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  • 1.
    Ahlén, Caroline
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Outcome of patients with severe aortic stenosis – A retrospective follow-up study2008Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats
    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.

    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 2. Alfonso, Julieta
    et al.
    Pollevick, Guido
    Castensson, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Jazin, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Frasch, Alberto
    Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels2002Ingår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, nr 2, s. 225-34Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Almgren, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Endotracheal Suction a Reopened Problem2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Side effects of endotracheal suction in pressure and volume controlled ventilation
    Öppna denna publikation i ny flik eller fönster >>Side effects of endotracheal suction in pressure and volume controlled ventilation
    2004 (Engelska)Ingår i: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, nr 3, s. 1077-1080Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    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
    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-92641 (URN)10.1378/chest.125.3.1077 (DOI)15006972 (PubMedID)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Negative tracheal pressure during suction differs between suction systems and catheter sizes
    Öppna denna publikation i ny flik eller fönster >>Negative tracheal pressure during suction differs between suction systems and catheter sizes
    2005 (Engelska)Artikel i tidskrift (Refereegranskat) Published
    Ort, förlag, år, upplaga, sidor
    Uppsala: Institutionen för medicinsk cellbiologi, 2005
    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-7236 (URN)
    Tillgänglig från: 2007-10-24 Skapad: 2007-10-24 Senast uppdaterad: 2018-01-13
    3. Effectiveness and side effects of closed and open suctioning: an experimental evaluation
    Öppna denna publikation i ny flik eller fönster >>Effectiveness and side effects of closed and open suctioning: an experimental evaluation
    Visa övriga...
    2004 Ingår i: Intensive Care Medicine, Vol. 30, nr 8, s. 1630-7Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-92643 (URN)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25Bibliografiskt granskad
    4. Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs
    Öppna denna publikation i ny flik eller fönster >>Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs
    2004 (Engelska)Ingår i: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, nr 3, s. 339-345Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-92644 (URN)15264727 (PubMedID)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    5. The time frame for post-suction recruitment manoeuvre
    Öppna denna publikation i ny flik eller fönster >>The time frame for post-suction recruitment manoeuvre
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-92645 (URN)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 4.
    Almgren, Birgitta
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Strid, Niklas
    Wickerts, Carl-Johan
    Högman, Marieann
    Negative tracheal pressure during suction differs between suction systems and catheter sizes2005Artikel i tidskrift (Refereegranskat)
  • 5.
    Almgren, Birgitta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Wickerts, Carl-Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Heinonen, Erkki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Högman, Marieann
    Side effects of endotracheal suction in pressure and volume controlled ventilation2004Ingår i: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, nr 3, s. 1077-1080Artikel i tidskrift (Refereegranskat)
    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.

  • 6.
    Almgren, Birgitta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Wickerts, Carl-Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Högman, Marieann
    Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs2004Ingår i: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, nr 3, s. 339-345Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    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 rat2010Ingår i: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 14, nr 3, s. 245-248Artikel i tidskrift (Refereegranskat)
    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.

  • 8.
    Amandusson, Åsa
    et al.
    Linköpings Universitet.
    Hermansson, O
    Blomqvist, A
    Estrogen receptor-like immunoreactivity in the medullary and spinal dorsal horn of the female rat1995Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 196, nr 1-2, s. 25-28Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Department of Medical Cell Biology: Annual Report 20072008Samlingsverk (redaktörskap) (Övrig (populärvetenskap, debatt, mm))
    Ladda ner fulltext (pdf)
    fulltext
  • 10.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Department of Medical Cell Biology: Annual Report 20082009Samlingsverk (redaktörskap) (Övrig (populärvetenskap, debatt, mm))
    Ladda ner fulltext (pdf)
    fulltext
  • 11. 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.1995Ingår i: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 23, nr 11, s. 1872-81Artikel i tidskrift (Refereegranskat)
    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).

  • 12.
    Appelberg, Jonas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Ventilation and Lung Volume During Sleep and in Obstructive Sleep Apnea2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Ventilatory response to CO2 in patients with snoring, obstructive hypopnoea and obstructive apnoea
    Öppna denna publikation i ny flik eller fönster >>Ventilatory response to CO2 in patients with snoring, obstructive hypopnoea and obstructive apnoea
    1997 Ingår i: Clinical Physiology, Vol. 17, s. 497-507Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90212 (URN)
    Tillgänglig från: 2003-04-14 Skapad: 2003-04-14Bibliografiskt granskad
    2. Lung volume and its correlation to nocturnal apnoea and desaturation
    Öppna denna publikation i ny flik eller fönster >>Lung volume and its correlation to nocturnal apnoea and desaturation
    2000 Ingår i: Respiratory Medicine, Vol. 94, s. 233-239Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-90213 (URN)
    Tillgänglig från: 2003-04-14 Skapad: 2003-04-14Bibliografiskt granskad
    3. Lung aeration during sleep
    Öppna denna publikation i ny flik eller fönster >>Lung aeration during sleep
    Visa övriga...
    2007 (Engelska)Ingår i: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 131, nr 1, s. 122-129Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Airway closure, anesthesia, CT, lung aeration, lung volume, sleep, ventilation
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-90214 (URN)10.1378/chest.06-0359 (DOI)000243548100020 ()17218565 (PubMedID)
    Tillgänglig från: 2003-04-14 Skapad: 2003-04-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    4. Lung aeration during sleep in patients with obstructive sleep apnea
    Öppna denna publikation i ny flik eller fönster >>Lung aeration during sleep in patients with obstructive sleep apnea
    Visa övriga...
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-90215 (URN)
    Tillgänglig från: 2003-04-14 Skapad: 2003-04-14 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 13. Arvidsson, D
    et al.
    Rasmussen, I
    Almqvist, P
    Niklasson, F
    Haglund, U
    Splanchnic oxygen consumption in septic and hemorrhagic shock.1991Ingår i: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 109, nr 2, s. 190-7Artikel i tidskrift (Refereegranskat)
    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.

  • 14.
    Atuma, C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Engstrand, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Holm, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Helicobacter pylori extracts reduce gastric mucosal blood flow by a nitric oxide-independent but mast cell- and platelet-activating factor receptor-dependent pathway in rats1999Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 34, nr 12, s. 1183-1189Artikel i tidskrift (Refereegranskat)
    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.

  • 15.
    Atuma, Christer
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Gastrointestinal mucosal protective mechanisms: Mudolatory effects of Heliobacter pyroli on the gastric mucus gel barrier and mucosal blood flow in vivo2000Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 16.
    Atuma, Christer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Engstrand, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Holm, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för fysiologi.
    Extracts of Helicobacter pylori reduce gastric mucosal blood flow through a VacA- and CagA-independent pathway in rats1998Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 33, nr 12, s. 1256-1261Artikel i tidskrift (Refereegranskat)
    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.

  • 17.
    Axelson, Hans W.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Flink, Roland
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Successful localization of the Broca area with short-train pulses instead of "Penfield" stimulation.2009Ingår i: Seizure, ISSN 1059-1311, E-ISSN 1532-2688, Vol. 18, nr 5, s. 374-375Artikel i tidskrift (Refereegranskat)
    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.

  • 18.
    Babateen, Omar M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Bhandage, Amol K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Korol, Sergiy V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Westermark, Bengt
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nilsson, Karin Forsberg
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Uhrbom, Lene
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, nr S696, s. 100-100, artikel-id P74Artikel i tidskrift (Övrigt vetenskapligt)
  • 19.
    Backman, E. Louis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    Der osmotische Druck bei einigen Wasserkäfern1912Ingår i: Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere, ISSN 0365-267X, Vol. 149, nr 1/3, s. 93-114Artikel i tidskrift (Refereegranskat)
  • 20.
    Backman, E. Louis
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    Sundberg, Carl-Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    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 Brunacci1913Ingår i: Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere, ISSN 0365-267X, Vol. 151, nr 1/3, s. 52-56Artikel i tidskrift (Refereegranskat)
  • 21. Barragan, A.
    et al.
    Weidner, J. M.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Korpi, E. R.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    GABAergic signalling in the immune system2015Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, nr 4, s. 819-827Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 22.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    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 Disease2016Ingår i: ANNUAL REVIEW OF PHYSIOLOGY, VOL 78, ANNUAL REVIEWS, 2016, s. 437-461Kapitel i bok, del av antologi (Refereegranskat)
    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.

  • 23.
    Batool, Tahira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heparan sulfate dependent cell signaling and associated pathophysiology: Implications in tumorigenesis and embryogenesis2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    1. Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells
    Öppna denna publikation i ny flik eller fönster >>Overexpression of heparanase attenuated TGF-beta-stimulated signaling in tumor cells
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    2017 (Engelska)Ingår i: FEBS Open Bio, E-ISSN 2211-5463, Vol. 7, nr 3, s. 405-413Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    cancer cell, heparan sulfate, heparanase signaling, TGF-beta
    Nationell ämneskategori
    Biokemi och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Cancer och onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-322852 (URN)10.1002/2211-5463.12190 (DOI)000400298500011 ()28286736 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 2015-02595Vetenskapsrådet, K2013-66X-14936-10-5Cancerfonden, 150815Cancerfonden, 150834
    Tillgänglig från: 2017-06-07 Skapad: 2017-06-07 Senast uppdaterad: 2018-10-15Bibliografiskt granskad
    2. Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
    Öppna denna publikation i ny flik eller fönster >>Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
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    2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 40, s. 67553-67566Artikel i tidskrift (Refereegranskat) 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.

    Ort, förlag, år, upplaga, sidor
    IMPACT JOURNALS LLC, 2017
    Nyckelord
    tinzaparin, cancer, chemoresistance, Wnt, cisplatin
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-336049 (URN)10.18632/oncotarget.18738 (DOI)000410790500061 ()28978053 (PubMedID)
    Tillgänglig från: 2017-12-12 Skapad: 2017-12-12 Senast uppdaterad: 2018-10-15Bibliografiskt granskad
    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.
    Öppna denna publikation i ny flik eller fönster >>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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    (Engelska)Ingår i: Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-363257 (URN)
    Tillgänglig från: 2018-10-15 Skapad: 2018-10-15 Senast uppdaterad: 2018-10-15
    4. Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
    Öppna denna publikation i ny flik eller fönster >>Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells
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    2019 (Engelska)Ingår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 54, s. 122-129Artikel i tidskrift (Refereegranskat) 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.   

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2019
    Nyckelord
    BMP signaling, Heparan sulfate, MEF cells, Smad, Glucuronyl C5-epimerase, Bone Morphogenetic Protein
    Nationell ämneskategori
    Cell- och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
    Identifikatorer
    urn:nbn:se:uu:diva-363254 (URN)10.1016/j.cellsig.2018.11.010 (DOI)000456752900013 ()30458230 (PubMedID)
    Forskningsfinansiär
    Cancerfonden, CAN2015/496Vetenskapsrådet, 2015-02595Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Tillgänglig från: 2018-10-15 Skapad: 2018-10-15 Senast uppdaterad: 2019-02-12Bibliografiskt granskad
    5. Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development: Glucuronyl C5-epimerase in lung development
    Öppna denna publikation i ny flik eller fönster >>Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development: Glucuronyl C5-epimerase in lung development
    (Engelska)Ingår i: Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-363255 (URN)
    Tillgänglig från: 2018-10-15 Skapad: 2018-10-15 Senast uppdaterad: 2018-10-15
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  • 24.
    Becirovic Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Quantitative trait loci associated with angiotensin II and high-salt diet induced acute decompensated heart failure in Balb/CJ mice2019Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 51, nr 7, s. 279-289Artikel i tidskrift (Refereegranskat)
    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.

  • 25.
    Becirovic-Agic, Mediha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Jönsson, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Tveitarås, Maria K.
    Skogstrand, Trude
    Karlsen, Tine Veronica
    Lidén, Åsa
    Leh, Sabine
    Ericsson, Madelene
    Nilsson, Stefan K.
    Reed, Rolf K.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. 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 syndrome2019Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 316, nr 5, s. R563-R570Artikel i tidskrift (Refereegranskat)
    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.

  • 26. Belalov, V. V.
    et al.
    Dyagileva, Yu. O.
    Pavlenko, V. B.
    Kochukhova, Olga M.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Neurophysiological Analysis of Speech Perception in 2.5 to 3.5-Year-Old Orphans and Children Raised in a Family2014Ingår i: Neurophysiology (New York), ISSN 0090-2977, E-ISSN 1573-9007, Vol. 46, nr 1, s. 79-87Artikel i tidskrift (Refereegranskat)
    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.

  • 27.
    Bergfors, Monica
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Improved diagnosis of Carpal tunnel syndrome using amplitude difference between m. Abductor pollicis brevis and m. Pronator quadratus?2008Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats
    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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  • 28.
    Bergmann, Astrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    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 volunteers2020Ingår i: Respiratory Physiology & Neurobiology, ISSN 1569-9048, E-ISSN 1878-1519, Vol. 271, artikel-id 103287Artikel i tidskrift (Refereegranskat)
    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.

  • 29.
    Bergström, Ulrika
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. ekotoxikologi.
    Olsson, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. ekotoxikologi.
    Hvidsten, Torgeir R
    Komorowski, Jan
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi. ekotoxikologi.
    Neurotoxicity of the Olfactory toxicant 2,6-Dichlorophenyl Methylsulphone in Olfactory bulb:Impaired expression of genes relating to neurodegenerative disease2007Ingår i: DIOXIN2007, 2007, s. 1841-1844Konferensbidrag (Refereegranskat)
  • 30.
    Bhandage, Amol
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Ólafsson, Einar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    The mRNA expression of GABA-A, GABA-B receptor subunits and chloride transporters in peripheral blood mononuclear cells is influenced by gender, pregnancy and depression2015Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, s. 91-91Artikel i tidskrift (Övrigt vetenskapligt)
  • 31.
    Bhandage, Amol K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Glutamate and GABA signalling components in the human brain and in immune cells2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

    Delarbeten
    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
    Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, s. 11-Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Fysiologi Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-219489 (URN)10.3389/fncel.2014.00011 (DOI)000331053400001 ()24523671 (PubMedID)
    Tillgänglig från: 2014-03-03 Skapad: 2014-03-03 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    2. Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
    Öppna denna publikation i ny flik eller fönster >>Expression of specific ionotropic glutamate and GABA-A receptor subunits is decreased in central amygdala of alcoholics
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    2014 (Engelska)Ingår i: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, s. 288-Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-239603 (URN)10.3389/fncel.2014.00288 (DOI)000344465400002 ()
    Tillgänglig från: 2014-12-30 Skapad: 2014-12-29 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    3.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
    4. Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
    Öppna denna publikation i ny flik eller fönster >>Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 8, s. e42959-Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-172532 (URN)10.1371/journal.pone.0042959 (DOI)000307789700016 ()
    Tillgänglig från: 2012-04-11 Skapad: 2012-04-11 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    5. Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
    Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, nr 3, s. 575-585Artikel i tidskrift (Refereegranskat) 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.

    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-240372 (URN)10.1111/apha.12440 (DOI)000348531600007 ()25529063 (PubMedID)
    Tillgänglig från: 2015-01-07 Skapad: 2015-01-07 Senast uppdaterad: 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
    Öppna denna publikation i ny flik eller fönster >>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
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    2017 (Engelska)Ingår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 305, s. 51-58Artikel i tidskrift (Refereegranskat) 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.

    Nyckelord
    Glutamate, iGluR subunits, Immune cells, Pregnancy, Depression, Physiology-driven changes
    Nationell ämneskategori
    Medicin och hälsovetenskap Neurovetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-282410 (URN)10.1016/j.jneuroim.2017.01.013 (DOI)000397694200009 ()28284346 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 521-2012-1789
    Tillgänglig från: 2016-04-05 Skapad: 2016-04-05 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
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  • 32.
    Bhandage, Amol K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Olafsson, Einar B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Sundström-Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health2015Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, nr 3, s. 575-585Artikel i tidskrift (Refereegranskat)
    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.

  • 33.
    Bhandage, Amol K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Olafsson, Einar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Sundström, Iinger Poromaa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    GABA-A receptor subunit expression in human peripheral blood mononuclear cells2014Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, nr S696, s. 86-86, artikel-id P45Artikel i tidskrift (Övrigt vetenskapligt)
  • 34.
    Bhandage, Amol K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Bazov, Igor
    Kononenko, Olga
    Bakalkin, Georgy
    Korpi, Esa R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics2014Ingår i: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, artikel-id 415Artikel i tidskrift (Refereegranskat)
    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.

  • 35.
    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.2001Ingår i: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 181, nr 3, s. 171-83Artikel i tidskrift (Refereegranskat)
    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.

  • 36.
    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.2000Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 131, nr 4, s. 695-704Artikel i tidskrift (Refereegranskat)
    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.

  • 37.
    Birnir, Bryndis
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Eliasson, L.
    Lund Univ, Dept Clin Sci Malmo, Ctr Diabet, Lund, Sweden..
    She is in science to stay!2018Ingår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 223, nr 1, artikel-id e13048Artikel i tidskrift (Övrigt vetenskapligt)
  • 38.
    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.1994Ingår i: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 142, nr 1, s. 93-102Artikel i tidskrift (Refereegranskat)
    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.

  • 39.
    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.2000Ingår i: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 174, nr 1, s. 21-9Artikel i tidskrift (Refereegranskat)
    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.

  • 40.
    Birnir, Bryndis
    et al.
    Lund University, School of Medicine.
    Korpi, Esa R
    The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors.2007Ingår i: Current pharmaceutical design, ISSN 1873-4286, Vol. 13, nr 31, s. 3169-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.

  • 41.
    Birnir, Bryndis
    et al.
    Department of Physiology, UCLA School of Medicine.
    Lee, H S
    Hediger, M A
    Wright, E M
    Expression and characterization of the intestinal Na+/glucose cotransporter in COS-7 cells.1990Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1048, nr 1, s. 100-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cells derived from the simian kidney, COS-7 cells, were transfected with a eucaryotic expression vector (pEUK-C1) containing the clone for the rabbit intestinal Na+/glucose cotransporter. Expression was monitored after transfection with lipofectin by measuring the initial rate of alpha-methylglucopyranoside (MeGlc) uptake. Cells transfected with vector containing the cDNA for the Na+/glucose cotransporter expressed Na(+)-dependent MeGlc transport. Neither control cells nor cells transfected with vector lacking cloned cDNA expressed the cotransporter. Na(+)-dependent MeGlc uptake into transfected cells was saturable (Km 150 microM), phlorizin-sensitive (Ki 11 microM), and inhibited by sugar analogs (D-glucose greater than MeGlc greater than D-galactose greater than 3-O-methyl-D-glucoside greater than D-allose much greater than L-glucose). Europium was able to mimic Na+ in driving MeGIC uptake. Finally, tunicamycin, an inhibitor of asparagine-linked glycosylation, inhibited the expression of Na(+)-dependent MeGlc transport 80%. We conclude that the rabbit intestinal Na+/glucose cotransporter expressed in COS-7 cell exhibits very similar kinetic properties to that in the native brush border and to that expressed in Xenopus oocytes. In addition, N-linked glycosylation appears to be important for functional expression of this membrane protein.

  • 42.
    Birnir, Bryndis
    et al.
    Department of Physiology, UCLA School of Medicine.
    Loo, D D
    Wright, E M
    Voltage-clamp studies of the Na+/glucose cotransporter cloned from rabbit small intestine.1991Ingår i: Pflügers Archiv: European Journal of Physiology, ISSN 0031-6768, E-ISSN 1432-2013, Vol. 418, nr 1-2, s. 79-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inward Na+ currents associated with the cloned intestinal Na+/glucose cotransporter expressed in Xenopus oocytes have been studied using the two-microelectrode voltage-clamp method. The steady-state current/voltage relations showed voltage-dependent (Vm from +20 to -75 mV) and relatively voltage-independent (Vm from -75 to -150 mV) regions. The apparent Imax for Na+ and glucose increased with negative membrane potentials, and the apparent K0.5 for glucose (K(Glc)0.5) depended on Vm and [Na]o. Increasing [Na]o from 7 to 110 mmol/l had the same effect in decreasing K(Glc)0.5 from 0.44 to 0.03 mmol/l as increasing the Vm from -40 to -150 mV. The I/V curves under saturating conditions (20 mmol/l external sugars and 110 mmol/l [Na]o) were identical for D-glucose, D-galactose, alpha-methyl D-glucopyranoside and 3-O-methyl D-glucoside. The specificity of the cotransporter for sugars was: D-glucose, D-galactose, alpha-methyl D-glucopyranoside greater than 3-O-methyl D-glucoside much greater than D-xylose greater than D-allose much greater than D-mannose. Ki for phlorizin (approximately 10 mumol/l) was independent of Vm at saturating [Na]o. We conclude that a variety of sugars are transported by the cloned Na+/glucose cotransporter at the same maximal rate and that membrane potential affects both the maximal current and the apparent K0.5 of the cotransporter for Na+ and glucose.

  • 43.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Tierney, M L
    Dalziel, J E
    Cox, G B
    Gage, P W
    A structural determinant of desensitization and allosteric regulation by pentobarbitone of the GABAA receptor.1997Ingår i: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 155, nr 2, s. 157-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Functional properties of the alpha1beta1 GABAA receptor changes in a subunit-specific manner when a threonine residue in the M2 region at the 12' position was mutated to glutamine. The rate and extent of desensitization increased in all mutants but the rate of activation was faster in the beta1 mutants. A negligible plateau current and abolition of potentiation by pentobarbitone of the GABA-activated current depended on the Thr 12' Gln mutation being present in the beta1 subunit. The Hill coefficient of the peak current response to GABA was reduced to less than one also in a beta1 subunit-specific manner. It was concluded that the beta1 subunit dominated conformational changes activated by GABA.

  • 44.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Tierney, M L
    Howitt, S M
    Cox, G B
    Gage, P W
    A combination of human alpha 1 and beta 1 subunits is required for formation of detectable GABA-activated chloride channels in Sf9 cells.1992Ingår i: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 250, nr 1329, s. 307-12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The baculovirus expression system was used to produce alpha 1 and beta 1 subunits of the human GABAA receptor in Sf9 cells. In cells infected with both alpha 1 and beta 1 recombinant viruses, GABA elicited an outwardly rectifying chloride current that was blocked by bicuculline and potentiated by pentobarbitone. GABA did not produce detectable currents in cells infected with either alpha 1 or beta 1 recombinant viruses alone. In these cells, and in control (non-infected) Sf9 cells, pentobarbitone depressed the leakage current (Ki = 55 microM). Fluorescently labelled monoclonal antibodies to the alpha 1 subunit showed greater amounts of the alpha 1 subunit in cells infected with only the alpha 1 recombinant virus than in cells co-infected with the alpha 1 and beta 1 recombinant viruses. Fluorescence of the plasma membrane was seen in cells co-infected with the alpha 1 and beta 1 recombinant viruses, but was absent in cells infected with only the alpha 1 recombinant virus. It was concluded that the alpha 1 subunit normally interacts with the beta 1 subunit to be transported to the plasma membrane in Sf9 cells.

  • 45.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Tierney, M L
    Lim, M
    Cox, G B
    Gage, P W
    Nature of the 5' residue in the M2 domain affects function of the human alpha 1 beta 1 GABAA receptor.1997Ingår i: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 26, nr 3, s. 324-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effects on the functional properties of the alpha 1 beta 1 GABAA receptor when the 5' (alpha 1 Val260; beta 1 Ile255) hydrophobic amino acids in the second transmembrane (M2) region were changed to threonine were examined. In response to a saturating concentration of GABA, the current evoked in mutant receptors showed a decreased rate of desensitization and at equilibrium was a greater fraction of the peak current than in wild-type receptors. The half-saturation concentration of the peak current response to GABA in mutant receptors was comparable to that in wild-type receptors, but the Hill coefficient was reduced to less than one. It was concluded that the 5' amino acids in the M2 region have a role in the conformational changes that occur within the alpha 1 beta 1 GABAA receptor in response to GABA.

  • 46.
    Birnir, Bryndis
    et al.
    John Curtin School of Medical Research, Australian National University.
    Tierney, M L
    Pillai, N P
    Cox, G B
    Gage, P W
    Rapid desensitization of alpha 1 beta 1 GABA A receptors expressed in Sf9 cells under optimized conditions.1995Ingår i: Journal of Membrane Biology, ISSN 0022-2631, E-ISSN 1432-1424, Vol. 148, nr 2, s. 193-202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    alpha 1 and beta 1 subunits of human GABA A receptors were expressed in Sf9 cells using the Sf9-baculovirus system. Better expression was obtained by manipulating the system. Cell growth phase at the time of infection determined the practical range of virus titre, the period postinfection during which cells were useful for signal detection and the maximal current obtained. Cells in the early exponential phase were relatively insensitive to multiplicity of infection (MOI) whereas cells in the mid- to late-exponential phase were highly dependent on MOI and they responded with the largest Cl- current generated by GABA. Channels activated by GABA were chloride-selective. Half the maximum peak whole-cell current was obtained with 11 microM GABA. The time course of Cl- currents activated by saturating GABA concentrations in cells infected with alpha 1 beta 1-recombinant viruses was examined employing a rapid perfusion system which allowed whole-cell solution exchange in less than 1 msec. The current decay could be fitted by 3 to 4 exponentials for the first 8 sec. The initial fast current decrease had a time constant of about 23 msec. No voltage dependence of time constants was detected but the whole-cell IV relation showed outward rectification. Currents were depressed by bicuculline, penicillin and picrotoxin and potentiated by pentobarbitone.

  • 47. Bivol, Liliana Monica
    et al.
    Hultström, Michael
    Gudbrandsen, Oddrun A
    Berge, Rolf K
    Iversen, Bjarne M
    Tetradecylthioacetic acid downregulates cyclooxygenase 2 in the renal cortex of two-kidney, one-clip hypertensive rats.2008Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 295, nr 6, s. R1866-73Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effect of tetradecylthioacetic acid (TTA) on the cyclooxygenase (COX) system was investigated in two-kidney, one-clip (2K1C) hypertensive rats. The systolic blood pressure (BP) was increased 6 wk after clipping to 183 +/- 4 vs.127 +/- 3 mmHg in TTA-treated 2K1C rats. The COX1 protein expression was not affected either by the 2K1C procedure or by TTA treatment. COX2 expression was upregulated in both kidneys, but to a greater extent in the clipped kidney. COX2 activity was 16 +/- 3% in control and 38 +/- 2% (P < 0.001) in the clipped kidney, and COX2 protein expression was 1.3 +/- 0.04 in control and 1.6 +/- 0.12 in the clipped kidney (P = 0.006). TTA reduced COX2 activity to control levels. Subcutaneously infusion of a COX2 inhibitor did not reduce BP. Peroxisome proliferator-activated receptors (PPARs) were detected in both kidneys, and PPARdelta was upregulated in the nonclipped kidney after TTA treatment. PGE2 in renal cortex was increased in 2K1C (31 +/- 0.3 in the clipped and 28 +/- 0.2 pg/ml nonclipped kidney, P < 0.001 compared with control). TTA lowered the PGE2 to control levels. Renal blood flow (RBF) response to exogenous ANG II injected in the control and nonclipped kidney was exaggerated after indomethacin treatment but unchanged in the nonclipped kidney of the K1C TTA group. Overall, these results indicate that, after 6 wk of treatment, TTA downregulated the COX2 activity, which have potentially important effects on the regulation of renal hemodynamics but does not explain TTAs ability to lower BP.

  • 48. Bivol, Liliana Monica
    et al.
    Iversen, Bjarne Magnus
    Hultström, Michael
    Department of Clinical Science, University of Bergen, Norway.
    Wallace, Paal W
    Reed, Rolf Kåre
    Wiig, Helge
    Tenstad, Olav
    Unilateral renal ischemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased peritubular capillary permeability2015Ingår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A better understanding of the inflammatory process associated with renal ischemia-reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, whereas plasma and renal cortical tissue samples returned to control levels after 120 min reperfusion. The responses were differentiated; Interleukin-1β, monocyte chemoattractant protein-1 and leptin were markedly increased in plasma before reperfusion, reflecting an extrarenal response possibly induced by afferent renal nerve activity from the ischemic kidney. Tumour necrosis factor-α  was the only mediator showing elevated lymph to plasma ratio following 30 min reperfusion, indicating that most cytokines were released directly into the bloodstream. The IR induced rise in cytokine levels was paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine. The latter was shown as a 14-166 fold increase in glomerular sieving coefficient of plasma proteins assessed by a novel proteomic approach, and indicated a temporarily reduced size selectivity of both glomerular and peritubular capillaries. Collectively, our data suggest that cytokines from the ischemic kidney explain most of the rise in plasma concentration, and that the locally produced substances enter the systemic circulation through transport directly to plasma and not via the interstitium to lymph.

  • 49. Bjurstöm, Helen
    et al.
    Wang, JunYang
    Ericsson, Ida
    Bengtsson, Martin
    Liu, Yawei
    Kumar-Mendu, Suresh
    Lund University, Diabetic Centre, CRC, Department of Clinical Sciences.
    Issazadeh-Navikas, Shohreh
    Birnir, Bryndis
    Lund University, Diabetic Centre, CRC, Department of Clinical Sciences.
    GABA, a natural immunomodulator of T lymphocytes2008Ingår i: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 205, nr 1-2, s. 44-50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    gamma-aminobutyric acid (GABA) is the main neuroinhibitory transmitter in the brain. Here we show that GABA in the extracellular space may affect the fate of pathogenic T lymphocytes entering the brain. We examined in encephalitogenic T cells if they expressed functional GABA channels that could be activated by the low (nM-1 microM), physiological concentrations of GABA present around neurons in the brain. The cells expressed the alpha1, alpha4, beta2, beta3, gamma1 and delta GABAA channel subunits and formed functional, extrasynaptic-like GABA channels that were activated by 1 microM GABA. 100 nM and higher GABA concentrations decreased T cell proliferation. The results are consistent with GABA being immunomodulatory.

  • 50. Björck, M
    et al.
    Bergqvist, D
    Rasmussen, I
    Piehl, E
    Haglund, U
    An experimental porcine model of partial ischaemia of the distal colon.1997Ingår i: European Journal of Surgery, ISSN 1102-4151, E-ISSN 1741-9271, Vol. 163, nr 11, s. 843-50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Ischaemia of the colon is a major challenge in aortoiliac surgery. The aim was to establish an animal model of partial distal colonic ischaemia to study interventional strategies.

    DESIGN: Randomised experiment.

    SETTING: University Hospital. Department of Experimental Research.

    MATERIAL: 19 pigs.

    INTERVENTIONS: 11 Pigs were subjected to ischaemia consisting of total occlusion of the inferior mesenteric artery and partial occlusion of the superior mesenteric artery. Eight animals were sham controls. Dextran was given.

    MAIN OUTCOME MEASURES: Haemodynamic measurements, intramucosal pH-measurements (pHi) and histological grading.

    RESULTS: Both ischaemic animals and controls remained haemodynamically stable. It was possible to maintain stable ischaemia in the distal colon in the pHi-range of 6.9-7.1. There was histological mucosal damage of the distal colon in ischaemic animals but not in controls.

    CONCLUSIONS: The model could be of value when studying interventional strategies to reduce or reverse ischaemia.

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