therapeutic as investigated in the research field of pharmacogenetics. This review summarizes the current knowledge on important primary headache disorders, including migraine, TTH, and cluster headache. We also summarize current acute and preventive treatment options for the three headache disorders based on drug classes and compounds taking important therapy guidelines into consideration. Importantly, the work summarizes and discusses the role of genetic polymorphisms regarding their impact on metabolism safety and the effect of therapeutics that are used to treat migraine, cluster headache, and TTH exploring drug classes such as nonsteroidal anti-inflammatory drugs, triptans, antidepressants, anticonvulsants, calcium channel blockers, drugs with effect on the renin-angiotensin system, and novel headache therapeutics such as ditans, anti-calcitonin-gene-related peptide antibodies, and gepants. Genetic variants in important phase I-, II-, and III-associated genes such as cytochrome P450 genes, UGT genes, and different transporter genes are scrutinized as well as variants in genes important for pharmacodynamics and several functions outside the pharmacokinetic and pharmacodynamic spectrum. Finally, the article evaluates the potential and limitations of pharmacogenetic approaches for individual therapy adjustments in headache disorders.

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  • 14.
    Benavides-Huerto, Miguel Armando
    et al.
    Lab Pathol & Cytopathol Dr Miguel Benavides, Morelia, Michoacan, Mexico..
    García-Figueroa, Jaime
    High Specialty Med Ctr, Moroleon, Guanajuato, Mexico..
    Chávez-Valencia, Venice
    Hosp Gen Reg 1 Inst Mexicano Seguro Social, Dept Nephrol, Morelia, Michoacan, Mexico..
    Lagunas-Rangel, Francisco Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Idiopathic granulomatous orchitis: A case study2024In: Urology Case Reports, E-ISSN 2214-4420, Vol. 54, article id 102754Article in journal (Refereed)
    Abstract [en]

    Idiopathic granulomatous orchitis (IGO) is a rare inflammatory disorder of unknown etiology affecting the testis. Presented here is the case of a young patient who developed IGO, potentially associated with an anti -sperm antibody-mediated autoimmune response.

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  • 15.
    Benavides-Huerto, Miguel Armando
    et al.
    Lab Pathol & Cytopathol Dr Miguel Benavides, Morelia 58260, Michoacan, Mexico..
    Paramo-Figueroa, Lourdes
    High Specialty Visual Clin, Acambaro 38600, Guanajuato, Mexico..
    Moreno-Paramo, Daniel
    High Specialty Visual Clin, Acambaro 38600, Guanajuato, Mexico..
    Lagunas-Rangel, Francisco Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Genet & Mol Biol, Mexico City 07360, Mexico..
    Primary Orbital Myxoid Liposarcoma2023In: Medical Sciences, E-ISSN 2076-3271, Vol. 11, no 4, article id 72Article in journal (Refereed)
    Abstract [en]

    Although liposarcoma is the most prevalent soft tissue sarcoma in adults, head and neck liposarcomas are rare and account for less than 5% of all liposarcomas. The primary orbital location is even more exceptional, with fewer than 100 cases documented in the medical literature. Given the scarcity of cases of orbital liposarcoma and the limited familiarity of physicians and pathologists with this pathology, there is an increased risk of non-diagnosis or misdiagnosis, which may lead to inappropriate patient management. To address these challenges, we present a case of primary orbital myxoid liposarcoma and subsequently discuss the primary findings of this case based on the evidence documented in the medical literature. This comprehensive text is designed to serve as a valuable resource for healthcare professionals and pathologists, with the goal of promoting both clinical suspicion and accurate diagnosis and treatment of this rare condition in future cases.

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  • 16.
    Bendre, Megha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland.
    Checknita, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åslund, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Hodgins, Sheilagh
    Univ Montreal, Ctr Rech Inst Natl Psychiat Legale Philippe Pinel, Montreal, PQ, Canada.;Univ Montreal, Dept Psychiat, Montreal, PQ, Canada..
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Mälardalen Univ, Sch Hlth Care & Social Welf, Div Publ Hlth Sci, Västerås, Sweden.
    Good parent-child relationship protects against alcohol use in maltreated adolescent females carrying the MAOA-uVNTR susceptibility allele2024In: Frontiers in Psychiatry, E-ISSN 1664-0640, Vol. 15, article id 1375363Article in journal (Refereed)
    Abstract [en]

    Introduction: Risk-allele carriers of a Monoamine oxidase A (MAOA) gene, short-allele (MAOA-S) in males and long-allele (MAOA-L) in females, in the presence of a negative environment, are associated with alcohol misuse. Whether MAOA-S/L alleles also present susceptibility to a positive environment to mitigate the risk of alcohol misuse is unknown. Thus, we assessed the association of the three-way interaction of MAOA, maltreatment, and positive parent-child relationship with alcohol consumption among adolescents.

    Methods: This prospective study included 1416 adolescents (females: 59.88%) aged 16 ̵ 19 years from Sweden, enrolled in the “Survey of Adolescent Life in Västmanland” in 2012. Adolescents self-reported alcohol consumption, maltreatment by a family (FM) or non-family member (NFM), parent-child relationship, and left saliva for MAOA genotyping.

    Results and discussion: We observed sex-dependent results. Females carrying MAOA-L with FM or NFM and a good parent-child relationship reported lower alcohol consumption than those with an average or poor parent-child relationship. In males, the interactions were not significant. Results suggest MAOA-L in females, conventionally regarded as a “risk”, is a “plasticity” allele as it is differentially susceptible to negative and positive environments. Results highlight the importance of a good parent-child relationship in mitigating the risk of alcohol misuse in maltreated individuals carrying genetic risk. However, the interactions were not significant after adjusting to several environmental and behavioural covariates, especially parent’s alcohol use, negative parent-child relationship, and nicotine use (smoking and/or snus), suggesting predictor and outcome intersection. Future studies and frameworks for preventive strategies should consider these covariates together with alcohol consumption. More studies with larger sample sizes are needed to replicate the findings.

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  • 17.
    Bondarev, Andrey D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Chubarev, Vladimir N.
    Adv Mol Technol LLC, Moscow, Russia..
    Tarasov, Vadim V.
    Adv Mol Technol LLC, Moscow, Russia..
    Liu, Wen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1057083Article, review/survey (Refereed)
    Abstract [en]

    The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors' will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.

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  • 18.
    Bondarev, Andrey D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Chubarev, Vladimir N.
    Adv Mol Technol LLC, Moscow 354340, Russia..
    V. Tarasov, Vadim
    Adv Mol Technol LLC, Moscow 354340, Russia..
    Lagunas-Rangel, Francisco Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Latvian Inst Organ Synth, Lab Pharmaceut Pharmacol, Riga, Latvia.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales2024In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 209, article id 107431Article in journal (Refereed)
    Abstract [en]

    The nucleic acid topoisomerases (TOP) are an evolutionary conserved mechanism to solve topological problems within DNA and RNA that have been historically well-established as a chemotherapeutic target. During investigation of trends within clinical trials, we have identified a very high number of clinical trials involving TOP inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 233 unique molecules with TOP-inhibiting activity. In this review, we provide an overview of the clinical drug development highlighting advances in current clinical uses and discussing novel drugs and indications under development. A wide range of bacterial infections, along with solid and hematologic neoplasms, represent the bulk of clinically approved indications. Negative ADR profile and drug resistance among the antibacterial TOP inhibitors and anthracycline-mediated cardiotoxicity in the antineoplastic TOP inhibitors are major points of concern, subject to continuous research efforts. Ongoing development continues to focus on bacterial infections and cancer; however, there is a degree of diversification in terms of novel drug classes and previously uncovered indications, such as glioblastoma multiforme or Clostridium difficile infections. Preclinical studies show potential in viral, protozoal, parasitic and fungal infections as well and suggest the emergence of a novel target, TOP III beta. We predict further growth and diversification of the field thanks to the large number of experimental TOP inhibitors emerging.

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  • 19.
    Bostrom, Adrian E. Desai
    et al.
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Karolinska Univ Hosp, Ctr Psychiat Res, Dept Clin Neurosci, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm Hlth Care Serv, Reg Stockholm, SE-17176 Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth Neuropediat, Stockholm, Sweden..
    Jamshidi, Esmail
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Reg Stockholm, Stockholm Hlth Care Serv, Stockholm, Sweden..
    Manu, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Kular, Lara
    Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med, Dept Clin Neruosci Neuro, Stockholm, Sweden..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Asberg, Marie
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Jokinen, Jussi
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Epigenetic changes in the CYP2D6 gene are related to severity of suicide attempt: A cross-sectional study of suicide attempters2023In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 160, p. 217-224Article in journal (Refereed)
    Abstract [en]

    Background: The ability to accurately estimate risk of suicide deaths on an individual level remains elusive.

    Methods: This study reports on a case-control study set-up from a well-characterized cohort of 88 predominantly female suicide attempters (SA), stratified into low- (n = 57) and high-risk groups (n = 31) based on reports of later death by suicide, as well as degree of intent-to-die and lethality of SA method. We perform an unbiased analysis of 12,930 whole-blood derived CpG-sites (Illumina Infinium EPIC BeadChip) previously demonstrated to be more conciliable with brain-derived variations. The candidate site was validated by pyrosequencing. External replication was performed in (1) relation to age at index suicide attempt in 97 women with emotionally unstable personality disorder (whole-blood) and (2) death by suicide in a mixed group of 183 prefrontal-cortex (PFC) derived samples who died by suicide or from non-psychiatric etiologies.

    Results: CYP2D6-coupled CpG-site cg07016288 was hypomethylated in severe suicidal behavior (p < 10E-06). Results were validated by pyrosequencing (p < 0.01). Replication analyses demonstrate hypomethylation of cg07016288 in relation to age at index SA in females (p < 0.05) and hypermethylation in PFC of male suicide completers (p < 0.05). Limitations: Genotyping of CYP2D6 was not performed and CpG-site associations to gene expression were not explored.

    Conclusions: CYP2D6-coupled epigenetic markers are hypomethylated in females in dependency of features known to confer increased risk of suicide deaths and hypermethylated in PFC of male suicide completers. Further elucidating the role of CYP2D6 in severe suicidality or suicide deaths hold promise to deduce clinically meaningful results.

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  • 20.
    Brooks, Samantha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Liverpool John Moores Univ, Sch Psychol, Liverpool, England.;Univ Witwatersrand, Neurosci Res Lab NeuRL, Dept Psychol, Sch Human & Community Dev, Johannesburg, South Africa..
    Dahl, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dudley-Jones, R.
    Liverpool John Moores Univ, Sch Psychol, Liverpool, England..
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    A neuroinflammatory compulsivity model of anorexia nervosa (NICAN)2024In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 159, article id 105580Article, review/survey (Refereed)
    Abstract [en]

    Anorexia nervosa (AN) is an eating disorder often highly resistant to treatment, characterised by restrictive eating and/or compensatory behaviours such as purging or excessive exercising, leading to low body weight and dysregulated appetite. The recovery rate is low for those with AN in standard treatment, including cognitive behavioural therapy (CBT), enhanced-CBT, and anti-depressant medication, and risk of relapse is high (Muratore, Attia, 2021; Monteleone et al., 2022; Dalle Grave et al., 2023) estimated at around an annual global rate of 50% (Steinhausen, 2002, Frostad et al., 2022). Moreover, longitudinal studies show that for those with over twenty years lived experience of AN, recovery rate is only 40–63% (Eddy et al., 2017, Fichter et al., 2017). And for the last five years in the UK (2017–2022), an alarming 84% rise in AN admissions to the National Health Service was reported (Royal College of Psychiatrists, 2022), a rise echoed around the world, especially in high-income countries (Zipfel et al., 2022). Given this alarming rise, some clinicians are dividing opinion by suggesting palliative care and medically assisted death for treatment resistant AN (Royal College of Psychiatrists, 2023). Considering the dangerous nature of AN and heightened risk of death, new approaches are urgently needed to examine novel neurobiological mechanisms maintaining the disorder that may improve global treatment resistance.

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  • 21.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Faculty of Health, School of Psychology, Liverpool John Moores University, Liverpool SE3 3AF, UK. Neuroscience Research Laboratory (NeuRL), Department of Psychology, School of Human and Community Development, University of the Witwatersrand, Johannesburg 2000, South Africa..
    Titova, Olga E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology.
    Ashworth, Emma L.
    Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool SE3 3AF, Merseyside, England..
    Bylund, Simon B. A.
    Uppsala Cty Council, S-75125 Uppsala, Sweden..
    Feldman, Inna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Self-Reported Psychosomatic Complaints and Conduct Problems in Swedish Adolescents2022In: Children, E-ISSN 2227-9067, Vol. 9, no 7, article id 963Article in journal (Refereed)
    Abstract [en]

    Physical conditions in children and adolescents are often under reported during mainstream school years and may underlie mental health disorders. Additionally, comparisons between younger and older schoolchildren may shed light on developmental differences regarding the way in which physical conditions translate into conduct problems. The aim of the current study was to examine the incidence of psychosomatic complaints (PSC) in young and older adolescent boys and girls who also report conduct problems. A total of 3132 Swedish adolescents (age range 15-18 years, 47% boys) completed the Uppsala Life and Health Cross-Sectional Survey (LHS) at school. The LHS question scores were categorised by two researchers who independently identified questions that aligned with DSM-5 conduct disorder (CD) criteria and PSC. MANOVA assessed the effects of PSC, age, and gender on scores that aligned with the DSM criteria for CD. The main effects of gender, age, and PSC on the conduct problem scores were observed. Adolescents with higher PSC scores had higher conduct problem scores. Boys had higher serious violation of rules scores than girls, particularly older boys with higher PSC scores. Psychosomatic complaints could be a useful objective identifier for children and adolescents at risk of developing conduct disorders. This may be especially relevant when a reliance on a child's self-reporting of their behavior may not help to prevent a long-term disturbance to their quality of life.

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  • 22.
    Chen, Cheng
    et al.
    Anhui Normal Univ, Sch Phys Educ, Wuhu, Peoples R China..
    Dang, Junhua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Huaibei Normal Univ, Sch Educ, Huaibei, Peoples R China.;Anhui Engn Res Ctr Intelligent Comp & Applicat Cog, Hefei, Anhui, Peoples R China..
    The Longitudinal Relationship Between Parenting and Self-Control Needs Reconsideration: A Commentary on Li et al. (2019)2023In: Perspectives on Psychological Science, ISSN 1745-6916, E-ISSN 1745-6924, Vol. 18, no 6, p. 1488-1491Article in journal (Other academic)
    Abstract [en]

    The relationship between parenting and self-control has received much attention from social and developmental psychologists. In a meta-analytic review, Li et al. (2019) identified a longitudinal association between parenting and subsequent self-control (P ? SC) of r = .157, p < .001, and a longitudinal association between adolescent self-control and subsequent parenting (SC ? P) of r = .155, p < .001. However, the longitudinal associations may have been substantially biased because Li et al. (2019) utilized the bivariate correlation between the predictor at Time 1 and the outcome at Time 2 to estimate the effect size. To provide a more accurate estimate of the longitudinal association between parenting and adolescent self-control, we reexamined the data on the basis of the cross-lagged association. The results showed weaker longitudinal associations for both P ? SC (r = .059, p < .001) and SC ? P (r = .062, p < .001). Our results point to the importance of utilizing the cross-lagged association in meta-analyzing the longitudinal relationship between variables.

  • 23.
    Chen, Liangkai
    et al.
    Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg,Hubei Key Lab Food Nutr & Saf, Wuhan 430030, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Minist Educ Key Lab Environm & Hlth, Wuhan 430030, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg, 13 Hangkong Rd, Wuhan 430030, Peoples R China..
    Li, Xingbang
    Wuhan Univ Sci & Technol, Wuhan Asia Heart Hosp, Congenital Heart Dis Ctr, Wuhan 430022, Peoples R China..
    Lv, Yanling
    Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg,Hubei Key Lab Food Nutr & Saf, Wuhan 430030, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Minist Educ Key Lab Environm & Hlth, Wuhan 430030, Peoples R China..
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Karolinska Inst, Dept Clin Neurosci, S-17165 Stockholm, Sweden..
    Zhong, Victor W.
    Shanghai Jiao Tong Univ, Sch Med, Sch Publ Hlth, Dept Epidemiol, Shanghai 200025, Peoples R China..
    Rong, Shuang
    Wuhan Univ Sci & Technol, Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg, Wuhan 430065, Peoples R China..
    Liu, Gang
    Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg,Hubei Key Lab Food Nutr & Saf, Wuhan 430030, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Minist Educ Key Lab Environm & Hlth, Wuhan 430030, Peoples R China..
    Liu, Liegang
    Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg,Hubei Key Lab Food Nutr & Saf, Wuhan 430030, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Minist Educ Key Lab Environm & Hlth, Wuhan 430030, Peoples R China.;Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Publ Hlth, Dept Nutr & Food Hyg, 13 Hangkong Rd, Wuhan 430030, Peoples R China..
    Physical frailty, adherence to ideal cardiovascular health and risk of cardiovascular disease: a prospective cohort study2023In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 52, no 1, article id afac311Article in journal (Refereed)
    Abstract [en]

    Background: longitudinal evidence concerning frailty phenotype and the risk of cardiovascular disease (CVD) remained insufficient, and whether CVD preventive strategies exert low CVD risk on frail adults is unclear.

    Objectives: we aimed to prospectively evaluate the association of frailty phenotype, adherence to ideal cardiovascular health (CVH) and their joint associations with the risk of CVD.

    Methods: a total of 314,093 participants from the UK Biobank were included. Frailty phenotype was assessed according to the five criteria of Fried et al.: weight loss, exhaustion, low physical activity, slow gait speed and low grip strength. CVH included four core health behaviours (smoking, physical activity and diet) and three health factors (weight, cholesterol, blood pressure and glycaemic control). The outcome of interest was incident CVD, including coronary heart disease, heart failure and stroke.

    Results: compared with the non-frail people whose incident rate of overall CVD was 6.54 per 1,000 person-years, the absolute rate difference per 1,000 person-years was 1.67 (95% confidence interval, CI: 1.33, 2.02) for pre-frail and 5.00 (95% CI: 4.03, 5.97) for frail. The ideal CVH was significantly associated with a lower risk of all CVD outcomes. For the joint association of frailty and CVH level with incident CVD, the highest risk was observed among frailty accompanied by poor CVH with an HR of 2.92 (95% CI: 2.68, 3.18).

    Conclusions: our findings indicate that physical frailty is associated with CVD incidence. Improving CVH was significantly associated with a considerable decrease in CVD risk, and such cardiovascular benefits remain for the frailty population.

  • 24. Chávez-Valencia, Venice
    et al.
    Orizaga-de-la-Cruz, Citlalli
    Lagunas-Rangel, Francisco Alejandro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Acute Kidney Injury in COVID-19 Patients: Pathogenesis, Clinical Characteristics, Therapy, and Mortality2022In: Diseases, E-ISSN 2079-9721, Vol. 10, no 3, article id 53Article, review/survey (Refereed)
    Abstract [en]

    Coronavirus disease 2019 (COVID-19) is a disease caused by infection with the SARS-CoV-2 virus and has represented one of the greatest challenges humanity has faced in recent years. The virus can infect a large number of organs, including the lungs and upper respiratory tract, brain, liver, kidneys, and intestines, among many others. Although the greatest damage occurs in the lungs, the kidneys are not exempt, and acute kidney injury (AKI) can occur in patients with COVID-19. Indeed, AKI is one of the most frequent and serious organic complications of COVID-19. The incidence of COVID-19 AKI varies widely, and the exact mechanisms of how the virus damages the kidney are still unknown. For this reason, the purpose of this review was to assess current findings on the pathogenesis, clinical features, therapy, and mortality of COVID-19 AKI.

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  • 25.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Challenges in Analyzing Functional Epigenetic Data in Perspective of Adolescent Psychiatric Health2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 10, article id 5856Article, review/survey (Refereed)
    Abstract [en]

    The formative period of adolescence plays a crucial role in the development of skills and abilities for adulthood. Adolescents who are affected by mental health conditions are at risk of suicide and social and academic impairments. Gene-environment complementary contributions to the molecular mechanisms involved in psychiatric disorders have emphasized the need to analyze epigenetic marks such as DNA methylation (DNAm) and non-coding RNAs. However, the large and diverse bioinformatic and statistical methods, referring to the confounders of the statistical models, application of multiple-testing adjustment methods, questions regarding the correlation of DNAm across tissues, and sex-dependent differences in results, have raised challenges regarding the interpretation of the results. Based on the example of generalized anxiety disorder (GAD) and depressive disorder (MDD), we shed light on the current knowledge and usage of methodological tools in analyzing epigenetics. Statistical robustness is an essential prerequisite for a better understanding and interpretation of epigenetic modifications and helps to find novel targets for personalized therapeutics in psychiatric diseases.

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  • 26.
    Cornejo, María Paula
    et al.
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina..
    Fernandez, Gimena
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina..
    Cabral, Agustina
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina..
    Barrile, Franco
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina..
    Heredia, Florencia
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina..
    García Romero, Guadalupe
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina..
    Zubimendi Sampieri, Juan Pablo
    YPF Tecnol CONICET, RA-1923 Berisso, Buenos Aires, Argentina..
    Quelas, Juan Ignacio
    YPF Tecnol CONICET, RA-1923 Berisso, Buenos Aires, Argentina..
    Cantel, Sonia
    Univ Montpellier, Inst Biomol Max Mousseron, CNRS, ENSCM, Montpellier, France..
    Fehrentz, Jean-Alain
    Univ Montpellier, Inst Biomol Max Mousseron, CNRS, ENSCM, Montpellier, France..
    Alonso, Antonia
    Univ Murcia, Fac Med, Dept Human Anat & Psychobiol, Murcia 30100, Spain..
    Pla, Ramon
    Univ Murcia, Fac Med, Dept Human Anat & Psychobiol, Murcia 30100, Spain.;Virgen de la Arrixaca Univ Hosp, Inst Biomed Res Murcia IMIB, Murcia 30100, Spain..
    Ferran, José Luis
    Univ Murcia, Fac Med, Dept Human Anat & Psychobiol, Murcia 30100, Spain.;Virgen de la Arrixaca Univ Hosp, Inst Biomed Res Murcia IMIB, Murcia 30100, Spain..
    Andreoli, María Florencia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Comis Invest Cient Prov Buenos Aires CIC PBA, Inst Desarrollo Invest Pediat IDIP, HIAEP Sor Maria Ludov La Plata, RA-1900 La Plata, Buenos Aires, Argentina.
    De Francesco, Pablo Nicolas
    Univ Nacl la Plata UNLP, Consejo Nacl Invest Cientif & Tecn CONICET, Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, RA-1900 La Plata, Buenos Aires, Argentina; Inst Multidisciplinario Biol Celular IMBICE, Grp Neurofisiol, Calle 526 S-N Entre 10 & 11 POB 403, RA-1900 La Plata, Buenos Aires, Argentina.
    Perelló, Mario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Grupo de Neurofisiología, Instituto Multidisciplinario de Biología Celular (IMBICE), Universidad Nacional la Plata (UNLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) y Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC-PBA), La Plata 1900, Buenos Aires, Argentina.
    GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice2024In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 165, no 7, article id bqae061Article in journal (Refereed)
    Abstract [en]

    The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)–producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)–expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation–induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.

  • 27.
    Dahlén, Amelia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Univ Roma Tor Vergata, Dept Biomed & Prevent, I-00133 Rome, Italy.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Liverpool John Moores Univ, Sch Psychol, Fac Hlth, Liverpool, Merseyside, England.;Univ Witwatersrand, Sch Human & Community Dev, Dept Psychol, Neurosci Res Lab NeuRL, Johannesburg, South Africa.
    Phonological working memory is adversely affected in adults with anorexia nervosa: a systematic literature review2022In: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 27, no 6, p. 1931-1952Article, review/survey (Refereed)
    Abstract [en]

    Purpose Cognitive restraint has potentiating and deleterious effects on working memory (WM) in anorexia nervosa (AN). Conflicting evidence may be due to heterogeneity of tasks examining different WM components (e.g., verbal/auditory versus visuospatial), and differences in adolescent versus adult AN. Additionally, differential cognitive profiles of restricting versus binge/purging subtypes, comorbid psychiatric disorders and psychotropic medication use may confound findings.

    Methods To address these conflicts, 25 studies, published between 2016 and 2021, investigating WM in children, adolescents and adults with AN were systematically reviewed using PRISMA guidelines.

    Results In 71% of WM tasks, no difference in performance between AN patients and age-matched controls was reported, while 29% of WM tasks showed worse performance. Adults with AN displayed deficits in 44% of the verbal/auditory tasks, while performance remained unaffected in 86% of visuospatial tasks.

    Conclusion Examining age groups and WM subsystems separately revealed novel findings of differentially affected WM components in AN. Comorbidities and psychotropic medications were common among AN participants and should be regarded as critical confounding factors for WM measures. Future studies examining different components of WM, acknowledging these confounding factors, may reveal specific deficits in AN to aid treatment improvement strategies.

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  • 28.
    Dahlén, Amelia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Schofield, Aphra
    Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool, Lancashire, England..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool, Lancashire, England.;Univ Witwatersrand, Sch Human & Community Dev, Dept Psychol, Johannesburg, South Africa..
    Subliminal Emotional Faces Elicit Predominantly Right-Lateralized Amygdala Activation: A Systematic Meta-Analysis of fMRI Studies2022In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 16, article id 868366Article, review/survey (Refereed)
    Abstract [en]

    Prior research suggests that conscious face processing occurs preferentially in right hemisphere occipito-parietal regions. However, less is known about brain regions associated with non-conscious processing of faces, and whether a right-hemispheric dominance persists in line with specific affective responses. We aim to review the neural responses systematically, quantitatively, and qualitatively underlying subliminal face processing. PubMed was searched for Functional Magnetic Resonance Imaging (fMRI) publications assessing subliminal emotional face stimuli up to March 2022. Activation Likelihood Estimation (ALE) meta-analyses and narrative reviews were conducted on all studies that met ALE requirements. Risk of bias was assessed using the AXIS tool. In a meta-analysis of all 22 eligible studies (merging clinical and non-clinical populations, whole brain and region of interest analyses), bilateral amygdala activation was reported in the left (x = -19.2, y = 1.5, z = -17.1) in 59% of studies, and in the right (x = 24.4, y = -1.7, z = -17.4) in 68% of studies. In a second meta-analysis of non-clinical participants only (n = 18), bilateral amygdala was again reported in the left (x = -18, y = 3.9, z = -18.4) and right (x = 22.8, y = -0.9, z = -17.4) in 56% of studies for both clusters. In a final meta-analysis of whole-brain studies only (n=14), bilateral amygdala was also reported in the left (x = -20.2, y = 2.9, z = -17.2) in 64% of studies, and right (x = 24.2, y = -0.7, z = -17.8) in 71% of studies. The findings suggest that non-consciously detected emotional faces may influence amygdala activation, especially right-lateralized (a higher percentage of convergence in studies), which are integral for pre-conscious affect and long-term memory processing.

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  • 29.
    Dambrova, Maija
    et al.
    Latvian Inst Organ Synth, Lab Pharmaceut Pharmacol, Aizkraukles Str 21, LV-1006 Riga, Latvia..
    Makrecka-Kuka, Marina
    Latvian Inst Organ Synth, Lab Pharmaceut Pharmacol, Aizkraukles Str 21, LV-1006 Riga, Latvia..
    Kuka, Janis
    Latvian Inst Organ Synth, Lab Pharmaceut Pharmacol, Aizkraukles Str 21, LV-1006 Riga, Latvia..
    Vilskersts, Reinis
    Latvian Inst Organ Synth, Lab Pharmaceut Pharmacol, Aizkraukles Str 21, LV-1006 Riga, Latvia..
    Nordberg, Didi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Smesny, Stefan
    Jena Univ Hosp, Dept Psychiat, Jena, Germany..
    Sen, Zumrut Duygu
    Jena Univ Hosp, Dept Psychiat, Jena, Germany..
    Guo, An Chi
    Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada..
    Oler, Eponine
    Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada..
    Tian, Siyang
    Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada..
    Zheng, Jiamin
    Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada..
    Wishart, David S.
    Univ Alberta, Dept Biol Sci, Edmonton, AB, Canada..
    Liepinsh, Edgars
    Latvian Inst Organ Synth, Lab Pharmaceut Pharmacol, Aizkraukles Str 21, LV-1006 Riga, Latvia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials2022In: Pharmacological Reviews, ISSN 0031-6997, E-ISSN 1521-0081, Vol. 74, no 3, p. 506-551Article, review/survey (Refereed)
    Abstract [en]

    Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal b-oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabo lome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. Significance Statement--This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.

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  • 30.
    Dang, Junhua
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Beijing Sport Univ, Sch Psychol, Beijing, Peoples R China..
    Jia, Lile
    Natl Univ Singapore, Dept Psychol, Singapore, Singapore.;Natl Univ Singapore, Ctr Populat Hlth, Singapore, Singapore..
    Validity issues in measures of COVID-19 preventive behaviours2023In: Journal of Global Health, ISSN 2047-2978, E-ISSN 2047-2986, Vol. 13, article id 03026Article in journal (Other academic)
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  • 31.
    Dang, Junhua
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Beijing Sport Univ, Sch Psychol, Beijing, Peoples R China..
    Xiao, Shanshan
    Stockholm Univ, Dept Psychol, Stockholm, Sweden..
    Collectivism reduces objective mobility trends to public areas during the COVID-19 pandemic2022In: Frontiers in Public Health, E-ISSN 2296-2565, Vol. 10, article id 996036Article in journal (Refereed)
    Abstract [en]

    In order to slow down the spread of the coronavirus, staying at home and avoiding going outside have been either strongly recommended or stringently enforced by governments all over the globe. Previous studies found that people with more collectivist orientation were more willing to comply with governmental guidelines and engage in preventive behaviors such as social distancing. However, these studies were based on self-report data within a short period. The current study aims to overcome these limitations by using objective mobility data generated by Google users all over the world during the past two years, thus providing a stronger test for the predictive effect of collectivism on preventive measures in response to the pandemic. We found consistent results at both the US state level (n = 50) and the country/territory level (n = 133), such that people in more collectivistic regions reduced their visits to and length of stay at certain public areas such as parks during the past two years. Our findings emphasize the importance of cultural values in face of global crises.

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  • 32.
    Dartora, Caroline
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden..
    Marseglia, Anna
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden..
    Martensson, Gustav
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden..
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Dang, Junhua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Muehlboeck, J-Sebastian
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden..
    Wahlund, Lars-Olof
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden..
    Moreno, Rodrigo
    KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Stockholm, Sweden..
    Barroso, Jose
    Univ Fernando Pessoa Canarias, Fac Ciencias Salud, Las Palmas Gran Canaria, Spain..
    Ferreira, Daniel
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden.;Univ Fernando Pessoa Canarias, Fac Ciencias Salud, Las Palmas Gran Canaria, Spain..
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience.
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Ctr Alzheimer Res, Stockholm, Sweden.;Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Neuroimaging Sci, Dept Neuroimaging, London, England..
    A deep learning model for brain age prediction using minimally preprocessed T1w images as input2024In: Frontiers in Aging Neuroscience, E-ISSN 1663-4365, Vol. 15, article id 1303036Article in journal (Refereed)
    Abstract [en]

    Introduction: In the last few years, several models trying to calculate the biological brain age have been proposed based on structural magnetic resonance imaging scans (T1-weighted MRIs, T1w) using multivariate methods and machine learning. We developed and validated a convolutional neural network (CNN)-based biological brain age prediction model that uses one T1w MRI preprocessing step when applying the model to external datasets to simplify implementation and increase accessibility in research settings. Our model only requires rigid image registration to the MNI space, which is an advantage compared to previous methods that require more preprocessing steps, such as feature extraction.

    Methods: We used a multicohort dataset of cognitively healthy individuals (age range = 32.0-95.7 years) comprising 17,296 MRIs for training and evaluation. We compared our model using hold-out (CNN1) and cross-validation (CNN2-4) approaches. To verify generalisability, we used two external datasets with different populations and MRI scan characteristics to evaluate the model. To demonstrate its usability, we included the external dataset's images in the cross-validation training (CNN3). To ensure that our model used only the brain signal on the image, we also predicted brain age using skull-stripped images (CNN4).

    Results: The trained models achieved a mean absolute error of 2.99, 2.67, 2.67, and 3.08 years for CNN1-4, respectively. The model's performance in the external dataset was in the typical range of mean absolute error (MAE) found in the literature for testing sets. Adding the external dataset to the training set (CNN3), overall, MAE is unaffected, but individual cohort MAE improves (5.63-2.25 years). Salience maps of predictions reveal that periventricular, temporal, and insular regions are the most important for age prediction.

    Discussion: We provide indicators for using biological (predicted) brain age as a metric for age correction in neuroimaging studies as an alternative to the traditional chronological age. In conclusion, using different approaches, our CNN-based model showed good performance using one T1w brain MRI pr