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1.
  • Björkqvist, Maria, et al. (författare)
  • Somatostatin, misoprostol and galanin inhibit gastrin- and PACAP-stimulated secretion of histamine and pancreastatin from ECL cells by blocking specific Ca(2+) channels.
  • 2005
  • Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 130:1-2, s. 81-90
  • Tidskriftsartikel (refereegranskat)abstract
    • The oxyntic mucosa is rich in ECL cells. They secrete histamine and chromogranin A-derived peptides, such as pancreastatin, in response to gastrin and pituitary adenylate cyclase-activating peptide (PACAP). Secretion is initiated by Ca2+ entry. While gastrin stimulates secretion by opening L-type and N-type Ca2+ channels, PACAP stimulates secretion by activating L-type and receptor-operated Ca2+ channels. Somatostatin, galanin and prostaglandin E2 (PGE2) inhibit gastrin- and PACAP-stimulated secretion from the ECL cells. In the present study, somatostatin and the PGE2 congener misoprostol inhibited gastrin- and PACAP-stimulated secretion 100%, while galanin inhibited at most 60–65%. Bay K 8644, a specific activator of L-type Ca2+ channels, stimulated ECL-cell secretion, an effect that was inhibited equally effectively by somatostatin, misoprostol and galanin (75–80% inhibition). Pretreatment with pertussis toxin, that inactivates inhibitory G-proteins, prevented all three agents from inhibiting stimulated secretion (regardless of the stimulus). Pretreatment with nifedipine (10 μM), an L-type Ca2+ channel blocker, reduced PACAP-evoked pancreastatin secretion by 50–60%, gastrin-evoked secretion by not, vert, similar 80% and abolished the response to Bay K 8644. The nifedipine-resistant response to PACAP was abolished by somatostatin and misoprostol but not by galanin. Gastrin and PACAP raised the intracellular Ca2+ concentration in a biphasic manner, believed to reflect mobilization of internal Ca2+ followed by Ca2+ entry. Somatostatin and misoprostol blocked Ca2+ entry (and histamine and pancreastatin secretion) but not mobilization of internal Ca2+. The present observations on isolated ECL cells suggest that Ca2+ entry rather than mobilization of internal Ca2+ triggers exocytosis, that gastrin and PACAP activate different (but over-lapping) Ca2+ channels, that somatostatin, misoprostol and galanin interact with inhibitory G-proteins to block Ca2+ entry via L-type Ca2+ channels, and that somatostatin and misoprostol (but not galanin) in addition block N-type and/or receptor-operated Ca2+ channels.
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3.
  • Duarte, Ana I., et al. (författare)
  • Dual Therapy with Liraglutide and Ghrelin Promotes Brain and Peripheral Energy Metabolism in the R6/2 Mouse Model of Huntington's Disease
  • 2018
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuronal loss alongside altered energy metabolism, are key features of Huntington's disease (HD) pathology. The orexigenic gut-peptide hormone ghrelin is known to stimulate appetite and affect whole body energy metabolism. Liraglutide is an efficient anti-type 2 diabetes incretin drug, with neuroprotective effects alongside anorectic properties. Combining liraglutide with the orexigenic peptide ghrelin may potentially promote brain/cognitive function in HD. The R6/2 mouse model of HD exhibits progressive central pathology, weight loss, deranged glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using a co-administration of liraglutide and ghrelin. We investigated their effect on brain cortical hormone-mediated intracellular signalling pathways, metabolic and apoptotic markers, and the impact on motor function in HD. We here demonstrate that liraglutide, alone or together with ghrelin (subcutaneous daily injections of 150 μg/kg (ghrelin) and 0.2 mg/kg (liraglutide), for 2 weeks), normalized glucose homeostatic features in the R6/2 mouse, without substantially affecting body weight or body composition. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels in R6/2 mice, alongside higher ADP levels. Liraglutide plus ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice. Taken together, our findings encourage further studies targeting energy metabolism in HD.
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6.
  • Reynolds, Regina Hertfelder, et al. (författare)
  • Perturbations in the p53/miR-34a/SIRT1 pathway in the R6/2 Huntington's disease model
  • 2018
  • Ingår i: Molecular and Cellular Neuroscience. - : Elsevier BV. - 1044-7431. ; 88, s. 118-129
  • Tidskriftsartikel (refereegranskat)abstract
    • The three factors, p53, the microRNA-34 family and Sirtuin 1 (SIRT1), interact in a positive feedback loop involved in cell cycle progression, cellular senescence and apoptosis. Each factor in this triad has roles in metabolic regulation, maintenance of mitochondrial function, and regulation of brain-derived neurotrophic factor (BDNF). Thus, this regulatory network holds potential importance for the pathophysiology of Huntington's disease (HD), an inherited neurodegenerative disorder in which both mitochondrial dysfunction and impaired neurotrophic signalling are observed. We investigated expression of the three members of this regulatory triad in the R6/2 HD mouse model. Compared to wild-type littermates, we found decreased levels of miR-34a-5p, increased SIRT1 mRNA and protein levels, and increased levels of p53 protein in brain tissue from R6/2 mice. The upregulation of SIRT1 did not appear to lead to an increased activity of the enzyme, as based on measures of p53 acetylation. In other words, the observed changes did not reflect the known interactions between these factors, indicating a general perturbation of the p53, miR-34a and SIRT1 pathway in HD. This is the first study investigating the entire triad during disease progression in an HD model. Given the importance of these three factors alone and within the triad, our results indicate that outside factors are regulating – or dysregulating – this pathway in HD.
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7.
  • Allbrand, Marianne, 1958-, et al. (författare)
  • Placental gene expression of inflammatory markers and growth factors : a case control study of obese and normal weight women
  • 2015
  • Ingår i: Journal of Perinatal Medicine. - : Walter de Gruyter. - 0300-5577 .- 1619-3997. ; 43:2, s. 159-164
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To survey the placental gene expression of inflammatory markers and growth factors in non-smoking obese women with an uncomplicated pregnancy without associated morbidity and delivery at term compared with normal weight women.Methods: Placental tissue samples from 32 obese women (body mass index, BMI >= 35.0 kg/m(2)) were compared with samples from 94 normal weight women (BMI 18.5-25.0 kg/m(2)) matched for age (+/- 1 year), gestational age (+/- 3 days), parity and mode of delivery. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to analyse toll receptor-2 and -4, interleukin-6 and -8, tumour necrosis factor-alpha, leptin, adiponectin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor.Results: There was no significant difference in gene expression in placental tissue samples from obese and normal weight women.Conclusion: We found no difference in the occurrence of inflammatory marker and growth factor mRNA levels in placental tissue samples from a large group of obese women without associated morbidity and with healthy infants compared to a closely matched control group of healthy normal weight women. Compared with the previous studies, this anomalous finding may be explained by the absence of associated morbidity in the obese women in our study.
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8.
  • Bacos, Karl, et al. (författare)
  • Islet beta-cell area and hormone expression are unaltered in Huntington's disease.
  • 2008
  • Ingår i: Histochemistry and Cell Biology. - : Springer Science and Business Media LLC. - 1432-119X .- 0948-6143. ; 129, s. 623-629
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurodegenerative disorders are often associated with metabolic alterations. This has received little attention, but might be clinically important because it can contribute to symptoms and influence the course of the disease. Patients with Huntington's disease (HD) exhibit increased incidence of diabetes mellitus (DM). This is replicated in mouse models of HD, e.g., the R6/2 mouse, in which DM is primarily caused by a deficiency of beta-cells with impaired insulin secretion. Pancreatic tissue from HD patients has previously not been studied and, thus, the pathogenesis of DM in HD is unclear. To address this issue, we examined pancreatic tissue sections from HD patients at different disease stages. We found that the pattern of insulin immunostaining, levels of insulin transcripts and islet beta-cell area were similar in HD patients and controls. Further, there was no sign of amyloid deposition in islets from HD patients. Thus, our data show that pancreatic islets in HD patients appear histologically normal. Functional studies of HD patients with respect to insulin secretion and islet function are required to elucidate the pathogenesis of DM in HD. This may lead to a better understanding of HD and provide novel therapeutic targets for symptomatic treatment in HD.
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9.
  • Bjerneby Häll, Maria (författare)
  • Allt har förändrats och allt är sig likt : En longitudinell studie av argument för grundskolans matematikundervisning
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Syftet med avhandlingen är att beskriva och analysera argument för matematik i grundskolan och att förstå varför och hur de officiella argumenten förändras, från de argument som återfinns i styrdokument till de argument som förs fram av undervisande matematiklärare. En utgångspunkt är att skolmatematikens villkor och verklighet kan beskrivas genom analys av officiella argument och av lärarstudenters och lärares personliga argument för matematik i grundskolan. Specifika forskningsfrågor i anslutning till syftet är:- Vilka argument för lärarstudenten fram inför yrkesdebuten?- Vilka argument för läraren fram under sina första år i yrket?- Vilka beskrivningar av skolmatematikens villkor ger lärarna?En longitudinell studie har genomförts där en grupp lärarstudenter följts genom utbildningen och under de första åren i yrket. Resultatet visar att lärarstudenter under utbildningen utvecklar en syn på matematik och matematikundervisning som stämmer väl med läroplanen och kursplanen i matematik enligt Lpo 94. De nyblivna lärarna med undervisning i matematik och NO-ämnen upplever i början av yrkeskarriären skilda villkor på olika skolor. Gemensamt för de lärare som undervisar i senare delen av grundskolan är upplevelser av krav på att ”hinna med kursen” inför det nationella provet i årskurs 9. Lärarnas mål med matematikundervisningen i grundskolan blir därför att förbereda eleverna för det nationella provet. En faktor som påverkar är kravet på att elever skall ha betyget godkänd för att vara behöriga till gymnasieskolans nationella program. De nyblivna lärarna upplever en konflikt mellan olika officiella argument för matematik i grundskolan. Faktorer som påverkar lärarnas och matematikämnets villkor och verklighet i grundskolan är bl.a. skolornas organisation i arbetslag och lärarnas kombination av undervisningsämnen.
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10.
  • Björkqvist, Maria, et al. (författare)
  • A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
  • 2008
  • Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205, s. 1869-1877
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
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  • Björkqvist, Maria, 1959- (författare)
  • Coagulase-negative staphylococci septicaemia in newborns : aspects on host-bacterial interactions with special regard to neutrophil and endothelial response
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Newborn infants, especially those born preterm, are immunologically immature and prone to invasive infections. As a result of the increasing survival of very preterm (VPT < 31 weeks gestational age) newborns, nosocomial septicaemia has become a major concern the neonatal intensive care, and coagulase-negative staphylococci (CoNS) are nowadays the most frequently isolated pathogens in neonatal blood cultures. Further insight into host-bacterial interactions is required for the development of preventive strategies against CoNS septicaemia in VPT newborns.Aim of the study: To investigate host-bacterial interactions in neonatal CoNS septicaemia with special regard to the neutrophil and endothelial response and to bacterial virulence factors.Methods and results: Neonatal blood isolates of CoNS collected at Örebro University Hospital, Örebro, Sweden during the years 1983-1997 were characterised clinically and according to species and to phenotypic and genotypic patterns. Biochemial fingerprinting was found useful as a screening tool for selection of phenotypically related strains, but for further discrimination within a phenotypic cluster, genetic fingerprinting by pulsed field gel electrophoresis (PFGE) was required.The isolates of S. epidermidis collected during the later part of the study period (1990-1997, n = 50) were further investigated. A hypervirulent clone of bacteria was identified, representing 7 of the 12 sepsis isolates in that cohort. These 12 isolates of S. epidermidis induced significantly higher endothelial release of neutrophil chemoattractants from human umbilical vein endothelial cell (HUVEC) cultures than did the isolates regarded as skin contaminants (n = 38). There were no differences between the sepsis and contaminant groups in the prevalence of genes for biofilm production, methicillin resistance or fibrinogen-binding protein.The neutrophil oxidative burst occuring after stimulation by different bacterial strains was investigated by a flow cytometric method applied to a whole blood model. The oxidative activity in unstimulated neutrophils was similar in term (n = 10) and preterm (n = 10) newborns. However, the term newborns showed a significantly higher capacity to up-regulate the oxidative burst after bacterial stimulation. Significant differences in oxidative responses to different bacterial strains were observed, but these differences could not be related exclusively to species or invasive capacity.A neutrophil granule protein, human neutrophil lipocalin (HNL), was evaluated as an early marker of neonatal septicaemia in newborns with clinical signs of infection. The serum level of HNL was significantly higher in the infected group of neonates (n = 25) than in the group with non-proven infection (n = 62). In healthy term controls the HNL level was similar at age 3 days to that at birth and close to the level reported in healthy adults.Conclusions: The increased up-regulation of endothelial inflammatory mediators induced by sepsis isolates of S. epidermidis represents an important step in the pathogenesis of neonatal CoNS septicaemia. HNL might be useful as a marker of neutrophil activity also in VPT newborns. The laboratory assays used in the present study can be further developed for future investigations of the pathogenesis and host-bacterial interactions in neonatal CoNS septicaemia.
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  • Björkqvist, Maria, 1959-, et al. (författare)
  • Colonization pattern of coagulase-negative staphylococci in preterm neonates and the relation to bacteremia
  • 2010
  • Ingår i: European Journal of Clinical Microbiology and Infectious Diseases. - : Springer. - 0934-9723 .- 1435-4373. ; 29:9, s. 1085-1093
  • Tidskriftsartikel (refereegranskat)abstract
    • Coagulase-negative staphylococci (CoNS) are the major cause of sepsis in extreme preterm (EPT) newborns, but data on the CoNS colonization in EPT newborns prior to invasive infection are limited. Our aim was to describe the early establishment of the CoNS microflora in EPT newborns and to compare the colonization pattern in neonates with and without positive CoNS blood cultures. From a cohort of 46 EPT neonates, newborns with positive CoNS blood culture were identified (n = 10) and compared with matched controls. Samples for bacterial cultures were obtained repetitively from nares, perineum, and umbilicus. All CoNS isolates were characterized using the PhenePlate system for biochemical fingerprinting. Persistent CoNS strains were found on day 2-3 after delivery in 7/20 newborns, and there was a tendency for earlier colonization in nares than in the perineum or umbilicus. The CoNS blood strains were prevalent in superficial sites prior to positive blood culture (11/14 blood strains), but no single invasive pathway was identified. Most CoNS blood strains (9/14) persisted on superficial sites after antibiotic treatment. We hypothesize that the invasive pathways in neonatal CoNS sepsis are complex and that the colonization of mucosal membranes and umbilical catheters might be of equal importance.
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16.
  • Björkqvist, Maria, et al. (författare)
  • Defective neutrophil oxidative burst in preterm newborns on exposure to coagulase-negative staphylococci
  • 2004
  • Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 55:6, s. 966-971
  • Tidskriftsartikel (refereegranskat)abstract
    • The neutrophil oxidative burst is a product of the regulated assembly of the multicomponent oxidase enzyme. Our aim was to compare the oxidative burst in term (n = 10) and preterm newborns <31 wk gestational age (n = 10) after stimulation with coagulase-negative staphylococci in vitro. Strains of Streptococcus epidermidis with different invasive and slime-producing properties, one strain of S. haemolyticus, and one strain of group B-streptococcus were investigated. A whole-blood flow cytometric assay using the oxidation of hydroethidine to ethidium bromide was used. The oxidative activity in unstimulated neutrophil granulocytes [polymorphonuclear leukocytes (PMNLs)] was similar in term and preterm newborns, but the preterm newborns showed a significantly lower capacity to up-regulate the oxidative burst intensity after bacterial stimulation (p = 0.004). In the term but not in the preterm group, the oxidative burst intensity after bacterial stimulation correlated with the baseline oxidative burst intensity. After bacterial stimulation, there was a trend toward a greater percentage of activated neutrophils in the term group than in the preterm group, but the difference was less pronounced than that in oxidative burst intensity. Significant differences in oxidative burst response to different bacterial strains were observed (p < 0.001), but the differences could not be correlated exclusively to invasive capacity or slime-producing properties. It is concluded that the baseline oxidative activity is similar in term and preterm PMNLs but that preterm PMNLs have a decreased capacity to increase the oxidative burst in response to bacterial stimulation.
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  • Björkqvist, Maria, et al. (författare)
  • Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer's disease.
  • 2012
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • There is an urgent need for biomarkers in plasma to identify Alzheimer's disease (AD). It has previously been shown that a signature of 18 plasma proteins can identify AD during pre-dementia and dementia stages (Ray et al, Nature Medicine, 2007). We quantified the same 18 proteins in plasma from 174 controls, 142 patients with AD, and 88 patients with other dementias. Only three of these proteins (EGF, PDG-BB and MIP-1δ) differed significantly in plasma between controls and AD. The 18 proteins could classify patients with AD from controls with low diagnostic precision (area under the ROC curve was 63%). Moreover, they could not distinguish AD from other dementias. In conclusion, independent validation of results is important in explorative biomarker studies.
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19.
  • Björkqvist, Maria, et al. (författare)
  • Harnessing immune alterations in neurodegenerative diseases.
  • 2009
  • Ingår i: Neuron. - : Elsevier BV. - 0896-6273. ; 64:1, s. 21-24
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune dysfunction, a well-established feature of neuroinflammatory disease, is increasingly recognized in neurodegenerative conditions. Its role is emerging as an early and active participant in neuropathology. Inflammation could be modified, with disease-slowing effects, by targeted interventions; it is also readily detectable and could serve as a source of valuable biomarkers.
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20.
  • Björkqvist, Maria, et al. (författare)
  • Human neutrophil lipocalin : normal levels and use as a marker for invasive infection in the newborn
  • 2004
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 93:4, s. 534-539
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: To evaluate human neutrophil lipocalin (HNL) as a marker of neonatal invasive infection and determine the normal serum levels of HNL in newborns. METHODS: HNL is released from neutrophil granulocytes and is regarded as a specific marker of neutrophil activity. In 81 newborns < or = 28 d of age with signs of infection on a total of 87 occasions, HNL and C-reactive protein (CRP) were measured at inclusion and on the three following days. As controls, term healthy newborns were recruited at birth (cord blood, n = 45) and at ages 3-5 d (n = 46). Serum HNL was measured by a radioimmunoassay. RESULTS: 25/87 episodes were classified as infection and 62 as non-proven infection. HNLmax was significantly higher in the infected group (mean 587.6 microg/l) than in the non-proven infected group (mean 217.7 microg/, p < 0.001). HNL peaked at inclusion, 1 d earlier than CRP. In the healthy controls. HNL was the same at 3-5 d of age as at birth (mean 82.4-81.7 microg/l) and similar to normal adult levels. CONCLUSIONS: The release of HNL is not increased in healthy newborns at birth, but neonatal neutrophils rapidly release HNL upon microbial stimulation in vivo. HNL might be useful as an early marker of neonatal infection.
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21.
  • Björkqvist, Maria (författare)
  • Immunomodulation - a disease-modifying avenue for treatment of Huntington's disease?
  • 2016
  • Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 137:5, s. 670-672
  • Tidskriftsartikel (refereegranskat)abstract
    • This Editorial highlights a study published in the current issue of Journal of Neurochemistry by Dobson et al. (), investigating whether the immunomodulatory agent, laquinimod exerts an immunomodulatory effect on isolated Huntington´s disease monocytes. In Huntington´s disease (HD) a central immune activation is mirrored in the periphery by a low-grade immune response and monocytes isolated from HD gene carriers have been shown pathologically hyperreactive in response to stimulation. This hyperreactive immune system has become recognized as an important feature of HD pathogenesis and the employment of a strategy to affect this hyperreactivity could be a potential disease-modifying avenue in HD. Read the highlighted article 'Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells' on doi: 10.1111/jnc.13553.
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22.
  • Björkqvist, Maria, et al. (författare)
  • Increased endothelial activation in neonatal sepsis isolates of Staphylococcus epidermidis, but no differences in biofilm producing properties between sepsis and contaminant isolates
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Staphylococcus epidermidis is the predominating etiological agent in neonatal septicemia today, but specific specific factors associated with S. epidermidis are incompletely described. We compared neonatal blood isolates of S. epidermidis representing sepsis (n = 12) or skin contaminants (n = 38) regarding endothelial activation, and the prevalence of genes encoding for biofilm production (icaAB and D), fibrinogen-binding protein (fbe) and methicillin resistance (mecA).Endothelial cells cultured from human umbilical veins (HUVEC) were challenged by the different isolates of S. epidermidis. Endothelial release of adhesion molecules and interleukin-8 (IL-8) was investigated by an ELISA. Endothelial cell death was determined by light microscopy. The different genes were detected by PCR, and phenotypic biofilm production was investigated by Trypan blue staining. The sepsis isolates of S. epidermidis induced significantly higher endothelial release of intracellular adhesion molecule 1 (ICAM-1, p = 0.0021), endothelial selectin (E-selectin, p = 0.002), and IL-8 (p = 0.010) compared to the contaminants. Vaseular cell adhesion molecules 1 (VCAM-1) was not released. The sepsis-isolates were more cytotoxic than the contaminants; Nine out of 12 sepsis strains induced ≥ 50% cytotoxicity to HUVEC, compared to 15/38 contaminant strains (p = 0.047). The prevalence of the ica-operon, biofilm-production, fbe-, or mecA genes did not discriminate between sepsis and contaminant isolates. It is concluded that sepsis isolates of S. epidermidis induced higher endothelial release of chemotactic inflammatory mediators compared to contaminant isolates, but that the production of biofilm might be less important in neonatal infections eaused by S. epidermidis.
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23.
  • Björkqvist, Maria (författare)
  • Inflammation Biomarkers in Huntington’s Disease
  • 2023
  • Ingår i: Contemporary Clinical Neuroscience. - 2627-5341 .- 2627-535X. ; Part F1569, s. 277-304
  • Bokkapitel (refereegranskat)abstract
    • Neurodegenerative diseases share many features, such as inflammation. Accumulating evidence support the role of neuroinflammation in the pathogenesis and treatment of neurodegenerative diseases, and inflammatory markers are suggested important tools to identify disease risk, diagnose disease, monitor disease progression or treatment response, as well as predict clinical outcomes. In Huntington’s disease (HD) inflammatory processes, both centrally and peripherally, are suggested to contribute to pathology, and modulating the immune system may be a potential therapeutic strategy. Neuroinflammation has been shown to be an important factor and microglial activation can be detected before onset of clinical features. Central inflammatory processes are mirrored peripherally, and a peripheral low-grade immune response has been demonstrated in premanifest HD. Both direct and in-direct effects of mutant huntingtin within inflammatory cells have been demonstrated. As circulating markers of inflammation has been shown to mirror brain inflammatory changes in HD, this has raised the possibility that these markers could be useful as markers of disease features. This chapter aims to summarize current knowledge on biofluid immune markers and discuss how these markers may assist in understanding of HD pathology and aid in detection of new therapeutic targets.
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24.
  • Björkqvist, Maria, et al. (författare)
  • Phenotypic and genotypic characterisation of blood isolates of coagulase-negative staphylococci in the newborn
  • 2002
  • Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley. - 0903-4641 .- 1600-0463. ; 110:4, s. 332-339
  • Tidskriftsartikel (refereegranskat)abstract
    • Coagulase-negative staphylococci (CNS) are the leading cause of late-onset sepsis in newborns (>72 h of age). Our aim was to determine whether phenotypic and/or genotypic differences existed between blood isolates of CNS regarded as inducers of sepsis or as contaminants. Ninety-seven bloodisolates of CNS recovered from newborns at the neonatal intensive care unit, Örebro, Sweden in 1983–1997 were analysed. Twenty-nine of them (30%) were classified as sepsis isolates and 68 (70%) as contaminants. The most prevalent species was Staphylococcus epidermidis (n=59). Staphylococcus haemolyticus (n=16) was most often isolated from newborns with the lowest gestational age and birth weight. Biochemical typing using the Phene Plate system (PhP) and genotyping using pulsed-field gel electrophoresis (PFGE) showed that the S. epidermidis isolates regarded as inducers of sepsis (n=16) were more homogeneous than isolates considered contaminants (n=37). One main genotypic group, representing seven (44%) isolates, was identified among the sepsis isolates. Phenotypically the S. epidermidis sepsis isolates comprised three major clusters. In contrast, among the S. epidermidis contaminants, eight genotypic groups and two phenotypic clusters were identified. The dominating genotypic group among the sepsis isolates of S. epidermidis may represent strains with higher invasive capacity.
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25.
  • Björkqvist, Maria, et al. (författare)
  • Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease
  • 2006
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:10, s. 1713-1721
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease (HD) is characterized by a triad of motor, psychiatric and cognitive symptoms. Although many of these symptoms are likely to be related to central nervous system pathology, others may be due to changes in peripheral tissues. The R6/2 mouse, a transgenic model of HD expressing exon 1 of the human HD gene, develops progressive alterations in the hypothalamic-pituitary-adrenal axis, reminiscent of a Cushing-like syndrome. We observed muscular atrophy, reduced bone mineral density, abdominal fat accumulation and insulin resistance in the mice. All these changes could be consequences of increased glucocorticoid levels. Indeed, hypertrophy of the adrenal cortex and a progressive increase in serum and urine corticosterone levels were found in R6/2 mice. In addition, the intermediate pituitary lobe was markedly enlarged and circulating adreno-corticotrophic hormone (ACTH) increased. Under normal conditions dopamine represses the ACTH expression. In the R6/2 mice, however, the expression of pituitary dopamine D2 receptors was reduced by half, possibly explaining the increase in ACTH. Urinary samples from 82 HD patients and 68 control subjects were analysed for cortisol: in accord with the observations in the R6/2 mice, urinary cortisol increased in parallel with disease progression. This progressive increase in cortisol may contribute to the clinical symptoms, such as muscular wasting, mood changes and some of the cognitive deficits that occur in HD.
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26.
  • Björkqvist, Maria, et al. (författare)
  • Role of gastrin in the development of gastric mucosa, ECL cells and A-like cells in newborn and young rats
  • 2002
  • Ingår i: Regulatory Peptides. - 1873-1686. ; 108:2-3, s. 73-82
  • Tidskriftsartikel (refereegranskat)abstract
    • Histamine-producing ECL cells and ghrelin-producing A-like cells are endocrine/paracrine cell populations in the acid-producing part of the rat stomach. While the A-like cells operate independently of gastrin, the ECL cells respond to gastrin with mobilization of histamine and chromogranin A (CGA)-derived peptides, such as pancreastatin. Gastrin is often assumed to be the driving force behind the postnatal development of the gastric mucosa in general and the ECL cells in particular. We tested this assumption by examining the oxyntic mucosa (with ECL cells and A-like cells) in developing rats under the influence of YF476, a cholecystokinin-2 (CCK2) receptor antagonist. The drug was administered by weekly subcutaneous injections starting at birth. The body weight gain was not affected. Weaning occurred at days 1522 in both YF476-treated and age-matched control rats. Circulating gastrin was low at birth and reached adult levels 2 weeks after birth. During and after weaning (but riot before), YF476 greatly raised the serum gastrin concentration (because of abolished acid feedback inhibition of gastrin release). The weight of the stomach was unaffected by YF476 during the first 2-3 weeks after birth. From 4 to 5 weeks of age, the weight and thickness of the gastric mucosa were lower in YF476-treated rats than in controls. Pancreastatin-immunoreactive cells (i.e. all endocrine cells in the stomach) and ghrelin-immunoreactive cells (A-like cells) were few at birth and increased gradually in number until 6-8 weeks of age (control rats). At first, YF476 did not affect the development of the pancreastatin-immunoreactive cells, but a few weeks after weaning, the cells were fewer in the YF476 rats. The ECL-cell parameters (oxyntic mucosal histamine and pancreastatin concentrations, the histidine decarboxylase (HDC) activity, the HDC mRNA levels and serum pancreastatin concentration) increased slowly until weaning in both YF476-treated and control rats. From then on, there was a further increase in the ECL-cell parameters in control rats but not in YF476 rats. The postnatal development of the ghrelin cells (i.e. the A-like cells) and of the A-like cell parameters (the oxyntic mucosal ghrelin concentration and the serum ghrelin concentrations) was not affected by YF476 at any point. We conclude that gastrin affects neither the oxyntic mucosa nor the endocrine cells before weaning. After weaning, CCK2 receptor blockade is associated with a somewhat impaired development of tire oxyntic mucosa and the ECL cells. While gastrin stimulation is of crucial importance for the onset of acid secretion during weaning and for the activation of ECL-cell histamine formation and secretion, the mucosal and ECL-cell growth at this stage is only partly gastrin-dependent. In contrast, the development of the A-like cells is independent of gastrin at all stages. (C) 2002 Elsevier Science B.V. All rights reserved.
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27.
  • Björkqvist, Maria (författare)
  • The Gastrin-ECL Cell Axis. Functional Aspects
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The ECL cells constitute a prominent endocrine cell population in the acid-producing part of the stomach. They are controlled by circulating gastrin released from G-cells in the antrum. In response to gastrin, they secrete histamine, that in turn stimulates the parietal cell to secrete acid. The first aim of the study was to prepare isolated ECL cells of high purity and to study and identify regulators of secretion from such cells in primary culture. Gastrin and pituitary adenylate cyclase activating peptide (PACAP) effectively evoked ECL-cell secretion. Vasoactive intestinal peptide (VIP) and adrenaline also evoked secretion but with a lower efficacy. Somatostatin, galanin and prostaglandins inhibited stimulated ECL-cell secretion. Elevation of the intracellular calcium concentration ([Ca2+]i) is a key event in the regulation of many cellular processes. Gastrin binds to the CCK2 receptor causing Ca2+ entry through L-type and N-type Ca2+ channels followed by exocytosis. PACAP binds to PAC1 receptors, causing Ca2+ entry through L-type and receptor-operated channels. Somatostatin, misoprostol and galanin bind to receptors that are coupled to inhibitory G-proteins that block conductance through Ca2+ channels. Somatostatin and misoprostol interfere with L-type, N-type and receptor-operated Ca2+ channels, thereby preventing Ca2+ influx following either gastrin or PACAP challenge. For unknown reasons, galanin interfere with L-type Ca2+ channels only. Gastrin is a recognized growth-promoting hormone for the acid-producing part of the stomach and for the ECL cells in particular. The trophic effect of gastrin is probably exerted on stem cells and ECL cells. The ECL cells are known to respond to gastrin not only with the mobilization of secretory products, but also with increased expression of proteins, such as the histamine-forming enzyme histidine decarboxylase (HDC). To elucidate the action of gastrin on the stomach we attempted to identify genes that are regulated by gastrin in oxyntic mucosa and in isolated ECL cells. In order to detect altered gene expression in oxyntic mucosa and in ECL cells in response to sustained hypergastrinemia, differential display reverse transcriptase reactions were conducted. Our results revealed gastrin-evoked upregulation of several genes that may be involved in secretory processes, e.g. mRNA for HDC and synaptotagmin V. The effects of gastrin on the ECL cell can be prevented by a CCK2 receptor antagonist. We conducted a pharmacological analysis of a series of CCK2 receptor antagonists on gastrin-stimulated secretion from ECL cells in primary culture. The most potent of the antagonists were YM022 and YF476. Both agents produced a rightward and parallell shift in the gastrin dose-response curve, suggesting surmountable and competitive antagonism. The effects of CCK2 receptor blockade on oxyntic mucosa and ECL cells were studied in the developing and mature rat. CCK2 receptor blockade in the rat affected the oxyntic mucosa but not extra-gastric sites. In the developing rat, neither the post-natal body weight gain nor the onset of weaning were affected by CCK2 receptor blockade. ECL cells failed to respond to gastrin before weaning, but their activity was clearly gastrin-dependent after weaning.
  •  
28.
  • Björkqvist, Maria, et al. (författare)
  • The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis.
  • 2005
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 14:5, s. 565-574
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in ß-cells. ß-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, ß-cell mass and pancreatic insulin content in R6/2 mice were 35±5 and 16±3% of that in wild-type mice, respectively. The normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Single cell patch-clamp experiments revealed unaltered electrical activity in R6/2 ß-cells. However, exocytosis was virtually abolished in ß- but not in {alpha}-cells. The blunting of exocytosis could be attributed to a 96% reduction in the number of insulin-containing secretory vesicles. Thus, diabetes in R6/2 mice is caused by a combination of deficient ß-cell mass and disrupted exocytosis.
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29.
  • Bode, Felix J., et al. (författare)
  • Increased numbers of motor activity peaks during light cycle are associated with reductions in adrenergic alpha(2)-receptor levels in a transgenic Huntington's disease rat model
  • 2009
  • Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 205:1, s. 175-182
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease (HID) is a neurodegenerative disorder caused by a CAG repeat expansion in the HD gene. Besides psychiatric, motor and cognitive symptoms, HD patients suffer from sleep disturbances. In order to screen a rat model transgenic for HD (tgHD rats) for sleep-wake cycle dysregulation, we monitored their circadian activity peaks in the present study. TgHD rats of both sexes showed hyperactivity during the dark cycle and more frequent light cycle activity peaks indicative for a disturbed sleep-wake cycle. Focusing on males at the age of 4 and 14 months, analyses of receptor levels in the hypothalamus and the basal forebrain revealed that 5-HT2A- and adrenergic alpha(2)-receptor densities in these regions were significantly altered in tgHD rats compared to their wild-type littermates. Adrenergic receptor densities correlated negatively with the light cycle hyperactivity peaks at later stages of the disease in male tgHD rats. Furthermore, reduced leptin levels, a feature associated with circadian misalignment, were present. Our study demonstrates that the male tgHD rat is a suitable model to investigate HD associated sleep alterations. Further studies are warranted to elucidate the role of adrenergic- and 5-HT2A- receptors as therapeutic targets for dysregulation of the circadian activity in HD. (C) 2009 Elsevier B.V. All rights reserved.
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30.
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31.
  • Brundin, Lena, et al. (författare)
  • Cocaine and amphetamine regulated transcript (CART) in suicide attempters.
  • 2008
  • Ingår i: Psychiatry Research. - : Elsevier BV. - 1872-7123 .- 0165-1781. ; 158:2, s. 117-122
  • Tidskriftsartikel (refereegranskat)abstract
    • Cocaine and amphetamine regulated transcript (CART) is a neuropeptide expressed in brain regions thought to regulate anxiety levels, depression, addiction and energy homeostasis. Individuals with a CART mutation display increased anxiety and depression. Severe anxiety is a core phenomenon of suicidality. We therefore studied levels of CART in the cerebrospinal fluid (CSF) of 98 patients with different psychiatric diagnoses, shortly after a suicide attempt. We also investigated the relationship between CSF-CART and relevant psychiatric symptoms. CART levels were determined using a radioimmunoassay and the psychiatric symptoms rated in structured interviews using the Comprehensive Psychopathological Rating Scale (CPRS) and the Karolinska Scales of Personality (KSP). No differences in CSF-CART were found between the diagnostic groups or controls. However, lower CART levels were associated with a higher degree of concentration difficulties. No significant association was found between CART levels and other psychiatric symptoms. CSF-CART correlated significantly with CSF-levels of orexin, but not with corticotrophin releasing factor (CRF). Further studies on the role of CART in psychiatric diseases where concentration difficulties are prominent, such as attention deficit disorder, are warranted.
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32.
  • Brundin, Lena, et al. (författare)
  • Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt.
  • 2009
  • Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; Jun 2, s. 179-182
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The orexins (hypocretins) and cocaine and amphetamine regulated transcript (CART) are hypothalamic peptides involved in the regulation of sleep and appetite. We have previously shown that levels of both orexin-A and CART in the cerebrospinal fluid (CSF) are related to specific psychiatric symptoms. METHODS: Ten patients took part in lumbar punctures and psychiatric evaluations in conjunction to a suicide attempt and after 6 and 12 months. We measured CSF-orexin and CART using radioimmunoassays. RESULTS: Mean CSF-orexin was significantly higher at the first and second follow-up than at the suicide attempt. In contrast, mean CSF-CART did not differ over time. Total SUAS scores, as well as ratings of CPRS item 66 (global illness) were significantly lower at follow-up. At one year, there was a significant negative correlation between the change in CSF-orexin and the change in total SUAS score. LIMITATIONS: The number of patients who participated was relatively small. CONCLUSIONS: Our results support the hypothesis that orexin is involved in psychiatric symptomatology.
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33.
  • Brundin, Lena, et al. (författare)
  • Orexin and psychiatric symptoms in suicide attempters.
  • 2007
  • Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 100:1-3, s. 259-263
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The orexins (hypocretins) are recently discovered hypothalamic peptides that are involved in the regulation of sleep, appetite and state of arousal. In the present study, we investigated the relationship between cerebrospinal fluid (CSF) orexin and specific psychiatric symptoms in suicidal patients. METHODS: A total of 101 patients were enrolled in the study shortly after a suicide attempt. All patients underwent a lumbar puncture after a wash-out period during which they did not receive any antipsychotic or antidepressive medication. Structured interviews were performed using the Comprehensive Psychopathological Rating Scale (CPRS). CSF-orexin-A was measured and correlated with ratings of psychiatric symptoms. RESULTS: There were significant and negative correlations between CSF-orexin and the symptoms lassitude (difficulty to initiate activities) and slowness of movement, as well as the ratings of global illness (p<0.005 for all three items, Spearman's rho). LIMITATIONS: Correlation analysis is an indirect method of investigation and does not demonstrate causal relationships. CONCLUSION: Low CSF-orexin levels are related to pronounced symptoms of inertia and reduced motor activity in suicidal patients. Interestingly, the lower the orexin levels, the higher were ratings of overall illness, as observed by a specialist in psychiatry. Our results suggest that reduced orexin levels are involved in the etiology of specific psychiatric symptoms.
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34.
  • Brundin, Lena, et al. (författare)
  • Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder.
  • 2007
  • Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 1873-7862 .- 0924-977X. ; 17:Mar 6, s. 573-579
  • Tidskriftsartikel (refereegranskat)abstract
    • Orexins are neuropeptides selectively expressed in a small number of neurons in the lateral–posterior hypothalamus. We measured orexin-A in the cerebrospinal fluid (CSF) of 66 patients with major depressive disorder (MDD), dysthymia and adjustment disorder after a suicide attempt. Blood samples confirmed that the patients were free from antidepressive and neuroleptic medication at the time of the lumbar punctures. CSF levels of orexin-A were significantly lower in patients with MDD than in patients with adjustment disorder and dysthymia. Orexin correlated significantly with CSF levels of somatostatin, delta sleep inducing peptide-like immunoreactivity (DSIP-LI) and corticotrophin releasing factor (CRF), but not with leptin or vasopressin. Plasma levels of thyroid-stimulating hormone (TSH) were not reduced in MDD patients, and did not correlate with CSF-orexin. Our results suggest that suicidal patients with MDD have distinct neurobiological features, involving compromised levels of hypothalamic peptides regulating the state of arousal.
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35.
  • de la Cour, Charlotta, et al. (författare)
  • A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control
  • 2001
  • Ingår i: Regulatory Peptides. - 1873-1686. ; 99:2-3, s. 141-150
  • Tidskriftsartikel (refereegranskat)abstract
    • Ghrelin is a 28 a.a. gastric peptide, recently identified as a natural ligand of the growth hormone secretagogue receptor (orphan receptor distinct from the receptor fur growth hormone releasing hormone). In the present study. radioimmunoassay demonstrated ghrelin-like material in the rat oxyntic mucosa with moderate amounts also in antrum and duodenum. Small amounts: were found in the distal intestines and pancreas. Northern blot analysis revealed abundant ghrelin mRNA in thr oxyntic mucosa. Immunocytochemistry demonstrated ghrelin-immunoreactivity in endocrine-like cells in the oxyntic mucosa. Such cells occurred in low numbers also in the antrum and duodenum. The mt oxyntic mucosa is rich in endocrine (chromogranin A/pancreastatin-immunoreactive) cells. such as the histamine-rich ECL cells (65-75% of the endocrine cells). the A-like cells (20-25%) and the D cells (somatostatin cells) (10%). The ghrelin-immunoreactive (IR) cells contained pancreastatin but differed from ECL cells and D cells by being devoid of histamine-forming enzyme (ECL cell constituent) and somatostatin (D cell constituent). Hence. ghrelin seems to occur in the A-like cells. The ghrelin-IR cells in the antrum were distinct from the gastrin cells, the serotonin-containing enterochromaffin cells and the D cells. Conceivably, ghrelin cells in the antrum and distally in the intestines also belong to the A-like cell population. The concentration of ghrelin in the circulation was: lowered by about 80% following the surgical removal of the acid-producing part of the stomach in line with the view that the oxyntic mucosa is the major sourer of ghrelin. The serum ghrelin concentration was higher in fasted rats than in fed rats; it was reduced upon re-feeding and seemed unaffected by 1-week treatment with the proton pump inhibitor omeprazole, resulting in elevated serum gastrin concentration. Infusion of gastrin-17 for 2 days failed to raise the serum ghrelin concentration. Omeprazole treatment for 10 weeks raised the level of HDC mRNA but not that of ghrelin mRNA or somatostatin mRNA in the oxyntic mucosa. Hence, unlike the ECL cells, ghrelin-containing A-like cells do not seem to operate under gastrin control.
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36.
  • Dickson, Elna, et al. (författare)
  • Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease
  • 2023
  • Ingår i: Journal of Huntington's disease. - 1879-6397. ; 12:3, s. 253-266
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Metabolic alterations contribute to disease onset and prognosis of Huntington's disease (HD). Weight loss in the R6/2 mouse model of HD is a consistent feature, with onset in mid-to-late stage of disease.OBJECTIVE: In the present study, we aimed to investigate molecular and functional changes in white adipose tissue (WAT) that occur at weight loss in R6/2 mice. We further elaborated on the effect of leptin-deficiency and early obesity in R6/2 mice.METHODS: We performed analyses at 12 weeks of age; a time point that coincides with the start of weight loss in our R6/2 mouse colony. Gonadal (visceral) and inguinal (subcutaneous) WAT depot weights were monitored, as well as adipocyte size distribution. Response to isoprenaline-stimulated glycerol release and insulin-stimulated glucose uptake in adipocytes from gonadal WAT was assessed.RESULTS: In R6/2 mice, WAT depot weights were comparable to wildtype (WT) mice, and the response to insulin and isoprenaline in gonadal adipocytes was unaltered. Leptin-deficient R6/2 mice exhibited distinct changes compared to leptin-deficient WT mice. At 12 weeks, female leptin-deficient R6/2 mice had reduced body weight accompanied by an increased proportion of smaller adipocytes, while in contrast; male mice displayed a shift towards larger adipocyte sizes without a significant body weight reduction at this timepoint.CONCLUSIONS: We here show that there are early sex-specific changes in adipocyte cell size distribution in WAT of R6/2 mice and leptin-deficient R6/2 mice.
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37.
  • Dickson, Elna, et al. (författare)
  • Hypothalamic expression of huntingtin causes distinct metabolic changes in Huntington's disease mice
  • 2022
  • Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 57
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: In Huntington's disease (HD), the disease-causing huntingtin (HTT) protein is ubiquitously expressed and causes both central and peripheral pathology. In clinical HD, a higher body mass index has been associated with slower disease progression, indicating that metabolic changes may be involved in disease pathogenesis. Underlying mechanisms of metabolic changes in HD are not fully known, but recent studies suggest involvement of hypothalamic dysfunction. The aim of the present study was to investigate whether modulation of hypothalamic HTT levels would affect metabolic phenotype and disease features in HD using mouse models.METHODS: We used the R6/2 and BACHD mouse models that express different lengths of mutant HTT and respectively develop lean- and obese phenotypes. We utilized adeno-associated viral vectors to overexpress either mutant or wild-type HTT in the hypothalamus of R6/2, BACHD, and their wild-type littermates. Metabolic phenotype was assessed by body weight measurements over time and body composition analysis using dual-energy x-ray absorptiometry at the endpoint. R6/2 mice were further characterized using behavioral analyses, including rotarod, nesting- and hindlimb clasping tests during early- and late timepoints of disease progression. Finally, gene expression analysis was performed in R6/2 mice and wild-type littermates in order to assess transcriptional changes in hypothalamus and adipose tissue.RESULTS: Hypothalamic overexpression of mutant HTT induced significant gender-affected body weight gain in all models, including wild-type mice. In R6/2 females, early weight gain shifted to weight loss during the corresponding late stage of disease despite increased fat accumulation. Body weight changes were accompanied by behavioral alterations. During the period of early weight gain, R6/2 mice displayed a comparable locomotor capacity to wild-type mice. When assessing behavior just prior to weight loss onset in R6/2 mice, decreased locomotor performance was observed in R6/2 females with hypothalamic overexpression of mutant HTT. Transcriptional downregulation of beta-3 adrenergic receptor (B3AR), adipose triglyceride lipase (ATGL) and peroxisome proliferator-activated receptor gamma (PPARγ) in gonadal white adipose tissue was accompanied with distinct alterations in hypothalamic gene expression profiles in R6/2 females after mutant HTT overexpression. No significant effect on metabolic phenotype in R6/2 was seen in response to wild-type HTT overexpression.CONCLUSIONS: Taken together, our findings provide further support for a role of HTT in metabolic control via hypothalamic neurocircuits. Understanding the specific central neurocircuits and their peripheral link underlying metabolic imbalance in HD may open up avenues for novel therapeutic interventions.
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38.
  • Dickson, Elna, et al. (författare)
  • Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models
  • 2022
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington’s disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. In the present study, we investigated whether transcriptional changes would be part of hypothalamic pathology induced by the disease-causing huntingtin (HTT) protein. We performed microarray analysis using the Affymetrix platform on total hypothalamic RNA isolated from two HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. To analyze microarray datasets (34760 variables) and obtain functional implications of differential expression patterns, we used Linear Models for Microarray Data (limma) followed by Gene Set Enrichment Analysis (GSEA) using ClusterProfiler. Limma identified 735 and 721 significantly differentially expressed genes (adjusted p < 0.05) in hypothalamus of AAV datasets wtHTT vs control and mHTT vs control. In contrast, for BACHD datasets and the AAV mHTT vs. wtHTT dataset, none of the genes were differentially expressed (adjusted p-value > 0.05 for all probe IDs). In AAV groups, from the combined limma with GSEA using ClusterProfiler, we found both shared and unique gene sets and pathways for mice with wtHTT overexpression compared to mice with mHTT overexpression. mHTT caused widespread suppression of neuroendocrine networks, as evident by GSEA enrichment of GO-terms related to neurons and/or specific neuroendocrine populations. Using qRT-PCR, we confirmed that mHTT overexpression caused significant downregulation of key enzymes involved in neuropeptide synthesis, including histidine and dopa decarboxylases, compared to wtHTT overexpression. Multiple biosynthetic pathways such as sterol synthesis were among the top shared processes, where both unique and shared genes constituted leading-edge subsets. In conclusion, mice with targeted overexpression of HTT (wtHTT or mHTT) in the hypothalamus show dysregulation of pathways, of which there are subsets of shared pathways and pathways unique to either wtHTT or mHTT overexpression.
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39.
  • Dickson, Elna, et al. (författare)
  • Microarray profiling of hypothalamic gene expression changes in Huntington's disease mouse models
  • 2022
  • Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Structural changes and neuropathology in the hypothalamus have been suggested to contribute to the non-motor manifestations of Huntington's disease (HD), a neurodegenerative disorder caused by an expanded cytosine-adenine-guanine (CAG) repeat in the huntingtin (HTT) gene. In this study, we investigated whether hypothalamic HTT expression causes transcriptional changes. Hypothalamic RNA was isolated from two different HD mouse models and their littermate controls; BACHD mice with ubiquitous expression of full-length mutant HTT (mHTT) and wild-type mice with targeted hypothalamic overexpression of either wild-type HTT (wtHTT) or mHTT fragments. The mHTT and wtHTT groups showed the highest number of differentially expressed genes compared to the BACHD mouse model. Gene Set Enrichment Analysis (GSEA) with leading-edge analysis showed that suppressed sterol- and cholesterol metabolism were shared between hypothalamic wtHTT and mHTT overexpression. Most distinctive for mHTT overexpression was the suppression of neuroendocrine networks, in which qRT-PCR validation confirmed significant downregulation of neuropeptides with roles in feeding behavior; hypocretin neuropeptide precursor (Hcrt), tachykinin receptor 3 (Tacr3), cocaine and amphetamine-regulated transcript (Cart) and catecholamine-related biological processes; dopa decarboxylase (Ddc), histidine decarboxylase (Hdc), tyrosine hydroxylase (Th), and vasoactive intestinal peptide (Vip). In BACHD mice, few hypothalamic genes were differentially expressed compared to age-matched WT controls. However, GSEA indicated an enrichment of inflammatory- and gonadotropin-related processes at 10 months. In conclusion, we show that both wtHTT and mHTT overexpression change hypothalamic transcriptome profile, specifically mHTT, altering neuroendocrine circuits. In contrast, the ubiquitous expression of full-length mHTT in the BACHD hypothalamus moderately affects the transcriptomic profile.
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40.
  • Duarte, Ane, et al. (författare)
  • IGF-1 protects against diabetic features in an in vivo model of Huntington's disease.
  • 2011
  • Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 231, s. 314-319
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.
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41.
  • Gaughwin, Philip, et al. (författare)
  • Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington's disease
  • 2011
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:11, s. 2225-2237
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease (HD) is a devastating, neurodegenerative condition, which lacks effective treatment. Normal Huntingtin (HTT) and mutant Huntingtin (mHTT) are expressed in multiple tissues and can alter transcription of microRNAs (miRs). Importantly, miRs are present in a bio-stable form in human peripheral blood plasma and have recently been shown to be useful biomarkers in other diseases. We therefore sought to identify potential miR biomarkers of HD that are present in, and have functional consequences for, neuronal and non-neuronal tissues. In a cell line over-expressing mHTT-Exon-1, miR microarray analysis was used to identify candidate miRs. We then examined their presence and bio-stability in control and HD plasma. We found that miR-34b is significantly elevated in response to mHTT-Exon-1, and its blockade alters the toxicity of mHTT-Exon-1 in vitro. We also show that miR-34b is detectable in plasma from small input volumes and is insensitive to freeze-thaw-induced RNA degradation. Interestingly, miR-34b is significantly elevated in plasma from HD gene carriers prior to symptom onset. This is the first study suggesting that plasma miRs might be used as biomarkers for HD.
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42.
  • Gram, Magnus, et al. (författare)
  • Increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease.
  • 2012
  • Ingår i: Frontiers in Bioscience (Elite Edition). - 1945-0508. ; 4, s. 950-957
  • Tidskriftsartikel (refereegranskat)abstract
    • Hemoglobin released from damaged erythrocytes is a major pro-oxidant, generator of free radicals and inflammatory mediator. Huntington's disease is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities, in which oxidative stress has been suggested as a possible pathogenic mechanism. In the present work we have investigated levels of hemoglobin and markers of oxidative damage, including the heme- and radical-scavenger alpha1-microglobulin, in plasma and urine samples from two separate sample cohorts, including controls, premanifest gene carriers and subjects at different stages of Huntington's disease. The results show statistically significant increased levels of hemoglobin and alpha1-microglobulin in Huntington's disease urine samples. Interestingly, urine hemoglobin levels correlate with clinical severity. The results suggest that hemolysis may be linked to the pathogenesis of Huntington's disease and that assay of hemoglobin and alpha1-microglobulin may provide biomarkers that are linked to biologically relevant processes.
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43.
  • Hansson, Björn, et al. (författare)
  • A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ
  • 2020
  • Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 533:1, s. 64-69
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding. Therefore, we hypothesized that the actin-driven myocardin-related transcription factor (MRTF-A) contributes to impaired mature adipocyte function. Primary human adipocytes were subjected to adenoviral overexpression of MRTF-A or MRTF-B, followed by Western blot analysis and tracer glucose uptake assay. Further, we assessed cell size distribution, insulin response, MRTF-A localization, actin organization and degree of polymerization in adipocytes isolated from Ob/Ob mice. Overexpression of MRTF-A, but not MRTF-B, markedly suppressed PPARγ expression. Further, MRTF-A expression resulted in decreased IRS-1 level, shifted phosphorylation of Akt (pS473/pT308), IRS-1 (pS302) and AS160 (pT642), and lowered insulin-stimulated glucose uptake. Hypertrophic adipocytes from Ob/Ob mice displayed an increased proportion of polymerized actin, and increased nuclear translocation of MRTF-A compared with control (Ob/+). Similar with human adipocytes overexpressing MRTF-A, adipocytes isolated from Ob/Ob mice had reduced expression of IRS-1 and PPARγ, as well as impaired insulin response. Together, these data demonstrate that MRTF-A negatively influences insulin sensitivity and the expression of key targets in fully mature human adipocytes. This suggests that MRTF-A is poised to exert a transcriptional response in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance.
  •  
44.
  • Henningsen, Jo B, et al. (författare)
  • Effects of excitotoxicity in the hypothalamus in transgenic mouse models of Huntington disease
  • 2021
  • Ingår i: Heliyon. - : Elsevier BV. - 2405-8440. ; 7:8, s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington disease (HD) is a fatal neurodegenerative movement disorder caused by an expanded CAG repeat in the huntingtin gene (HTT). The mutant huntingtin protein is ubiquitously expressed, but only certain brain regions are affected. The hypothalamus has emerged as an important area of pathology with selective loss of neurons expressing the neuropeptides orexin (hypocretin), oxytocin and vasopressin in human postmortem HD tissue. Hypothalamic changes in HD may have implications for early disease manifestations affecting the regulation of sleep, emotions and metabolism. The underlying mechanisms of selective vulnerability of certain neurons in HD are not fully understood, but excitotoxicity has been proposed to play a role. Further understanding of mechanisms rendering neurons sensitive to mutant huntingtin may reveal novel targets for therapeutic interventions. In the present study, we wanted to examine whether transgenic HD mice display altered sensitivity to excitotoxicity in the hypothalamus. We first assessed effects of hypothalamic injections of the excitotoxin quinolinic acid (QA) into wild-type (WT) mice. We show that neuronal populations expressing melanin-concentrating hormone (MCH) and cocaine and amphetamine-regulated transcript (CART) display a dose-dependent sensitivity to QA. In contrast, neuronal populations expressing orexin, oxytocin, vasopressin as well as tyrosine hydroxylase in the A13 area are resistant to QA-induced toxicity. We demonstrate that the R6/2 transgenic mouse model expressing a short fragment of mutant HTT displays hypothalamic neuropathology with discrete loss of the neuronal populations expressing orexin, MCH, CART, and orexin at 12 weeks of age. The BACHD mouse model expressing full-length mutant HTT does not display any hypothalamic neuropathology at 2 months of age. There was no effect of hypothalamic injections of QA on the neuronal populations expressing orexin, MCH, CART or oxytocin in neither HD mouse model. In conclusion, we find no support for a role of excitotoxicity in the loss of hypothalamic neuronal populations in HD.
  •  
45.
  • Hoque, Sanzana, et al. (författare)
  • Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington’s disease
  • 2022
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Huntington’s disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise.In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice.We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage.Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.
  •  
46.
  • Huebener, Jeannette, et al. (författare)
  • Automated Behavioral Phenotyping Reveals Presymptomatic Alterations in a SCA3 Genetrap Mouse Model
  • 2012
  • Ingår i: Journal of Genetics and Genomics. - : Elsevier BV. - 1673-8527. ; 39:6, s. 287-299
  • Tidskriftsartikel (refereegranskat)abstract
    • Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner. Therefore, automated high-resolution behavior test systems such as the homecage based LabMaster system are of particular interest. We demonstrate the power of the automated LabMaster system by discovering previously unrecognized features of a recently characterized atxn3 mutant mouse model. This model provided neurological symptoms including gait ataxia, tremor, weight loss and premature death at the age of 12 months usually detectable just 2 weeks before the mice died. Moreover, using the LabMaster system we were able to detect hypoactivity in presymptomatic mutant mice in the dark as well as light phase. Additionally, we analyzed inflammation, immunological and hematological parameters, which indicated a reduced immune defense in phenotypic mice. Here we demonstrate that a detailed characterization even of organ systems that are usually not affected in SCA3 is important for further studies of pathogenesis and required for the preclinical therapeutic studies.
  •  
47.
  • Hussain, Rashida, 1976- (författare)
  • Cell responses in infected and cystic fibrosis respiratory epithelium
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Respiratory Epithelium. Örebro Studies in Medicine 99. Cystic fibrosis (CF) is caused by a mutation in a cAMP-activated chloride (Cl-) channel (CFTR). Mortality and morbidity in CF is mainly due to the deregulated responses of the airway epithelial cells. The purpose of the thesis was to investigate the behaviour of the airway epithelial cells that are involved in maintaining the homeostasis in the airways.Nasal brush biopsies obtained from anesthetized human nasal mucosa can be an easy source to establish primary epithelial cell lines (Paper I). We found that CF and non CF cellular models cannot fully show the relation between CFTR and the phenotypic differences between CF and healthy cells (Paper II). The possibility to correct the Cl- transport defect in CF by the use of stable NOdonors, and ambroxol was investigated. NO-donors stimulated Cl- efflux, and decreased ENaC mRNA expression in CFBE cells (Paper III), while ambroxol increased Cl- efflux from CFBE cells, and showed a positive effect on the biosynthesis of CFTR (Paper IV). This suggests that these substances may be a potentially interesting group of compounds for the treatment of CF. Increased levels of IL-6 and IL-8 upon infection in CF cells can increase the susceptibility of P. aeruginosa infected CF cells to apoptosis and/or internalization of these bacteria in CF cells and hence, may have important roles in the pathology of P. aeruginosa infection in CF airways. If internalization is beneficial for the host then glucocorticoids (GCs) are not beneficial for the treatment of CF patients. However, GCs may improve airway hydration. Whether the benefits of GC treatment outweigh the negative effects is questionable, and further clinical studies need to be carried out (Paper V). The neonatal isolates S. epidermidis 94B080 and S. aureus 90B083 can modulate CFTR and ENaC expression in airway epithelial cells, which may disturb the ion transport in the respiratory epithelium upon bacterial exposure. Airway epithelial cells also show excessive inflammatory responses to these bacteria, which means that these bacteria may induce pulmonary inflammation (Paper VI).
  •  
48.
  • Hussain, Rashida, 1976-, et al. (författare)
  • Modulation of ENaC, CFTR, and iNOS expression in bronchial epithelial cells after stimulation with Staphylococcus epidermidis (94B080) and Staphylococcus aureus (90B083)
  • 2013
  • Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Hoboken, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 121:9, s. 814-826
  • Tidskriftsartikel (refereegranskat)abstract
    • Bacteria affect the respiratory epithelium, which is covered by airway surface liquid (ASL) and mucus. Ion concentrations in the ASL are determined by the cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial Na+ channel (ENaC). Neonatal sepsis is a major risk factor for subsequent pulmonary disease in preterm newborns. Predominating are coagulase-negative staphylococci (e.g., Staphylococccus epidermidis and Staphylococccus aureus). The aim of this study was to investigate modulation of CFTR, ENaC, mucins, proinflammatory cytokines, and inducible nitric oxide synthase (iNOS) in respiratory epithelial cells after S. epidermidis 94B080 and S. aureus 90B083 exposure. Bronchial epithelial cells were incubated with S. epidermidis 94B080 and S. aureus 90B083 (neonatal blood isolates) for 1-36h. Expression of CFTR, ENaC, iNOS, and mucins was analyzed by real-time PCR and Western blotting. Release of cytokines was analyzed by ELISA, and production of NO by the Griess assay. Expression of CFTR significantly decreased after 36h incubation with S. epidermidis and more prominently with S. aureus, whereas S. epidermidis caused a significant increase in the expression of - and -ENaC. Expression of iNOS increased, but NO was not detected. Both staphylococci caused a decrease in the intracellular Ca2+ concentration. S. aureus induced increased secretion of IL-6, IL-8, and transforming nuclear factor (TNF)- in a time-dependent manner as compared with S. epidermidis. In conclusion, expression of ENaC, CFTR, and iNOS is modulated by exposure to S. aureus 90B083 and S. epidermidis 94B080. S. aureus is more potent in causing release of IL-6, IL-8, and TNF- by bronchial epithelial cells as compared with S. epidermidis. The mRNA expression for the mucus proteins MUC2, MUC5AC, and MUC5B could not be measured, neither in the presence nor in the absence of bacteria.
  •  
49.
  • Ivarsson, Mikael, et al. (författare)
  • Staphylococcus epidermidis and Staphylococcus aureus trigger different interleukin-8 and intercellular adhesion molecule-1 in lung cells : implications for inflammatory complications following neonatal sepsis
  • 2013
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 102:10, s. 1010-1016
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Staphylococci are a major contribution for neonatal sepsis, which is the main risk factor for bronchopulmonary dysplasia. This study investigated the expression of pro-inflammatory mediators in endothelial and respiratory cells from newborns exposed to staphylococci.Methods: Human vascular endothelial cells and small airway epithelial cells were incubated with neonatal blood isolates of Staphylococcus epidermidis (n = 14) and Staphylococcus aureus (n = 14). The extracellular release of IL-8, IL-10, sICAM-1, ICAM-1 mRNA and the expression of membrane bound ICAM-1 were assessed by ELISA, RT-PCR and immunofluorescence microscopy.Results: Staphylococcus epidermidis induced higher levels of IL-8 (mean 38.5 ng/mL) and ICAM-1 mRNA (mean ratio 1.037) in the small airway epithelial cells than S. aureus (IL-8 mean 22.2 ng/mL, p < 0.01 and ICAM-1 mRNA mean ratio 0.715, p < 0.01). In the endothelial cells, ICAM-1 remained more integrated in the cell membranes after exposure to S. epidermidis compared with S. aureus, which induced disintegration and release of soluble ICAM-1 into the supernatants.Conclusion: Staphylococcus epidermidis induced a higher chemoattractive response than S. aureus. A persistent transmigration of granulocytes into the lung tissue in neonatal S. epidermidis sepsis might contribute to the development of bronchopulmonary dysplasia.
  •  
50.
  • Kalliolia, Eirini, et al. (författare)
  • A 24-Hour Study of the Hypothalamo-Pituitary Axes in Huntington's Disease.
  • 2015
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington's disease is an inherited neurodegenerative disorder characterised by motor, cognitive and psychiatric disturbances. Patients exhibit other symptoms including sleep and mood disturbances, muscle atrophy and weight loss which may be linked to hypothalamic pathology and dysfunction of hypothalamo-pituitary axes.
  •  
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