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  • 1.
    Addinsall, Alex B.
    et al.
    Department of Physiology and PharmacologyKarolinska InstituteStockholm.
    Cacciani, Nicola
    Department of Physiology and PharmacologyKarolinska InstituteStockholm;Department of Clinical NeuroscienceKarolinska InstituteStockholm.
    Akkad, Hasem
    Department of Physiology and PharmacologyKarolinska InstituteStockholm.
    Moruzzi, Noah
    Department of Molecular Medicine and SurgeryKarolinska InstituteStockholm.
    Maestri, Alice
    Department of MedicineKarolinska InstituteStockholm.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ruas, Jorge
    Department of Physiology and PharmacologyKarolinska InstituteStockholm.
    Larsson, Lars
    Department of Physiology and PharmacologyKarolinska InstituteStockholm;Viron Molecular Medicine InstituteBostonMA.
    Ruxolitinib Prevents Ventilator Induced Diaphragm Dysfunction2022In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 36, no S1Article in journal (Refereed)
    Abstract [en]

    Mechanical ventilation (MV), however brief results in the loss of diaphragm muscle mass and strength, termed ventilator induced diaphragm dysfunction (VIDD). VIDD increases dependence, complicates and prolongs weaning and significantly increases discharge mortality rate and health care costs worldwide. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway was recently identified as an important signalling pathway implicated in VIDD, upregulated in the diaphragm following MV and limb muslces during critical care. Regulation of STAT3 is imperritve to skeletal muscle mass and function, as STAT3 is required in proper muscle growth and regeneration, while chronic activation of STAT3 is implicated in muscle dysfunction. As JAK/STAT pathway inhibition can restrict the development of chronic muscle wasting conditons, this study aimed to explore the therapeutic potential of Ruxolitinib, an approved JAK1/2 inhibitor for myelofibrosis, for treatment of CIM. We hypothesised Ruxolitinib would reduce loss of muscle mass and function associated with VIDD. Here, rats were subjected to five days controlled MV (CMV) with and without daily Ruxolitinib gavage. Five-days CMV significantly reduced diaphragm muscle size and impaired specific force, which was associated with 2-fold upregulation of P-STAT3, disrupted mitochondrial structure and respiratory function. Expression of the motor protein myosin was not affected, however CMV may alter myosin function through deamidation post translational modification. Ruxolitinib increases five-day survival rate, restored P-STAT3 expression and preserved diaphragm muscle size and specific force. These functional improvements were associated with improved mitochondrial structure, augmented mitochondrial respiratory function and reversal or augmentation of myosin deamidations. These results provide evidence of the preclinical potential of repurposing Ruxolitinib for the treatment of VIDD.

  • 2.
    Addinsall, Alex B.
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden..
    Cacciani, Nicola
    Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden.;Karolinska Inst, Dept Clin Neurosci, Solna, Sweden..
    Backeus, Anders
    Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden..
    Hedstrom, Yvette
    Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden..
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Larsson, Lars
    Karolinska Inst, Dept Physiol & Pharmacol, Basic & Clin Muscle Biol Grp, Solnavagen 9, S-17165 Solna, Sweden.;Karolinska Inst, Dept Clin Neurosci, Solna, Sweden.;Viron Mol Med Inst Boston, Boston, MA USA..
    Electrical stimulated GLUT4 signalling attenuates critical illness-associated muscle wasting2022In: Journal of Cachexia, Sarcopenia and Muscle, ISSN 2190-5991, E-ISSN 2190-6009, Vol. 13, no 4, p. 2162-2174Article in journal (Refereed)
    Abstract [en]

    Background Critical illness myopathy (CIM) is a debilitating condition characterized by the preferential loss of the motor protein myosin. CIM is a by-product of critical care, attributed to impaired recovery, long-term complications, and mortality. CIM pathophysiology is complex, heterogeneous and remains incompletely understood; however, loss of mechanical stimuli contributes to critical illness-associated muscle atrophy and weakness. Passive mechanical loading and electrical stimulation (ES) therapies augment muscle mass and function. While having beneficial outcomes, the mechanistic underpinning of these therapies is less known. Therefore, here we aimed to assess the mechanism by which chronic supramaximal ES ameliorates CIM in a unique experimental rat model of critical care. Methods Rats were subjected to 8 days of critical care conditions entailing deep sedation, controlled mechanical ventilation, and immobilization with and without direct soleus ES. Muscle size and function were assessed at the single cell level. RNAseq and western blotting were employed to understand the mechanisms driving ES muscle outcomes in CIM. Results Following 8 days of controlled mechanical ventilation and immobilization, soleus muscle mass, myosin : actin ratio, and single muscle fibre maximum force normalized to cross-sectional area (CSA; specific force) were reduced by 40-50% (P < 0.0001). ES significantly reduced the loss of soleus muscle fibre CSA and myosin : actin ratio by approximately 30% (P < 0.05) yet failed to effect specific force. RNAseq pathway analysis revealed downregulation of insulin signalling in the soleus muscle following critical care, and GLUT4 trafficking was reduced by 55% leading to an 85% reduction of muscle glycogen content (P < 0.01). ES promoted phosphofructokinase and insulin signalling pathways to control levels (P < 0.05), consistent with the maintenance of GLUT4 translocation and glycogen levels. AMPK, but not AKT, signalling pathway was stimulated following ES, where the downstream target TBC1D4 increased 3 logFC (P = 0.029) and AMPK-specific P-TBC1D4 levels were increased approximately two-fold (P = 0.06). Reduction of muscle protein degradation rather than increased synthesis promoted soleus CSA, as ES reduced E3 ubiquitin proteins, Atrogin-1 (P = 0.006) and MuRF1 (P = 0.08) by approximately 50%, downstream of AMPK-FoxO3. Conclusions ES maintained GLUT4 translocation through increased AMPK-TBC1D4 signalling leading to improved muscle glucose homeostasis. Soleus CSA and myosin content was promoted through reduced protein degradation via AMPK-FoxO3 E3 ligases, Atrogin-1 and MuRF1. These results demonstrate chronic supramaximal ES reduces critical care associated muscle wasting, preserved glucose signalling, and reduced muscle protein degradation in CIM.

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  • 3.
    Ahlén, Caroline
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Outcome of patients with severe aortic stenosis – A retrospective follow-up study2008Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Aortic stenosis is the most common valvular disease in the adult population. A significant aortic stenosis is a serious condition, and if a symptomatic patient is not operated on, it may in most cases cause death. We have examined how many aortic stenoses that were diagnosed during one year, and a follow-up of the patients was also performed. We found 77 patients with significant aortic stenosis with a mean age of 76±13 years. At the time of follow-up 30 (39%) patients, aged between 29-85 years, had been surgically treated with implantation of a valve prosthesis within 2-23 months after the initial examination. At this initial examination 14 of the 30 patients who later underwent surgery had no symptoms. A coronary bypass operation was also performed on seven patients. Postoperative complications were observed in six patients, but none of them was fatal. At the initial examinations there were 26 (34%) patients with a significant aortic stenosis and symptoms who were not treated surgically. The main reason why these patients were not operated was high age, unwillingness, or severe left ventricular dysfunction. This study indicates the importance of repeated clinical and echocardiograpic examinations in patients with aortic stenosis. Almost half of the patients, that later underwent surgery, had no symptoms at the initial examination, but later developed symptoms which made surgery necessary. In one third of the patients no surgery was performed in spite of clinical symptoms.

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  • 4. Alfonso, Julieta
    et al.
    Pollevick, Guido
    Castensson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frasch, Alberto
    Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels2002In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, no 2, p. 225-34Article in journal (Refereed)
    Abstract [en]

    In mammals, gene transcription is a step subjected to tight regulation mechanisms. In fact, changes in mRNA levels in the central nervous system (CNS) can account for numerous phenotypic differences in brain function. We performed a high-resolution analysis of mRNA expression levels for 37 genes selected from a normal rat hippocampus cDNA library. mRNA amounts were quantified using a Real Time PCR SYBR Green assay. We found that, in general, individuals from an inbred rat population (n = 20) have shown 2-3 times differences in the basal level of expression of the genes analyzed. Up to several fold differences among individuals were observed for certain genes. These inter-individual differences were obtained after correction for the different amounts of mRNA in each sample. Power calculations were performed to determine the number of individuals required to detect reliable differences in expression levels between a control and an experimental group. These data indicated that, depending on the variability of the candidate gene selected, it was necessary to analyze from five to 135 individuals in each group to detect differences of 50% in the levels of mRNA expression between two groups investigated. The comparison of mRNA abundance from different genes revealed a wide range of expression levels for the 37 genes, showing a 26,000-fold difference between the highest and lowest expressed gene.

  • 5.
    Al-Lashi, Lord Laith Zuhair
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    GABA and SGLT2 inhibitor modulate human T lymphocyte effector function2023Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Sodium Glucose Co-Transporter 2 (SGLT2) inhibitors are one of the dominant drug groups used today for treatment of type 2 diabetes. There are several agents within the group that were investigated in this project: Phlorizin, Empagliflozin, Canagliflozin, Dapagliflozin and Ipragliflozin. SGLT2 inhibitors influence immune cells such as CD4+ T cells, and Gamma Aminobutyric Acid (GABA) also affects CD4+ T cells functions. This study aims to investigate how different SGLT2 inhibitors together with GABA in the presence/absence of insulin affect the effector function of CD4+ T cells. As these are very popular and usable substances in medical fields, it becomes an important basis to study what effect they have on CD4+ T cells effector functions.

    Peripheral Blood Mononuclear Cells (PBMCs) were collected from buffy coat of healthy donors to isolate CD4+ T cells. Cells were activated with anti-CD3 antibody and incubated with different concentrations of SGLT2 inhibitors at 5 mM and 16.7 mM glucose and examined by MTT assay and culture supernatant was collected. Empagliflozin (1uM and 10 uM) was chosen to proceed with to test together with GABA and insulin on CD4+ T cells. Western blot was performed to detect the SGLT2 protein and Sandwich IFNg ELISA was also performed to examine how cytokines such as IFNg were affected in the samples. 

    The presented results show that the SGLT2 protein can be detected in the samples and the IFNg levels were decreased in samples without insulin and increased with the addition of insulin as expected. This should be further investigated, and additional experiments need to be performed to confirm the effect on the CD4+ T cell effector functions.

  • 6.
    Almgren, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Endotracheal Suction a Reopened Problem2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During mechanical ventilation, patients are connected to the ventilator by an endotracheal tube. The tube needs to be cleaned from mucus by suction, which can cause negative effects such as lung collapse, hypoxemia and desaturation. These can be avoided by preoxygenation, change of ventilator settings, use of closed suction systems and recruitment manoeuvres. The aim of the study was to investigate the effects of endotracheal suction during different ventilator settings and by different suction methods. A method to reverse side effects was investigated.

    In anaesthetized pigs, the effect of suction during volume and pressure-controlled ventilation was investigated, and the effect of different suction systems and catheter sizes were compared. Suction efficacy was investigated in a bench study. The effect of recruitment manoeuvre added after suction, i.e. post-suction recruitment manoeuvre was evaluated.

    Endotracheal suction causes lung volume loss leading to impaired gas exchange, an effect that is more severe in pressure-controlled ventilation than in volume-controlled ventilation. When 14 French suction catheters were used more side effects were found compared to 12 French catheters, but no difference was found between open and closed suction system in pressure-controlled ventilation. Open suction system was more effective to remove mucus compared to closed system. Post-suction recruitment manoeuvre restored the side effects after the first recruitment when it was applied directly after suction.

    In conclusion, open endotracheal suction causes impairment in gas exchange and lung mechanics, and more so in pressure-controlled than in volume-controlled mode. These changes can be minimized if smaller suction catheters are used. A post-suction recruitment manoeuvre applied directly after suction restores lung function. It is obvious that the recruitment manoeuvre should be added directly after suction, because if the manoeuvre is delayed and the lung is collapsed and left collapsed, it will be more difficult to recruit the lung.

    List of papers
    1. Side effects of endotracheal suction in pressure and volume controlled ventilation
    Open this publication in new window or tab >>Side effects of endotracheal suction in pressure and volume controlled ventilation
    2004 (English)In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, no 3, p. 1077-1080Article in journal (Refereed) Published
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate the effects of endotracheal suction in volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) with an open suction system (OSS) or a closed suction system (CSS).

    DESIGN:

    Randomized comparison.

    SETTING:

    Animal research laboratory.

    PATIENTS:

    Twelve healthy anesthetized pigs.

    INTERVENTIONS:

    The effects of endotracheal suction during VCV and PCV with tidal volume (VT) of 14 mL/kg were compared. A 60-mm inner-diameter endotracheal tube was used. Ten-second suction was performed using OSS and CSS with 12F and 14F catheters connected to - 14 kPa vacuum.

    MEASUREMENTS AND RESULTS:

    Thirty minutes after suction in PCV, VT was still decreased by 27% (p < 0.001), compliance (Crs) by 28% (p < 0.001), and PaO(2) by 26% (p < 0.001); PaCO(2) was increased by 42% (p < 0.0001) and venous admixture by 158% (p = 0.003). Suction in VCV affected only Crs (decreased by 23%, p < 0.001) and plateau pressure (increased by 24%, p < 0.001). The initial impairment of gas exchange following suction in VCV was no longer statistically significant after 30 min.

    CONCLUSIONS:

    In conclusion, endotracheal suction causes lung collapse leading to impaired gas exchange, an effect that is more severe and persistent in PCV than in VCV.

    Keywords
    Animals, Intubation; Intratracheal/*adverse effects, Lung Compliance, Pulmonary Gas Exchange, Respiration; Artificial/*methods, Suction/*adverse effects, Support; Non-U.S. Gov't, Swine, Tidal Volume
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-92641 (URN)10.1378/chest.125.3.1077 (DOI)15006972 (PubMedID)
    Available from: 2005-02-25 Created: 2005-02-25 Last updated: 2018-01-13Bibliographically approved
    2. Negative tracheal pressure during suction differs between suction systems and catheter sizes
    Open this publication in new window or tab >>Negative tracheal pressure during suction differs between suction systems and catheter sizes
    2005 (English)Article in journal (Refereed) Published
    Place, publisher, year, edition, pages
    Uppsala: Institutionen för medicinsk cellbiologi, 2005
    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-7236 (URN)
    Available from: 2007-10-24 Created: 2007-10-24 Last updated: 2018-01-13
    3. Effectiveness and side effects of closed and open suctioning: an experimental evaluation
    Open this publication in new window or tab >>Effectiveness and side effects of closed and open suctioning: an experimental evaluation
    Show others...
    2004 In: Intensive Care Medicine, Vol. 30, no 8, p. 1630-7Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92643 (URN)
    Available from: 2005-02-25 Created: 2005-02-25Bibliographically approved
    4. Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs
    Open this publication in new window or tab >>Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs
    2004 (English)In: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, no 3, p. 339-345Article in journal (Refereed) Published
    Abstract [en]

    Endotracheal suction can cause partial lung collapse and hypoxia and alter lung mechanics. We investigated the effects of adding a recruitment manoeuvre directly after endotracheal suction to restore lung volume in volume-controlled ventilation and pressure-controlled ventilation modes. Five anaesthetized pigs were investigated. The effects of endotracheal suction with or without a recruitment manoeuvre were compared in random order. In volume-controlled ventilation, compliance decreased after suction from 33 +/- 5 to 26 +/- 6 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 6 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 8 +/- 4% (P<0.05), but had recovered at 30 minutes. In pressure-controlled ventilation, compliance decreased after suction from 34 +/- 3 to 25 +/- 7 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 7 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 13 +/- 7% (P<0.05), and had not recovered after 30 minutes, 10 +/- 4%. When a recruitment manoeuvre was applied directly after suction, no negative side-effects were registered in volume-controlled ventilation or pressure-controlled ventilation. We conclude that the impairment of lung mechanics and gas exchange induced by endotracheal suction can be prevented by a simple post-suction recruitment manoeuvre. Further studies are needed to identify a suitable suction recruitment manoeuvre in patients with diseased lungs.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-92644 (URN)15264727 (PubMedID)
    Available from: 2005-02-25 Created: 2005-02-25 Last updated: 2018-01-13Bibliographically approved
    5. The time frame for post-suction recruitment manoeuvre
    Open this publication in new window or tab >>The time frame for post-suction recruitment manoeuvre
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92645 (URN)
    Available from: 2005-02-25 Created: 2005-02-25 Last updated: 2010-01-13Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 7.
    Almgren, Birgitta
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Strid, Niklas
    Wickerts, Carl-Johan
    Högman, Marieann
    Negative tracheal pressure during suction differs between suction systems and catheter sizes2005Article in journal (Refereed)
  • 8.
    Almgren, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wickerts, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Heinonen, Erkki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Högman, Marieann
    Side effects of endotracheal suction in pressure and volume controlled ventilation2004In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, no 3, p. 1077-1080Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate the effects of endotracheal suction in volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) with an open suction system (OSS) or a closed suction system (CSS).

    DESIGN:

    Randomized comparison.

    SETTING:

    Animal research laboratory.

    PATIENTS:

    Twelve healthy anesthetized pigs.

    INTERVENTIONS:

    The effects of endotracheal suction during VCV and PCV with tidal volume (VT) of 14 mL/kg were compared. A 60-mm inner-diameter endotracheal tube was used. Ten-second suction was performed using OSS and CSS with 12F and 14F catheters connected to - 14 kPa vacuum.

    MEASUREMENTS AND RESULTS:

    Thirty minutes after suction in PCV, VT was still decreased by 27% (p < 0.001), compliance (Crs) by 28% (p < 0.001), and PaO(2) by 26% (p < 0.001); PaCO(2) was increased by 42% (p < 0.0001) and venous admixture by 158% (p = 0.003). Suction in VCV affected only Crs (decreased by 23%, p < 0.001) and plateau pressure (increased by 24%, p < 0.001). The initial impairment of gas exchange following suction in VCV was no longer statistically significant after 30 min.

    CONCLUSIONS:

    In conclusion, endotracheal suction causes lung collapse leading to impaired gas exchange, an effect that is more severe and persistent in PCV than in VCV.

  • 9.
    Almgren, Birgitta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Wickerts, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Högman, Marieann
    Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs2004In: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, no 3, p. 339-345Article in journal (Refereed)
    Abstract [en]

    Endotracheal suction can cause partial lung collapse and hypoxia and alter lung mechanics. We investigated the effects of adding a recruitment manoeuvre directly after endotracheal suction to restore lung volume in volume-controlled ventilation and pressure-controlled ventilation modes. Five anaesthetized pigs were investigated. The effects of endotracheal suction with or without a recruitment manoeuvre were compared in random order. In volume-controlled ventilation, compliance decreased after suction from 33 +/- 5 to 26 +/- 6 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 6 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 8 +/- 4% (P<0.05), but had recovered at 30 minutes. In pressure-controlled ventilation, compliance decreased after suction from 34 +/- 3 to 25 +/- 7 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 7 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 13 +/- 7% (P<0.05), and had not recovered after 30 minutes, 10 +/- 4%. When a recruitment manoeuvre was applied directly after suction, no negative side-effects were registered in volume-controlled ventilation or pressure-controlled ventilation. We conclude that the impairment of lung mechanics and gas exchange induced by endotracheal suction can be prevented by a simple post-suction recruitment manoeuvre. Further studies are needed to identify a suitable suction recruitment manoeuvre in patients with diseased lungs.

  • 10.
    Amandusson, Åsa
    et al.
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University.
    Blomqvist, Anders
    Estrogen receptor-α expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat2010In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, no 3, p. 245-248Article in journal (Refereed)
    Abstract [en]

    Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERalpha-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12% of ERalpha-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERalpha, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.

  • 11.
    Amandusson, Åsa
    et al.
    Linköpings Universitet.
    Hermansson, O
    Blomqvist, A
    Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat1995In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, no 1-2, p. 25-28Article in journal (Refereed)
    Abstract [en]

    Using an immunohistochemical technique, we demonstrate that large numbers of neurons in the laminar spinal trigeminal nucleus and spinal gray matter of the female rat express estrogen receptors (ER). Densely packed ER-immunoreactive neurons were present in lamina II, but labeled neurons were also present in lamina I, the neck of the dorsal horn, and in lamina X. Labeling was present throughout the length of the spinal cord, with the exception of segments caudal to S1, which were unlabeled. The distribution of ER-containing neurons to areas that are involved in processing of primary afferent nociceptive information suggests that the pain modulatory effects of estrogen may be exerted at the spinal level.

  • 12.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20072008Collection (editor) (Other (popular science, discussion, etc.))
    Download full text (pdf)
    fulltext
  • 13.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Department of Medical Cell Biology: Annual Report 20082009Collection (editor) (Other (popular science, discussion, etc.))
    Download full text (pdf)
    fulltext
  • 14. Antonsson, J B
    et al.
    Engström, L
    Rasmussen, I
    Wollert, S
    Haglund, U H
    Changes in gut intramucosal pH and gut oxygen extraction ratio in a porcine model of peritonitis and hemorrhage.1995In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 23, no 11, p. 1872-81Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To establish the relationship between gut intramucosal pH and blood flow to the gut, gut oxygen delivery, and gut oxygen extraction ratio in a porcine model of peritonitis and hemorrhage.

    DESIGN: Prospective, controlled study.

    SETTING: Experimental laboratory in a university teaching hospital.

    SUBJECTS: Thirty pigs of both sexes, weighing 15 to 22 kg.

    INTERVENTIONS: Animals were anesthetized, intubated, and mechanically ventilated. A flow probe was placed around the superior mesenteric artery for registration of blood flow. A tonometer was placed in the lumen of midileum for calculation of gut intramucosal pH. Hourly, for 5 hrs, blood samples were taken from mixed venous, mesenteric venous, and arterial blood. Five animals served as controls, ten animals had peritonitis induced by fecal instillation in the abdominal cavity, five were bled stepwise, five were bled rapidly (to a mean arterial pressure of 30 mm Hg), and five were bled rapidly and reinfused after 3 hrs.

    MEASUREMENTS AND MAIN RESULTS: Both peritonitis and hemorrhage caused decreases in gut blood flow and intramucosal pH. In mild peritonitis, the intramucosal pH decrease preceded that of blood flow. In all experimental groups, oxygen delivery decreased over time; in both mild and severe peritonitis, this decrease was preceded by a decrease of intramucosal pH. Intramucosal pH correlated well with gut oxygen extraction ratio in peritonitis (r2 = .86). In hemorrhage, there was a correlation of r2 = .66, but in intramucosal pH of < 7.12, a further decrease was accompanied only by minor changes in extraction ratio.

    CONCLUSIONS: Since a reduction in blood flow was preceded by a decrease in intramucosal pH, low intramucosal pH in peritonitis cannot be explained by low flow alone. Gut oxygen delivery proved to be a poor indicator of gut acidosis (i.e., low intramucosal pH). In peritonitis, a decreasing intramucosal pH was associated with an increasing oxygen extraction ratio. In hemorrhage, this association had a sharp deflection point below which a further decrease in intramucosal pH occurred concomitantly with an unchanged gut oxygen extraction ratio. Increased extraction ratio was not sufficient, not even initially, to maintain aerobic metabolism (i.e., unchanged intramucosal pH).

  • 15.
    Appelberg, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ventilation and Lung Volume During Sleep and in Obstructive Sleep Apnea2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obstructive sleep apnea (OSA) appears to affect up to 5% of the population. The extent to what pulmonary function awake and during sleep relates to obstructive breathing and hypoxemia during sleep in these patients is unclear. The aim of this study was to investigate respiratory function in patients with varying degree of snoring and OSA and to analyse regional lung aeration during sleep.

    In all, 35 healthy subjects and 90 patients with snoring and OSA were studied. The ventilatory response to CO2 (VRCO2) was measured. Lung function tests were performed. A technique based on computed tomography was developed to study lung aeration during sleep.

    Patients with OSA displayed a higher VRCO2 in comparison to healthy subjects and snorers (p<0.01). Increased closing volume and reduced expiratory reserve volume (ERV) were found in patients with OSA (p<0.001). In a multiple regression analysis, ERV was an independent predictor of nocturnal apnea (R2=0.13; p=0.001) and desaturation frequency (R2=0.11; p<0.01). In both healthy subjects and OSA patients, lung aeration was reduced during sleep by 0.10 ml gas/g tissue in the dorsal lung region (p<0.05 and p<0.01). OSA patients had a significantly lower gas/tissue ratio in comparison to healthy subjects both awake (-23%; p<0.04) and during sleep (-25%; p<0.04). In a univariate analysis, functional residual capacity (FRC) correlated with the change in lung aeration from wakefulness to sleep (r=-0.78; p<0.001). In patients with OSA, ERV (r=-0.69; p<0.05) and sleep time (r=0.69; p<0.05) correlated with the fall in lung aeration.

    In conclusion, patients with OSA display an increased ventilatory response to CO2, reduced ERV and increased closing volume. ERV predicts nocturnal apnea and desaturation frequency to a similar extent as obesity. Lung aeration is reduced in the dorsal region during sleep and patients with OSA display a lower amount of gas in comparison to healthy subjects. Decrease in lung volumes, promoting airway closure, and loss of muscle tone contributed to the altered lung function during sleep.

    List of papers
    1. Ventilatory response to CO2 in patients with snoring, obstructive hypopnoea and obstructive apnoea
    Open this publication in new window or tab >>Ventilatory response to CO2 in patients with snoring, obstructive hypopnoea and obstructive apnoea
    1997 In: Clinical Physiology, Vol. 17, p. 497-507Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90212 (URN)
    Available from: 2003-04-14 Created: 2003-04-14Bibliographically approved
    2. Lung volume and its correlation to nocturnal apnoea and desaturation
    Open this publication in new window or tab >>Lung volume and its correlation to nocturnal apnoea and desaturation
    2000 In: Respiratory Medicine, Vol. 94, p. 233-239Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90213 (URN)
    Available from: 2003-04-14 Created: 2003-04-14Bibliographically approved
    3. Lung aeration during sleep
    Open this publication in new window or tab >>Lung aeration during sleep
    Show others...
    2007 (English)In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 131, no 1, p. 122-129Article in journal (Refereed) Published
    Abstract [en]

    Background: During sleep, ventilation and functional residual capacity (FRC) decrease slightly. This study addresses regional lung aeration during wakefulness and sleep. Methods: Ten healthy subjects underwent spirometry awake and with polysomnography, including pulse oximetry, and also CT when awake and during sleep. Lung aeration in different lung regions was analyzed. Another three subjects were studied awake to develop a protocol for dynamic CT scanning during breathing. Results: Aeration in the dorsal, dependent lung region decreased from a mean of 1.14 ± 0.34 mL (± SD) of gas per gram of lung tissue during wakefulness to 1.04 ± 0.29 mL/g during non-rapid eye movement (NREM) sleep (- 9%) [p = 0.034]. In contrast, aeration increased in the most ventral, nondependent lung region, from 3.52 ± 0.77 to 3.73 ± 0.83 mL/g (+ 6%) [p = 0.007]. In one subject studied during rapid eye movement (REM) sleep, aeration decreased from 0.84 to 0.65 mL/g (- 23%). The fall in dorsal lung aeration during sleep correlated to awake FRC (R2 = 0.60; p = 0.008). Airway closure, measured awake, occurred near and sometimes above the FRC level. Ventilation tended to be larger in dependent, dorsal lung regions, both awake and during sleep (upper region vs lower region, 3.8% vs 4.9% awake, p = 0.16, and 4.5% vs 5.5% asleep, p = 0.09, respectively). Conclusions: Aeration is reduced in dependent lung regions and increased in ventral regions during NREM and REM sleep. Ventilation was more uniformly distributed between upper and lower lung regions than has previously been reported in awake, upright subjects. Reduced respiratory muscle tone and airway closure are likely causative factors.

    Keywords
    Airway closure, anesthesia, CT, lung aeration, lung volume, sleep, ventilation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90214 (URN)10.1378/chest.06-0359 (DOI)000243548100020 ()17218565 (PubMedID)
    Available from: 2003-04-14 Created: 2003-04-14 Last updated: 2017-12-14Bibliographically approved
    4. Lung aeration during sleep in patients with obstructive sleep apnea
    Open this publication in new window or tab >>Lung aeration during sleep in patients with obstructive sleep apnea
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90215 (URN)
    Available from: 2003-04-14 Created: 2003-04-14 Last updated: 2010-01-13Bibliographically approved
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    FULLTEXT01
  • 16. Arvidsson, D
    et al.
    Rasmussen, I
    Almqvist, P
    Niklasson, F
    Haglund, U
    Splanchnic oxygen consumption in septic and hemorrhagic shock.1991In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 109, no 2, p. 190-7Article in journal (Refereed)
    Abstract [en]

    Oxygen consumption (VO2) is dependent on oxygen delivery (DO2) in septic shock. Local hypoxia with later secondary organ failure may develop, however, despite an often hyperdynamic circulation. The splanchnic organs seem to be of vital importance in this context. In experiments performed in pigs we compared total body VO2 and DO2 with oxygen consumption and delivery in the gastrointestinal organs and the liver in two different shock states: (1) septic shock induced by peritonitis (n = 6) and (2) hemorrhagic shock (n = 6). Another group of six animals not in shock served as controls. Total, gastrointestinal, and liver DO2 decreased in a similar pattern in both septic and hemorrhagic shock. Gastrointestinal and liver VO2 increased in sepsis, whereas it was unchanged in hemorrhage. In the later phase of sepsis, liver VO2, but not gastrointestinal VO2, again decreased, because liver oxygen extraction was almost total and liver DO2 decreased further. The development of flow-dependent liver hypoxia was reflected in a decrease in liver lactate turnover (increased liver lactate release) during late sepsis. Early hypoxia in the splanchnic region is suggested as a plausible mechanism behind the development of secondary organ failure, especially in sepsis.

  • 17. Asghar, Afshan
    et al.
    Sharif, Ali
    Awan, Sana Javaid
    Akhtar, Bushra
    Akhtar, Muhammad Furqan
    Ali, Sajid
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Shahnaz,
    "Ficus johannis Boiss. leaves ethanolic extract ameliorate streptozotocin-induced diabetes in rats by upregulating the expressions of GCK, GLUT4, and IGF and downregulating G6P"2023In: Environmental Science and Pollution Research, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 30, no 17, p. 49108-49124Article in journal (Refereed)
    Abstract [en]

    The leaves of Ficus johannis Boiss (F. johannis), commonly known as Fig tree, Anjir, and Teen, are used by the folk medicinal practitioners in Iran for controlling hyperglycemia in diabetic patients. This study investigated the pharmacological basis for antidiabetic effect of the ethanolic extract of F. johannis leaves using in vitro and in vivo experimental models. Qualitative screening of phytochemicals, estimation of total phenolic and flavonoid contents, and in vitro antioxidant and α-amylase inhibition assays were performed. Moreover, the High-performance liquid chromatography (HPLC) quantification, acute toxicity, glucose tolerance, and in vivo antidiabetic effect along with the evaluation of gene expressions involved in diabetes mellitus were carried out. Significant quantities of phenolic (71.208 ± 2.89 mgg−1 GAE) and flavonoid (26.38 ± 3.53 mgg−1 QE) were present. Inhibitory concentration (IC50) of the plant extract exhibited an excellent in vitro antioxidant (IC50 = 33.81 µg/mL) and α-amylase (IC50 = 12.18 µg/mL) inhibitory potential. The HPLC analysis confirmed the gallic acid (257.79 mgg−1) as main constituent of the extract followed by kaempferol (22.86 mgg−1), myricetin (0.16 mgg−1), and quercetin (3.22 mgg−1). Ethanolic extract displayed glucose tolerance in normo-glycemic rats. Streptozotocin-induced hyperglycemia declined dose dependently in the extract treated rats with improvement in lipid profile and liver and renal function biomarkers. The F. johannis-treated groups showed an increase in mRNA expressions of glucose transporter 4 (GLUT-4), glucokinase, insulin growth like factor 1 and peroxisomal proliferator activating receptor gamma in pancreas. However, the Glucose-6-phosphatase was downregulated. Present study suggests that the ethanolic extract of F. johannis leaves demonstrates a good anti-diabetic profile by improving insulin sensitivity, GLUT-4 translocation, and carbohydrate metabolism while inhibiting lipogenesis.

  • 18.
    Atuma, C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide-independent but mast cell- and platelet-activating factor receptor-dependent pathway in rats1999In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, no 12, p. 1183-1189Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously shown that water extracts from Helicobacter pylori reduce gastric mucosal blood flow by approximately 15%. It has also been suggested that H. pylori can inhibit endogenous nitric oxide (NO) biosynthesis. Our aim was to examine whether the reduction in blood flow induced by H. pylori is the direct consequence of an NO synthase inhibition and the possible involvement of mast cell degranulation.

    METHODS: A water extract was produced from wildtype strain 88-23. The extract was applied on the exteriorized gastric corporal mucosa in inactin-anesthetized rats, after removing as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured with laser-Doppler flowmetry.

    RESULTS: In rats pretreated with the NO synthase inhibitor N-nitro-L-arginine there was a 19% +/- 6% reduction in blood flow 40 min after application of the extract, and a 27% +/- 9% reduction after another 20 min with saline. The reduction was abolished by concomitant pretreatment with the mast cell stabilizer ketotifen or the platelet-activating factor (PAF) receptor antagonist WEB2086.

    CONCLUSION: The reduction in mucosal blood flow induced by the extract was probably mediated through an acute inflammatory response involving mast cell degranulation with consequent PAF secretion. The effect on blood flow was not the result of a decrease in vascular tone due to an inhibition of endogenous NO biosynthesis.

  • 19.
    Atuma, Christer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Physiology.
    Gastrointestinal mucosal protective mechanisms: Mudolatory effects of Heliobacter pyroli on the gastric mucus gel barrier and mucosal blood flow in vivo2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The gastrointestinal mucus gel layer and blood flow are two important mechanisms for protection at the pre-epithelial and sub-epithelial levels, respectively. Helicobacter pylori might circumvent these mechanisms and elicit a chronic inflammatory response with consequent ulcers in the stomach and duodenum. In this thesis, the physical state and properties of the adherent mucus gel layer was studied from the stomach to colon. Furthermore, the acute and chronic effects of H. pylori on the integrity of the mucus gel layer and mucosal blood flow were studied in the anesthetized rat.

    A translucent mucus gel covers all studied segments of the gastrointestinal tract during fasting conditions, with the thickest layers in the colon and ileum. Carefully applied suction revealed that the mucus gel was a multi-layered structure comprising a firmly adherent layer covering the mucosa, impossible to remove, and a loosely adherent upper layer. The firmly adherent layer was thick and continuous in the corpus (80μm), antrum (154μm) and colon (116μm), but thin (<20μm) and discontinuous in the small intestine.

    Following mucus removal, a rapid renewal of the loosely adherent layer ensued. The highest rate was observed in the colon with intermediate values in the small intestine. Mucus renewal in the stomach was attenuated on acute luminal application of water extracts from H. pylori (HPE). In animals with a chronic H. pylori infection the mucus renewal rate was unaffected, but the total gastric mucus gel thickness was reduced and the mucus secretory response to luminal acid (pH1) attenuated in the antrum.

    HPE from type I strains acutely reduced corporal mucosal blood flow, measured with laser-Doppler flowmetry, by approximately 15%. The reduction in blood flow was mediated by a heat stable factor other than VacA and CagA. Inhibition of endogenous nitric oxide production with Nω-nitro-l-arginine augmented the decrease. However, ketotifen, a mast cell stabilizer, completely attenuated the effect of the extract as did the platelet activating factor (PAF) receptor-antagonist, WEB2086, thus depicting a detrimental role for the microvascular actions of PAF.

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  • 20.
    Atuma, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Engstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology.
    Extracts of Helicobacter pylori reduce gastric mucosal blood flow through a VacA- and CagA-independent pathway in rats1998In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 33, no 12, p. 1256-1261Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Helicobacter pylori may interfere with gastroduodenal protective mechanisms. Such effects could be due to a direct interaction with gastric epithelial cells but also to the action of a wide range of secreted and membrane-bound virulence factors. Our aim was to study the acute effects of water extracts produced from H. pylori on gastric mucosal blood flow and acid secretion and to relate them to VacA and CagA activity.

    METHOD: Extracts were produced from strains 88-23 and A5, both wild type; A5VacA, an isogenic mutant lacking expression of the vacuolating cytotoxin (VacA) and the immunodominant antigen (CagA); and Escherichia coli strain ATCC-25922. Bacterial extracts were applied on the exteriorized gastric corporal mucosa in inactin-anaesthetized rats after removal of as much as possible of the mucus layer, during intravital microscopy. Blood flow was measured by means of laser-Doppler flowmetry.

    RESULTS: All H. pylori extracts, including the extract from 88-23 heated to 100 degrees C for 30 min, significantly reduced blood flow by 15%-19%, whereas E. coli had no significant effect on blood flow.

    CONCLUSION: A factor or a combination of factors, other than VacA and CagA released from H. pylori, might compromise the natural defence of the gastric corporal mucosa by reducing mucosal blood flow. The factor is heat-stable and lacking or less potent in E. coli.

  • 21.
    Axelson, Hans W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Successful localization of the Broca area with short-train pulses instead of "Penfield" stimulation.2009In: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 18, no 5, p. 374-375Article in journal (Refereed)
    Abstract [en]

    Direct electrical stimulation of functional cortical areas is a standard procedure in epilepsy and glioma surgery. Many previous studies support that stimulation of the motor cortex with short-train pulses is a less epileptogenic alternative to the 50–60 Hz ‘Penfield’ technique. However, whether the short-train stimulation is useful also in mapping of speech areas is unclear. In this case report we present a patient with oligodendroglioma near the Broca area. Extraoperative electrical stimulation via a subdural grid electrode was primarily performed to locate the speech area. The cortex was stimulated with short-train pulses (5 pulses, 0.5 pulse duration and 3 ms interpulse interval) in addition to 1–3 s 50 Hz stimulation.The patient had speech arrest from both types of stimulation techniques during a naming task. It was however critical that the short (14.5 ms) train stimulation was synchronized with the presentation of the naming objects. If not, there was no speech arrest. Despite this possible pitfall, this case has encouraged us to further try short-train stimulation in attempts to reduce stimulus-triggered seizures during mapping of eloquent areas.

  • 22.
    Axling, Ulrika
    et al.
    Lund Univ, Diabet Ctr, Dept Expt Med Sci, Lund, Sweden..
    Cavalera, Michele
    Lund Univ, Diabet Ctr, Dept Expt Med Sci, Lund, Sweden.;Lund Univ, Dept Lab Med, Lund, Sweden..
    Degerman, Eva
    Lund Univ, Diabet Ctr, Dept Expt Med Sci, Lund, Sweden..
    Gåfvels, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Lund Univ, Dept Lab Med, Lund, Sweden.
    Eggertsen, Gosta
    Karolinska Inst, Karolinska Univ Hosp Huddinge, Dept Lab Med, Stockholm, Sweden..
    Holm, Cecilia
    Lund Univ, Diabet Ctr, Dept Expt Med Sci, Lund, Sweden..
    Increased whole body energy expenditure and protection against diet-induced obesity in Cyp8b1-deficient mice is accompanied by altered adipose tissue features2020In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 9, no 1, p. 587-599Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to elucidate mechanisms whereby bile acids exert beneficial metabolic effects, using theCyp8b1(-/-)mouse as model. These mice are unable to synthesize cholic acid, resulting in increased synthesis of chenodeoxycholic acid and enlarged bile acid pool.Cyp8b1(-/-)mice were found to be protected against high-fat diet induced obesity. Bomb calorimetry measurements showed increased faecal energy output inCyp8b1(-/)mice. Indirect calorimetry measurements demonstrated increased energy expenditure inCyp8b1(-/-)mice. Meal tolerance tests revealed no differences in glucose disposal, but the insulin response was lower inCyp8b1(-/-)mice. Intravenous glucose tolerance tests, as well as static incubations of isolated islets, showed no difference between the groups, whereas insulin tolerance tests demonstrated improved insulin sensitivity inCyp8b1(-/-)mice. The genes encoding mitochondrial transcription factor A (TFAM) and type 2-iodothyronine deiodinase were upregulated in brown adipose tissue ofCyp8b1(/-)mice and Western blot analyses showed increased abundance of TFAM, and a trend towards increased abundance of UCP1. The upregulation of TFAM and UCP1 was accompanied by increased mitochondrial density, as shown by transmission electron microscopy. White adipocytes ofCyp8b1(-/-)mice exhibited increased responsiveness to both catecholamines and insulin in lipolysis experiments and increased insulin-stimulated lipogenesis. In conclusion, increased energy expenditure, mitochondrial density of brown adipocytes and faecal energy output may all contribute to the protection against diet-induced obesity ofCyp8b1(-/-)mice. Enhanced insulin sensitivity ofCyp8b1(-/-)mice is accompanied by increased hormonal responsiveness of white adipocytes.

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  • 23.
    Babateen, Omar M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 100-100, article id P74Article in journal (Other academic)
  • 24.
    Bacchetti, Tiziana
    et al.
    Department of Life and Environmental Sciences, Marche Polytechnic University, Via Brecce Bianche, 60131 Ancona, Italy.
    Morresi, Camilla
    Department of Life and Environmental Sciences, Marche Polytechnic University, Via Brecce Bianche, 60131 Ancona, Italy.
    Ferretti, Gianna
    Department of Clinical Science and Odontostomatology, Marche Polytechnic University, Via Brecce Bianche, 60131 Ancona, Italy;Center for Health Promotion, Marche Polytechnic University, Via Brecce Bianche, 60131 Ancona, Italy.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svensson, Michael
    Section of Sports Medicine, Department of Community Medicine and Rehabilitation, Umeå University, 90 187 Umeå, Sweden;Umeå School of Sport Sciences, Umeå University, 90 187 Umeå, Sweden.
    Effects of Seven Weeks of Combined Physical Training on High-Density Lipoprotein Functionality in Overweight/Obese Subjects2023In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 13, no 10, p. 1068-1068Article in journal (Refereed)
    Abstract [en]

    Our study aimed to investigate the effects of exercise on HDL composition and functional properties in overweight/obese subjects. Eighteen overweight/obese subjects (nine F and nine M, BMI = 30.3 ± 3 kg/m2) attended supervised training for 7 weeks. The protocol included combined resistance and conditioning training four to five times each week. The activity of the antioxidant enzyme paraoxonase-1 (PON1) associated with HDL was evaluated in all subjects before and after the training intervention. Moreover, myeloperoxidase (MPO) levels and oxidative stress markers (ox-LDLs and total antioxidant capacity) were studied in the serums of the subjects. At the end of the intervention, the activity of PON1 was increased (p < 0.0001), and MPO levels and the MPO/PON1 ratio were decreased (p < 0.0001). In addition, a significant improvement in muscle strength and maximal oxygen uptake (VO2max) (p < 0.0001) and a significant reduction in total and visceral adipose tissue mass (p < 0.001) and waist circumference (p < 0.008), without any significant decrease in body weight, were observed. A significant correlation was established between serum MPO/PON ratios, HDL redox activity and ox-LDLs. In conclusion, our results demonstrate that exercise training, without modifications of dietary habits, improved HDL functionality in overweight/obese adults, without any significant reduction in BMI or modifications of glucose and lipid biochemical parameters.

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  • 25.
    Backman, E. Louis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Der osmotische Druck bei einigen Wasserkäfern1912In: Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere, ISSN 0365-267X, Vol. 149, no 1/3, p. 93-114Article in journal (Refereed)
  • 26.
    Backman, E. Louis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Sundberg, Carl-Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Zur Frage des Verhaltens der Amphibien in verschieden konzentrierten Lösungen: Bemerkungen zu der im ersten und zweiten Hefte von Pflüger's Archiv Bd. 150. 1912 veröffentlichten Mitteilung von Dr. Bruno Brunacci1913In: Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere, ISSN 0365-267X, Vol. 151, no 1/3, p. 52-56Article in journal (Refereed)
  • 27. Barragan, A.
    et al.
    Weidner, J. M.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korpi, E. R.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABAergic signalling in the immune system2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 4, p. 819-827Article, review/survey (Refereed)
    Abstract [en]

    The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter c-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.

  • 28.
    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.

  • 29.
    Bartlett, Christina S.
    et al.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Quaggin, Susan E.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Vascular Growth Factors and Glomerular Disease2016In: ANNUAL REVIEW OF PHYSIOLOGY, VOL 78, ANNUAL REVIEWS, 2016, p. 437-461Chapter in book (Refereed)
    Abstract [en]

    The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. VEGF, ANGPT, EGF, SEMA3A, TGF-beta, and CXCL12 signal in paracrine fashions between the podocytes, endothelium, and mesangium associated with the glomerular capillary bed to maintain filtration barrier function. In this review, we summarize the current understanding of these signaling pathways in the development and maintenance of the glomerulus and the progression of disease.

  • 30.
    Batool, Tahira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparan sulfate dependent cell signaling and associated pathophysiology: Implications in tumorigenesis and embryogenesis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heparan sulfate proteoglycans (HSPGs) consist of a protein core to which several linear, negatively charged heparan sulfate (HS) chains are covalently attached. HSPGs are expressed on the cell surface and in the extra-cellular matrix (ECM) where they have diverse biological functions, for example co-receptor functions. The diverse functions of HS are linked to structural variability of the polysaccharide. In this thesis, I investigated HS structure-function relationship by using different cell and animal models of one HS-biosynthetic enzyme, glucuronyl C5-epimerase (Hsepi) and one enzyme responsible for post synthetic modification, heparanase.

    Deletion of Hsepi in mice resulted in neonatal lethality, with multiple organ defects, indicating the importance of HS in embryogenesis. Up-regulated expression of heparanase is found in most human tumor tissues, correlating with increased metastatic potential and decreased survival of cancer patients.

    In the first project, I focused on the effects of HS on cancer associated cell signaling and found that heparanase overexpression attenuated TGF-β1 stimulated Smad phosphorylation in tumor cells because of increased sulfation degree and turnover rate of HS.

    Heparanase role in cancer progression has led to clinical trials where inhibition of heparanase activity is currently being evaluated as a potential cancer treatment. Heparin, a HS-related polysaccharide, is being used to inhibit heparanase activity. In my second project, we studied the effect of low molecular weight heparin (LMWH) on cisplatin resistance of ovarian cancer cells (A2780cis). LMWH treatment of A2780cis cells reduced Wnt-activity in these cells and consequently reduce the drug resistance.

    In paper III, we continued exploring the HS/heparanase role in cancer by using heparanase overexpressing mice (Hpa-tg). We found Lewis Lung Carcinoma (LLC2) cells showed faster growth, bigger tumors and more metastasis in the Hpa-tg mice as compared to wild-type (WT) mice, because of suppressed antitumor immunity in the Hpa-tg mice.

    In paper IV and V, we studied the structure-function relationship of HS by using Hsepi-/- mice model. Hsepi-/- results in HS-chains lacking IdoA, which makes the chain rigid and consequently affects its co-receptor function. Skeletal malformation in Hsepi-/- mice, led us in paper IV to investigate bone morphogenic protein (BMP), an important signal molecule during embryogenesis and known to interact with HS. We found upregulation of a number of BMPs and expression of P-smad1/5/8, but reduced expression of inhibitory Smads and Gremlin1 in the Hsepi-/- MEF cells. The study indicated that the developmental defects in Hsepi mice could be contributed by a higher BMP signaling. In paper V we investigated the lung of the Hsepi-/- mice. The distal lung of 17.5 days old embryos remained populated by epithelial tubules, because of impaired differentiation of type I cells of the lungs. Potential mechanisms behind the failure of type I cell formation was identified to be reduced vascularization and a sustained signaling of Smad pathways.

    List of papers
    1. Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells
    Open this publication in new window or tab >>Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells
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    2017 (English)In: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, no 3, p. 405-413Article in journal (Refereed) Published
    Abstract [en]

    Heparan sulfate (HS) mediates the activity of various growth factors including TGF-beta. Heparanase is an endo-glucuronidase that specifically cleaves and modifies HS structure. In this study, we examined the effect of heparanase expression on TGF-beta 1-dependent signaling activities. We found that overexpression of heparanase in human tumor cells (i.e., Fadu pharyngeal carcinoma, MCF7 breast carcinoma) attenuated TGF-beta 1-stimulated Smad phosphorylation and led to a slower cell proliferation. TGF-beta 1-stimulated Akt and Erk phosphorylation was also affected in the heparanase overexpression cells. This effect involved the enzymatic activity of heparanase, as overexpression of mutant inactive heparanase did not affect TGF-beta 1 signaling activity. Analysis of HS isolated from Fadu cells revealed an increase in sulfation of the HS that had a rapid turnover in cells overexpressing heparanase. It appears that the structural alterations of HS affect the ability of TGF-beta 1 to signal via its receptors and elicit a growth response. Given that heparanase expression promotes tumor growth in most cancers, this finding highlights a crosstalk between heparanase, HS, and TGF-beta 1 function in tumorigenesis.

    Keywords
    cancer cell, heparan sulfate, heparanase signaling, TGF-beta
    National Category
    Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-322852 (URN)10.1002/2211-5463.12190 (DOI)000400298500011 ()28286736 (PubMedID)
    Funder
    Swedish Research Council, 2015-02595Swedish Research Council, K2013-66X-14936-10-5Swedish Cancer Society, 150815Swedish Cancer Society, 150834
    Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2018-10-15Bibliographically approved
    2. Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
    Open this publication in new window or tab >>Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
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    2017 (English)In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 40, p. 67553-67566Article in journal (Refereed) Published
    Abstract [en]

    Low molecular weight heparin (LMWH), the guideline based drug for prophylaxis and treatment of cancer-associated thrombosis, was recently shown to sensitize cisplatin resistant A2780cis human ovarian cancer cells for cisplatin cytotoxicity upon 24 h pretreatment with 50 mu g x mL(-1) of the LMWH tinzaparin in vitro, equivalent to a therapeutic dosage. Thereby, LMWH induced sensitization by transcriptional reprogramming of A2780cis cells via not yet elucidated mechanisms that depend on cellular proteoglycans. Here we aim to illuminate the underlying molecular mechanisms of LMWH in sensitizing A2780cis cells for cisplatin. Using TCF/LEF luciferase promotor assay (Top/Flash) we show that resistant A2780cis cells possess a threefold higher Wnt signaling activity compared to A2780 cells. Furthermore, Wnt pathway blockade by FH535 leads to higher cisplatin sensitivity of A2780cis cells. Glypican-3 (GPC3) is upregulated in A2780cis cells in response to LMWH treatment, probably as counter-regulation to sustain the high Wnt activity against LMWH. Hence, LMWH reduces the cisplatin-induced rise in Wnt activity and TCF-4 expression in A2780cis cells, but keeps sensitive A2780 cells unaffected. Consequently, Wnt signaling pathway appears as primary target of LMWH in sensitizing A2780cis cells for cisplatin toxicity. Considering the outstanding role of LMWH in clinical oncology, this finding appears as promising therapeutic option to hamper chemoresistance.

    Place, publisher, year, edition, pages
    IMPACT JOURNALS LLC, 2017
    Keywords
    tinzaparin, cancer, chemoresistance, Wnt, cisplatin
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-336049 (URN)10.18632/oncotarget.18738 (DOI)000410790500061 ()28978053 (PubMedID)
    Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2024-01-17Bibliographically approved
    3. Heparanase expression soils the microenvironment for tumor growth by enhancing Notch signaling and suppressing antitumor immunity.: Heparanase effects on immune response in tumor microenvironment.
    Open this publication in new window or tab >>Heparanase expression soils the microenvironment for tumor growth by enhancing Notch signaling and suppressing antitumor immunity.: Heparanase effects on immune response in tumor microenvironment.
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    (English)In: Article in journal (Other academic) Submitted
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-363257 (URN)
    Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15
    4. Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
    Open this publication in new window or tab >>Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
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    2019 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, p. 122-129Article in journal (Refereed) Published
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce,in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF-2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re-expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells.   

    Place, publisher, year, edition, pages
    Elsevier, 2019
    Keywords
    BMP signaling, Heparan sulfate, MEF cells, Smad, Glucuronyl C5-epimerase, Bone Morphogenetic Protein
    National Category
    Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-363254 (URN)10.1016/j.cellsig.2018.11.010 (DOI)000456752900013 ()30458230 (PubMedID)
    Funder
    Swedish Cancer Society, CAN2015/496Swedish Research Council, 2015-02595Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2019-02-12Bibliographically approved
    5. Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development
    Open this publication in new window or tab >>Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development
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    2021 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 31, no 3, p. 223-230Article in journal (Refereed) Published
    Abstract [en]

    Glucuronyl C5-epimerase (Hsepi) is a key enzyme in the biosynthesis of heparan sulfate that is a sulfated polysaccharide expressed on the cell surface and in the extracellular matrix of alveolar walls and blood vessels. Targeted interruption of the Hsepi gene, Glce, in mice resulted in neonatal lethality, which is most likely due to lung atelectasis. In this study, we examined the potential mechanisms behind the defect in lung development. Histological analysis of the lungs from embryos revealed no difference in the morphology between wild-type and mutant animals up to E16.5. This suggests that the initial events leading to formation of the lung primordium and branching morphogenesis are not disturbed. However, the distal lung of E17.5-18.5 mutants is still populated by epithelial tubules, lacking the typical saccular structural characteristic of a normal E17.5 lung. Immunostaining revealed strong signals of surfactant protein-C, but a weaker signal of T1 alpha in the mutant lungs in comparison to WT littermates, suggesting differentiation of type I alveolar epithelial cells (AT1) is impaired. One of the parameters contributed to the failure of AT1 maturation is reduced vascularization in the developing lungs.

    Place, publisher, year, edition, pages
    Oxford University Press, 2021
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-363255 (URN)10.1093/glycob/cwaa065 (DOI)000642302300008 ()32651954 (PubMedID)
    Funder
    Swedish Heart Lung FoundationSwedish Research Council, 2018-02503Swedish Cancer Society, 150815
    Note

    Title in dissertation list of papers: Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development: Glucuronyl C5-epimerase in lung development

    Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2024-01-15Bibliographically approved
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  • 31.
    Becirovic Agic, Mediha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jönsson, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Quantitative trait loci associated with angiotensin II and high-salt diet induced acute decompensated heart failure in Balb/CJ mice2019In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 51, no 7, p. 279-289Article in journal (Refereed)
    Abstract [en]

    Genetic background of different mouse strains determines their susceptibility to disease. We have previously shown that Balb/CJ and C57BL/6J mice develop cardiac hypertrophy to the same degree when treated with a combination of angiotensin II and high-salt diet (ANG II+ Salt). but only Balb/CJ show impaired cardiac function associated with edema development and substantial mortality. We hypothesized that the different response to ANG II +Salt is due to the different genetic backgrounds of Balb/CJ and C57BL/6J. To address this we performed quantitative trait locus (QTL) mapping of second filial generation (F2) of mice derived from a backcross between Balb/CJ and first filial generation (Fl) of mice. Cardiac function was measured with echocardiography, glomerular filtration rate using FITC-inulin clearance, fluid and electrolyte balance in metabolic cages, and blood pressure with tail-cuff at baseline and on the fourth day of treatment with ANG II+Salt. A total of nine QTLs were found to be linked to different phenotypes in ANG II + Salt-treated F2 mice. A QTL on chromosome 3 was linked to cardiac output. and a QTL on chromosome 12 was linked to isovolumic relaxation time. QTLs on chromosome 2 and 3 were linked to urine excretion and sodium excretion. Eight genes located at the different QTLs contained coding nonsynonymous SNPs published in the mouse genome database that differ between Balb/CJ and C57BL/6J. In conclusion. ANG II+Salt-induced acute decompensation in Balb/CJ is genetically linked to several QTLs, indicating a multifaceted phenotype. The present study identified potential candidate genes that may represent important pathways in acute decompensated heart failure.

  • 32.
    Becirovic-Agic, Mediha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jönsson, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Tveitarås, Maria K.
    Skogstrand, Trude
    Karlsen, Tine Veronica
    Lidén, Åsa
    Leh, Sabine
    Ericsson, Madelene
    Nilsson, Stefan K.
    Reed, Rolf K.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Department of Biomedicine, University of Bergen, Bergen, Norway.
    Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome2019In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, no 5, p. R563-R570Article in journal (Refereed)
    Abstract [en]

    The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

  • 33.
    Beháňová, Andrea
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Klemm, Anna H
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wählby, Carolina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction.
    Spatial Statistics for Understanding Tissue Organization2022In: Frontiers in Physiology, E-ISSN 1664-042X, Vol. 13, article id 832417Article, review/survey (Refereed)
    Abstract [en]

    Interpreting tissue architecture plays an important role in gaining a better understanding of healthy tissue development and disease. Novel molecular detection and imaging techniques make it possible to locate many different types of objects, such as cells and/or mRNAs, and map their location across the tissue space. In this review, we present several methods that provide quantification and statistical verification of observed patterns in the tissue architecture. We categorize these methods into three main groups: Spatial statistics on a single type of object, two types of objects, and multiple types of objects. We discuss the methods in relation to four hypotheses regarding the methods' capability to distinguish random and non-random distributions of objects across a tissue sample, and present a number of openly available tools where these methods are provided. We also discuss other spatial statistics methods compatible with other types of input data.

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  • 34. Belalov, V. V.
    et al.
    Dyagileva, Yu. O.
    Pavlenko, V. B.
    Kochukhova, Olga M.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Neurophysiological Analysis of Speech Perception in 2.5 to 3.5-Year-Old Orphans and Children Raised in a Family2014In: Neurophysiology (New York), ISSN 0090-2977, E-ISSN 1573-9007, Vol. 46, no 1, p. 79-87Article in journal (Refereed)
    Abstract [en]

    In 2.5-3.5-year-old orphans (n = 41) and children raised in a family (n = 50), we examined specificities of speech perception-related changes in the spectral power density (SPD) of the EEG rhythms. Changes in the SPDs of the theta-, alpha-, beta-, and gamma-rhythms in 16 EEG leads where estimated at presentation of a meaningful speech fragment record (short poem) and of a reversed record of the same signal (direct and reversed speech, respectively). The Bayley Scales of Infant and Toddler Development III demonstrated the existence of noticeable delays in the development of speech in orphans. Comparison of background EEGs and EEGs in the course of listening for direct speech showed that the alpha-rhythm is desynchronized, while the theta-, beta-, and, especially, gamma-oscillations are synchronized upon perception of the above stimulus. In this case, children raised in a family demonstrated significant increases in the gamma-rhythm SPD in 13 leads of both hemispheres; in orphans, this was observed only in 8 loci localized mostly in the left hemisphere. In children of both groups, listening for reversed speech induced mostly desynchronization of all EEG rhythms with the greatest drops in the gamma SPD mostly in the frontal and left temporal leads. Comparison of SPDs of the EEG components (rhythms) at listening for direct and reversed speech demonstrated that powers of theta-, beta-, and gamma-oscillations increased at presentation of a direct (comprehended) speech in children of both groups. In children raised in families, greater SPDs of the gamma-rhythm were observed in 13 leads (differences were most significant in the frontal parts of the left hemisphere). In institutionalized children, the number of leads with significant increments of the gamma-rhythm power was significantly smaller (only 9). It is supposed that smaller increases in the SPD of of gamma-range oscillations in orphans are related to deviations in the processing of a semantic component of speech perception. This can result from insufficient development of cerebral neuronal networks responsible for processing of verbal information.

  • 35.
    Berg, Hans E.
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Orthopaed Surg, SE-14186 Stockholm, Sweden..
    Truong, Daniel
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Orthopaed Surg, SE-14186 Stockholm, Sweden..
    Skoglund, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Karolinska Inst, Div Clin Physiol, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ Hosp, Unit Clin Physiol, Stockholm, Sweden..
    Gustafsson, Thomas
    Karolinska Inst, Div Clin Physiol, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ Hosp, Unit Clin Physiol, Stockholm, Sweden..
    Lundberg, Tommy R.
    Karolinska Inst, Div Clin Physiol, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ Hosp, Unit Clin Physiol, Stockholm, Sweden..
    Threshold-automated CT measurements of muscle size and radiological attenuation in multiple lower-extremity muscles of older individuals2020In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 40, no 3, p. 165-172Article in journal (Refereed)
    Abstract [en]

    Muscle atrophy and fat infiltration, two indicators of deconditioning and weakness in elderly frail patients, are typically assessed by means of manual image analysis from computed tomography (CT) scans. As this time-consuming image analysis limits its wider use in clinical studies, the use of tissue thresholds to semi-automatically assess muscle composition has been suggested. Here, we aimed to investigate the relationship between manual and semi-automated analysis of both cross-sectional area (CSA) and radiological attenuation (RA), in multiple muscles of the lower extremities in aged (77 +/- 6 years) sedentary individuals (n = 40). The participants underwent CT scans of their lower limbs, including hip, thigh and calf muscles. The subsequent analysis of CSA and RA was conducted using both manual segmentation and semi-automatic thresholds (-30 to +150 Hounsfield units). Automated measurements were generally strongly correlated with manually encircled CSA in all muscle groups (R = 0.79-0.99, p < .05) and shortened the analysis time by 70% (p < .05). In m. iliopsoas, however, the CSA became overestimated (15%, p < .05) with thresholded measurements, while the assessment of both CSA and RA was underestimated in muscles with high-fat content (i.e., the gluteal muscles) and in individuals with high-fat infiltration. In conclusion, using the semi-automated technique with conventional thresholds is a time-saving method that delivers accurate gross size of the muscle groups, particularly in the thigh. However, caution should be exercised when using semi-automated techniques for assessing CSA and fat infiltration in muscles with high-fat content.

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  • 36.
    Bergfors, Monica
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Improved diagnosis of Carpal tunnel syndrome using amplitude difference between m. Abductor pollicis brevis and m. Pronator quadratus?2008Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The purpose of this study was to investigate the difference in amplitude between M-response from m. Abductor pollicis brevis/m. Pronator quadratus and m. Abductor pollicis brevis/m. Abductor digiti minimi on patients with carpal tunnel syndrome, compared with control subjects. We wanted to see if m. Pronator quadratus is a better alternative than m. Abductor digiti minimi as comparison with m. Abductor pollicis brevis on patients with carpal tunnel syndrome.

    Nerve conduction studies were performed on 20 patients with carpal tunnel syndrome and on 31 healthy subjects.

    The test-retest result shows that this method was reproducible. The amplitude difference of m. Abductor pollicis brevis-m. Abductor digiti minimi, for the patients, was 1,5mV lower and the amplitude for m. Abductor pollicis brevis-m. Pronator quadratus was 2mV lower than for healthy subjects. Two of the patients were outside the 2SD for the m. Abductor pollicis brevis-m. Pronator quadratus difference but not on the m. Abductor pollicis brevis-m. Abductor digiti minimi. This may indicate that m. Pronator quadratus was better than m. Abductor digiti minimi in the comparison with the m. Abductor pollicis brevis amplitude.

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  • 37.
    Bergman, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Clinical Obstetrics. Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Obstet & Gynecol, Gothenburg, Sweden; Sahlgrens Univ Hosp, Dept Obstet & Gynecol, Gothenburg, Sweden; Stellenbosch Univ, Dept Obstet & Gynecol, Stellenbosch, South Africa.
    Escudero, Carlos Alonso
    Univ Bio Bio, Dept Basic Sci, Vasc Physiol Lab, Chillan, Chile.;Grp Res & Innovat Vasc Hlth, GRIVAS Hlth, Chillan, Chile..
    Cluver, Catherine
    Stellenbosch Univ, Dept Obstet & Gynecol, Stellenbosch, South Africa.;Mercy Hosp Women, Dept Obstet & Gynaeol, Mercy Perinatal, Melbourne, Vic, Australia.;Univ Melbourne, Dept Obstet & Gynaecol, Melbourne, Vic, Australia..
    Hastie, Roxanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Clinical Obstetrics. Stellenbosch Univ, Dept Obstet & Gynecol, Stellenbosch, South Africa; Univ Melbourne, Dept Obstet & Gynaecol, Melbourne, Vic, Australia.
    Torres-Vergara, Pablo
    Grp Res & Innovat Vasc Hlth, GRIVAS Hlth, Chillan, Chile.;Univ Concepcion, Fac Farm, Dept Farm, Concepcion, Chile..
    Editorial: Preeclampsia and the brain: Pre-clinical and clinical studies of cerebral involvement in preeclampsia2023In: Frontiers in Physiology, E-ISSN 1664-042X, Vol. 14, article id 1151091Article in journal (Other academic)
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    fulltext
  • 38.
    Bergmann, Astrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Otto von Guericke Univ, Cardiothorac Anesthesia, Dept Anesthesiol & Intens Care Med, Magdeburg, Germany.
    Jovanovska, Elena
    Otto von Guericke Univ, Dept Anesthesiol & Intens Care Med, Anesthesiol, Magdeburg, Germany.
    Schilling, Thomas
    Otto von Guericke Univ, Dept Anesthesiol & Intens Care Med, Anesthesia, Magdeburg, Germany.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Follner, Sebastian
    Otto von Guericke Univ, Dept Pulmonol, Magdeburg, Germany.
    Schreiber, Jens
    Otto von Guericke Univ, Dept Pulmonol, Pulmonol, Magdeburg, Germany.
    Hachenberg, Thomas
    Otto von Guericke Univ, Anesthesia, Magdeburg, Germany;Otto von Guericke Univ, Dept Anesthesiol & Intens Care Med, Leipziger Str 44, D-39120 Magdeburg, Germany.
    Early and late effects of remote ischemic preconditioning on spirometry and gas exchange in healthy volunteers2020In: Respiratory Physiology & Neurobiology, ISSN 1569-9048, E-ISSN 1878-1519, Vol. 271, article id 103287Article in journal (Refereed)
    Abstract [en]

    Purpose: Remote ischemic preconditioning (RIP) may protect remote organs from ischemia-reperfusion-injury (IRI) in surgical and non-surgical patients. There are few data available on RIP and lung function, especially not in healthy volunteers. The null-hypothesis was tested that RIP does not have an effect on pulmonary function when applied on healthy volunteers that were breathing spontaneously and did not experience any intervention. After approval of the Ethics Committee and informed consent of the study subjects, 28 healthy non-smoking volunteers were included and randomized in either the RIP group (n = 13) or the control group (n = 15). In the RIP group, lower limb ischemia was induced by inflation of a blood pressure cuff to a pressure 20 mmHg above the systolic blood pressure. After five minutes the blood pressure cuff was released for five minutes rest. The procedure was repeated three times resulting in 40 min ischemia and reperfusion. Capillary blood samples were taken, and lung function tests were performed at baseline (T1) and 60 min (T2) and 24 h (T3) after RIP. The control group was treated in the same fashion, but the RIP procedure was replaced by a sham protocol.

    Results: 60 min after RIP capillary pO(2) decreased significantly and returned to baseline level after 24 h in the RIP group. This did not occur in the control group. Capillary pCO(2), variables of lung function tests and pulmonary capillary blood volume remained unchanged throughout the experiment in both groups.

    Conclusion: Oxygenation is impaired early after RIP which is possibly induced by transient ventilation-perfusion inequality. No late effects of RIP were observed. The null hypothesis has to be rejected that RIP has no effect on respiratory variables in healthy volunteers.

  • 39.
    Bergmann, Astrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Department of Anesthesiology and Intensive Care Medicine, Otto-von-Guericke-University Magdeburg, Germany.
    Schilling, Thomas
    Perchiazzi, Gaetano
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kretzschmar, Moritz
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Hachenberg, Thomas
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Effect of remote ischemic preconditioning on exhaled nitric oxide concentration in piglets during and after one-lung ventilation2020In: Respiratory Physiology & Neurobiology, ISSN 1569-9048, E-ISSN 1878-1519, Vol. 276, article id 103426Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Remote ischemic preconditioning (RIP) may protect target organs from ischemia - reperfusion injury, however, little is known on pulmonary effects of RIP prior to, immediately after and several hours after one-lung ventilation (OLV). The present randomized, controlled, animal experiment was undertaken to analyze these issues.

    METHODS: After animal ethics committee approval, twelve piglets (26 ± 2 kg) were anesthetized and randomly assigned to a control (n = 6) or to a RIP group (n = 6). For RIP, arterial perfusion of a hind limb was suspended by an inflated blood pressure cuff (200 mmHg for 5 min) and deflated for another 5 min, this was repeated four times. After intubation, mechanical ventilation (MV) was kept constant with tidal volume 10 ml/kg, inspired oxygen fraction (FIO2) 0.40, and positive end-expiratory pressure (PEEP) 5cmH2O. FIO2 was increased to 1 after RIP in the RIP group and after the sham procedure in the control group, respectively, for the time of OLV. OLV was established by left-sided bronchial blockade. After OLV, TLV was re-established until the end of the protocol. Exhaled nitric oxide (NO) was measured by ozon chemiluminiscense and ventilatory and hemodynamic variables were assessed according to the protocol.

    RESULTS: Hemodynamic and respiratory data were similar in both groups. Arterial pO2 was higher in the RIP group after two hours of OLV. In the control group, exhaled NO decreased during OLV and remained at low levels for the rest of the protocol. In the RIP group, exhaled NO decreased as well during OLV but returned to baseline levels when TLV was re-established.

    CONCLUSIONS: RIP has no effects on hemodynamic and respiratory variables in juvenile, healthy piglets. RIP improves the oxygenation after OLV and prevents the decline of exhaled NO after OLV.

  • 40.
    Bergström, Ulrika
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. ekotoxikologi.
    Olsson, Jan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. ekotoxikologi.
    Hvidsten, Torgeir R
    Komorowski, Jan
    Brandt, Ingvar
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology. ekotoxikologi.
    Neurotoxicity of the Olfactory toxicant 2,6-Dichlorophenyl Methylsulphone in Olfactory bulb:Impaired expression of genes relating to neurodegenerative disease2007In: DIOXIN2007, 2007, p. 1841-1844Conference paper (Refereed)
  • 41.
    Bhandage, Amol
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Ólafsson, Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    The mRNA expression of GABA-A, GABA-B receptor subunits and chloride transporters in peripheral blood mononuclear cells is influenced by gender, pregnancy and depression2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 91-91Article in journal (Other academic)
  • 42.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Glutamate and GABA signalling components in the human brain and in immune cells2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions.

    Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.

    List of papers
    1. Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics
    Open this publication in new window or tab >>Selective increases of AMPA, NMDA, and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics
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    2014 (English)In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 8, p. 11-Article in journal (Refereed) Published
    Abstract [en]

    Glutamate is the main excitatory transmitter in the human brain. Drugs that affect the glutamatergic signaling will alter neuronal excitability. Ethanol inhibits glutamate receptors. We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects. RNA from hippocampal dentate gyrus (HP-DG), orbitofrontal cortex (OFC), and dorso-lateral prefrontal cortex (DL-PFC) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study. Total RNA was assayed using quantitative RT-PCR. Out of the 16 glutamate receptor subunits, mRNAs encoding two AMPA [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid] receptor subunits GluA2 and GluA3; three kainate receptor subunits GluK2, GluK3 and GluK5 and five NMDA (N-methyl-D-aspartate) receptor subunits GluN1, GluN2A, GluN2C, GluN2D, and GluN3A were significantly increased in the HP-DG region in alcoholics. In the OFC, mRNA encoding the NMDA receptor subunit GluN3A was increased, whereas in the DL-PFC, no differences in mRNA levels were observed. Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics (Jin et al., 2011). Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known. The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner. It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes.

    National Category
    Physiology Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-219489 (URN)10.3389/fncel.2014.00011 (DOI)000331053400001 ()24523671 (PubMedID)
    Available from: 2014-03-03 Created: 2014-03-03 Last updated: 2023-02-22Bibliographically approved
    2. Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
    Open this publication in new window or tab >>Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
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    2014 (English)In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 8, p. 288-Article in journal (Refereed) Published
    Abstract [en]

    The central amygdala (CeA) has a role for mediating fear and anxiety responses. It is also involved in emotional imbalance caused by alcohol abuse and dependence and in regulating relapse to alcohol abuse. Growing evidences suggest that excitatory glutamatergic and inhibitory gamma-aminobutyric acid-ergic (GABAergic) transmissions in the CeA are affected by chronic alcohol exposure. Human post-mortem CeA samples from male alcoholics (n = 9) and matched controls (n = 9) were assayed for the expression level of ionotropic glutamate and GABA-A receptors subunit mRNAs using quantitative real-time reverse transcription-PCB (RT-qPCR). Our data revealed that out of the 16 ionotropic glutamate receptor subunits, mRNAs encoding two AMPA P-amino-3-(3-hydroxy-5-methyl-isoxazol-4-y1)propanoic acid] receptor subunits GluA1 and GluA4; one kainate receptor subunit GluK2; one NMDA (N-methyl-D-aspartate) receptor subunit GluN2D and one delta receptor subunit GluD2 were significantly decreased in the CeA of alcoholics. In contrast, of the 19 GABA-A receptor subunits, only the mRNA encoding the a2 subunit was significantly down-regulated in the CeA of the alcoholics as compared with control subjects. Our findings imply that the down-regulation of specific ionotropic glutamate and GABA-A receptor subunits in the CeA of alcoholics may represent one of the molecular substrates underlying the new balance between excitatory and inhibitory neurotransmission in alcohol dependence.

    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-239603 (URN)10.3389/fncel.2014.00288 (DOI)000344465400002 ()
    Available from: 2014-12-30 Created: 2014-12-29 Last updated: 2023-02-22Bibliographically approved
    3.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    4. Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
    Open this publication in new window or tab >>Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
    2012 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 8, p. e42959-Article in journal (Refereed) Published
    Abstract [en]

    γ-aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronalGABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primarytargets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. Wehave examined in human, mouse and rat CD4+ and CD8+ T cells which subunit isoforms of the GABA-A channels areexpressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn isdetermined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoformsidentified in human, mouse and rat CD4+ and CD8+ T cells, respectively. Importantly, the γ2 subunit that imposesbenzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots andimmunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activatedwhole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline,antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed butthe subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal modelsto study the physiological role and pharmacological properties of GABA-A channels in CD4+ and CD8+ T cells and whenselecting drugs aimed at modulating the human T cells function.

    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-172532 (URN)10.1371/journal.pone.0042959 (DOI)000307789700016 ()
    Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2021-06-14Bibliographically approved
    5. Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
    Open this publication in new window or tab >>Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
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    2015 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, p. 575-585Article in journal (Refereed) Published
    Abstract [en]

    AIM: The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain and receptors activated by GABA can be expressed by immune cells. Here we examined if the expression of GABA receptors and chloride transporters in human peripheral mononuclear cells (PBMCs) were influenced by gender, pregnancy or mental health.

    METHODS: We used RT-qPCR to determine the mRNA expression level in men (n=16), non-pregnant women (n=19), healthy pregnant women (n=27) and depressed pregnant women (n=15).

    RESULTS: The ρ2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The δ and ρ2 subunits were up-regulated by pregnancy whereas the ε subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in-turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs.

    CONCLUSION: The results demonstrate the impact gender, pregnancy and mental health have on expression of GABA receptors plus chloride transporters expressed in human PBMCs.

    National Category
    Physiology
    Identifiers
    urn:nbn:se:uu:diva-240372 (URN)10.1111/apha.12440 (DOI)000348531600007 ()25529063 (PubMedID)
    Available from: 2015-01-07 Created: 2015-01-07 Last updated: 2018-01-11
    6. AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women
    Open this publication in new window or tab >>AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women
    Show others...
    2017 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 305, p. 51-58Article in journal (Refereed) Published
    Abstract [en]

    The amino acid glutamate opens cation permeable ion channels, the iGlu receptors. These ion channels are abundantly expressed in the mammalian brain where glutamate is the main excitatory neurotransmitter. The neurotransmitters and their receptors are being increasingly detected in the cells of immune system. Here we examined the expression of the 18 known subunits of the iGlu receptors families; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-D-aspartate (NMDA) and delta in human peripheral blood mononuclear cells (PBMCs). We compared the expression of the subunits between four groups: men, non-pregnant women, healthy pregnant women and depressed pregnant women.

    Out of 18 subunits of the iGlu receptors, mRNAs for 11 subunits were detected in PBMCs from men and nonpregnant women; AMPA: GluA3, GluA4, kainate: GluK2, GluK4, GluK5, NMDA: GluN1, GluN2C, GluN2D, GluN3A, GluN3B, and delta: GluD1. In the healthy and the depressed pregnant women, in addition, the delta GluD2 subunit was identified. The mRNAs for GluK4, GluK5, GluN2C and GluN2D were expressed at a higher level than other subunits. Gender, pregnancy or depression during pregnancy altered the expression of GluA3, GluK4, GluN2D, GluN3B and GluD1 iGlu subunit mRNAs. The greatest changes recorded were the lower GluA3 and GluK4 mRNA levels in pregnant women and the higher GluN2D mRNA level in healthy but not in depressed pregnant women as compared to non-pregnant individuals. Using subunit specific antibodies, the GluK4, GluK5, GluNl, GluN2C and GluN2D subunit proteins were identified in the PBMCs. The results show expression of specific iGlu receptor subunit in the PBMCs and support the idea of physiology-driven changes of iGlu receptors subtypes in the immune cells.

    Keywords
    Glutamate, iGluR subunits, Immune cells, Pregnancy, Depression, Physiology-driven changes
    National Category
    Medical and Health Sciences Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-282410 (URN)10.1016/j.jneuroim.2017.01.013 (DOI)000397694200009 ()28284346 (PubMedID)
    Funder
    Swedish Research Council, 521-2012-1789
    Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2018-01-10Bibliographically approved
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  • 43.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Olafsson, Einar B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, p. 575-585Article in journal (Refereed)
    Abstract [en]

    AIM: The concept of nerve-driven immunity recognizes a link between the nervous and the immune system. γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain and receptors activated by GABA can be expressed by immune cells. Here we examined if the expression of GABA receptors and chloride transporters in human peripheral mononuclear cells (PBMCs) were influenced by gender, pregnancy or mental health.

    METHODS: We used RT-qPCR to determine the mRNA expression level in men (n=16), non-pregnant women (n=19), healthy pregnant women (n=27) and depressed pregnant women (n=15).

    RESULTS: The ρ2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The δ and ρ2 subunits were up-regulated by pregnancy whereas the ε subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in-turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs.

    CONCLUSION: The results demonstrate the impact gender, pregnancy and mental health have on expression of GABA receptors plus chloride transporters expressed in human PBMCs.

  • 44.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Olafsson, Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sundström, Iinger Poromaa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA-A receptor subunit expression in human peripheral blood mononuclear cells2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 86-86, article id P45Article in journal (Other academic)
  • 45.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bazov, Igor
    Kononenko, Olga
    Bakalkin, Georgy
    Korpi, Esa R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics2014In: Frontiers in Cellular Neuroscience, E-ISSN 1662-5102, Vol. 8, article id 415Article in journal (Refereed)
    Abstract [en]

    Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the δ, ε, and ρ2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A γ1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior.

  • 46.
    Birnir, Bryndis
    et al.
    Molecular and Cellular Physiology, Dept. of Physiological Sciences, Lund University.
    Eghbali, M
    Cox, G B
    Gage, P W
    GABA concentration sets the conductance of delayed GABAA channels in outside-out patches from rat hippocampal neurons.2001In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 181, no 3, p. 171-83Article in journal (Refereed)
    Abstract [en]

    GABAA channels were activated by GABA in outside-out patches from rat cultured hippocampal neurons. They were blocked by bicuculline and potentiated by diazepam. In 109 of 190 outside-out patches, no channels were active before exposure to GABA (silent patches). The other 81 patches showed spontaneous channel activity. In patches containing spontaneous channel activity, rapid application of GABA rapidly activated channels. In 93 of the silent patches, channels could be activated by GABA but only after a delay that was sometimes as long as 10 minutes. The maximum channel conductance of the channels activated after a delay increased with GABA concentration from less than 10 pS (0.5 microm GABA) to more than 100 pS (10 mm GABA). Fitting the data with a Hill-type equation gave an EC50 value of 33 microm and a Hill coefficient of 0.6. The channels showed outward rectification and were chloride selective. In the presence of 1 microm diazepam, the GABA EC50 decreased to 0.2 microm but the maximum conductance was unchanged. Diazepam decreased the average latency for channel opening. Bicuculline, a GABA antagonist, caused a concentration-dependent decrease in channel conductance. In channels activated with 100 microm GABA the bicuculline IC50 was 19 microm. The effect of GABA on channel conductance shows that the role of the ligand in GABAA receptor channel function is more complex than previously thought.

  • 47.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Eghbali, M
    Everitt, A B
    Gage, P W
    Bicuculline, pentobarbital and diazepam modulate spontaneous GABA(A) channels in rat hippocampal neurons.2000In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 131, no 4, p. 695-704Article in journal (Refereed)
    Abstract [en]

    Spontaneously opening, chloride-selective channels that showed outward rectification were recorded in ripped-off patches from rat cultured hippocampal neurons and in cell-attached patches from rat hippocampal CA1 pyramidal neurons in slices. In both preparations, channels had multiple conductance states and the most common single-channel conductance varied. In the outside-out patches it ranged from 12 to 70 pS (Vp=40 mV) whereas in the cell-attached patches it ranged from 56 to 85 pS (-Vp=80 mV). Application of GABA to a patch showing spontaneous channel activity evoked a rapid, synchronous activation of channels. During prolonged exposure to either 5 or 100 microM GABA, the open probability of channels decreased. Application of GABA appeared to have no immediate effect on single-channel conductance. Exposure of the patches to 100 microM bicuculline caused a gradual decrease on the single-channel conductance of the spontaneous channels. The time for complete inhibition to take place was slower in the outside-out than in the cell-attached patches. Application of 100 microM pentobarbital or 1 microM diazepam caused 2 - 4 fold increase in the maximum channel conductance of low conductance (<40 pS) spontaneously active channels. The observation of spontaneously opening GABA(A) channels in cell-attached patches on neurons in slices suggests that they may have a role in neurons in vivo and could be an important site of action for some drugs such as benzodiazepines, barbiturates and general anaesthetics.

  • 48.
    Birnir, Bryndis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Eliasson, L.
    Lund Univ, Dept Clin Sci Malmo, Ctr Diabet, Lund, Sweden..
    She is in science to stay!2018In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 223, no 1, article id e13048Article in journal (Other academic)
  • 49.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Everitt, A B
    Gage, P W
    Characteristics of GABAA channels in rat dentate gyrus.1994In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 142, no 1, p. 93-102Article in journal (Refereed)
    Abstract [en]

    Single channel currents were activated by GABA (0.5 to 5 microM) in cell-attached and inside-out patches from cells in the dentate gyrus of rat hippocampal slices. The currents reversed at the chloride equilibrium potential and were blocked by bicuculline (100 microM). Several different kinds of channel were seen: high conductance and low conductance, rectifying and "nonrectifying." Channels had multiple conductance states. The open probability (Po) of channels was greater at depolarized than at hyperpolarized potentials and the relationship between Po and potential could be fitted with a Boltzmann equation with equivalent valency (z) of 1. The combination of outward rectification and potential-dependent open probability gave very little chloride current at hyperpolarized potentials but steeply increasing current with depolarization, useful properties for a tonic inhibitory mechanism.

  • 50.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Everitt, A B
    Lim, M S
    Gage, P W
    Spontaneously opening GABA(A) channels in CA1 pyramidal neurones of rat hippocampus.2000In: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 174, no 1, p. 21-9Article in journal (Refereed)
    Abstract [en]

    Spontaneous, single channel, chloride currents were recorded in 48% of cell-attached patches on neurones in the CA1 region of rat hippocampal slices. In some patches, there was more than 1 channel active. They showed outward rectification: both channel conductance and open probability were greater at depolarized than at hyperpolarized potentials. Channels activated by gamma-aminobutyric acid (GABA) in silent patches on the same neurones had similar conductance and outward rectification. The spontaneous currents were inhibited by bicuculline and potentiated by diazepam. It was concluded that the spontaneously opening channels were constitutively active, nonsynaptic GABA(A) channels. Such spontaneously opening GABA(A) channels may provide a tonic inhibitory mechanism in these cells and perhaps in other cells that have GABA(A) receptors although not having a GABA(A) synaptic input. They may also be a target for clinically useful drugs such as the benzodiazepines.

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