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  • 251.
    Alemi, Mansour
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular biological techniques as a tool in diagnostic pathology: Applications in B-cell lymphoproliferative disease, medullary thyroid carcinoma and cervical carcinoma2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Identification of malignancy associated with mutations in gene sequences requires detection ofas little as a single base difference. A powerful technique in mutation detection is polymerasechain reaction (PCR) followed by single-strand conformational polymorphism (SSCP) andsequencing.

    The present investigation is focused on improving tests for the following diagnostic questions:(i) clonality in malignancy of lymphoid origin by developing simple laboratory methodsbased on PCR in which the monoclonal B-cell lineage can be distinguished from thepolyclonal, (ii) presence of mutations in RET proto-oncogene involved in sporadic medullarythyroid carcinoma (MTC), and (iii) development of a simple test which can distinguishbetween prototype human papillomavirus 16 (HPV16) and variant HPV16 containing a pointmutation at codon 83 of the E6 gene.

    The rearrangement of the immunoglobulin heavy chain gene can be used as a marker of B-celllineage and clonality. By using PCR with specific primers corresponding to the variable and joining regions, it is possible to detect the rearrangement of a small amount of clonal B-cells ina polyclonal background. This study has shown that the SSCP analysis of PCR fragmentsincreases the sensitivity and the specificity of the test.

    Oncogenic activation of the RET related to somatic missense mutations has been shown insporadic MTC. These mutations are believed to play an important role in the tumorigenesis ofMTC. By combining microdissection of tumor cells followed by PCR-SSCP, fragment sizeanalysis and sequencing, a small proportion of cells with mutation in a subpopulation of cellswithin a tumor can be detected. A variant of HPV 16 has previously been shown to be moreprevalent in invasive cervical carcinoma than in preinvasive lesions. In the present study asimple, rapid PCR-SSCP assay has been developed to identify women who are at increasedrisk of progression to invasive cervical carcinoma.

  • 252.
    Alenius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Treatment Response in Psychotic Patients in a Naturalistic Setting: Classification, Genes, Drugs, Insight and Social Networks2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Many patients with psychotic symptoms respond poorly to treatment. Various approaches have been made to classify these patients according to treatment response. However, existing classifications have been criticized for various reasons and a new classification system is needed. Further, no satisfactory explanation of the poor treatment response has been apparent. The general aim of this thesis was therefore to develop and validate a new classification method of functional remission in a naturalistic population of patients with psychosis and to utilize this classification to investigate the population from genetic, drug treatment, insight and social network points of view.

    Data for this cross-sectional study of patients (n=123) attending the Psychosis Outpatient Care clinic in the county of Jönköping, Sweden, were obtained from patient interviews, blood samples and information from patient files. The new classification method CANSEPT, which combines the CAN rating scale (CAN), the UKU side effect rating scale (SE) and the patient’s previous treatment history (PT), showed validity in discriminating the patients and was accepted well by the patients. CANSEPT was used to group the patients in the other studies in this thesis.

    The results indicated that the gene polymorphism ABCB1 3435T, was related to worse significant social and clinical needs for patients on olanzapine, while the polymorphism DRD2 Taq1 A1 was related to a greater risk of significant side effects; especially if male, or taking strong dopamine D2-receptor antagonistic drugs. Drug treatment factors were also related to treatment response; longer duration of untreated prodromal and early psychosis was seen for patients with current significant social and clinical needs and non-adherence to treatment was associated with worse significant side effects. Worse treatment outcomes also appeared to be associated with smaller social network groups, worse insight into illness, poorer knowledge of warning signs and worse coping strategies.

    In summary, CANSEPT was shown to be a useful valid, multidimensional tool for classification of treatment response. Gene polymorphisms, duration of untreated illness, non-adherence to treatment, social networks and knowledge should be taken into consideration when investigating inadequate treatment response.

    Delarbeid
    1. Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Åpne denne publikasjonen i ny fane eller vindu >>Treatmentresponse in psychotic patients classified according to social and clinical needs, drug side effects, and previous treatment; a method to identify functional remission
    Vise andre…
    2009 (engelsk)Inngår i: Comprehensive Psychiatry, ISSN 0010-440X, E-ISSN 1532-8384, Vol. 50, nr 5, s. 453-462Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory. Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. METHOD: A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersøgelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. RESULTS: In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. CONCLUSION: In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98078 (URN)10.1016/j.comppsych.2008.11.001 (DOI)000269251100009 ()19683616 (PubMedID)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2022-01-28bibliografisk kontrollert
    2. Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Åpne denne publikasjonen i ny fane eller vindu >>Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting
    Vise andre…
    2008 (engelsk)Inngår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

    Emneord
    DRD2, 5-HT2, ABCB1, Cytochrome P-450 CYP2D6, Antipsychotic agents, Schizophrenia
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98079 (URN)10.1016/j.jpsychires.2007.10.007 (DOI)000258798300002 ()18086475 (PubMedID)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2022-01-28
    3. Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    Åpne denne publikasjonen i ny fane eller vindu >>Current and retrospective antipsychotic drug use in relation to treatment response in a naturalistic setting of psychotic patients
    2009 (engelsk)Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-98080 (URN)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2011-05-11bibliografisk kontrollert
    4. Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    Åpne denne publikasjonen i ny fane eller vindu >>Knowledge and insight in relation to functional remission in patients with long-term psychotic disorders
    2010 (engelsk)Inngår i: Social Psychiatry and Psychiatric Epidemiology, ISSN 0933-7954, E-ISSN 1433-9285, Vol. 45, nr 5, s. 523-529Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND: Patients with psychotic symptoms often respond poorly to treatment. Outcomes can be affected by biological, physiological and psychological factors according to the vulnerability-stress model. The patient's coping strategies and beliefs have been correlated with outcomes. OBJECTIVES: To investigate the knowledge and insight in relation to treatment response. METHODS: A naturalistic study was performed using patient interviews and information gathered from patient drug charts. Apart from the rating scales used for classification of treatment response (CANSEPT method), the SPKS knowledge of illness and drugs rating scale was utilized. RESULTS: In the group of patients in functional remission (FR; n = 38), 37% had insight into their illness as compared to 10% among those not in functional remission (non-FR; n = 78; P < 0.01). As much as 23% of the non-FR group had no strategy for responding to warning signs versus 8% in the FR group (P < 0.05). CONCLUSIONS: Better treatment outcomes appear to be associated with better insight into illness, higher knowledge of warning signs and better coping strategies.

    Emneord
    Health knowledge, Treatment outcome, Schizophrenia, Psychotic disorders, Insight
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-123011 (URN)10.1007/s00127-009-0096-3 (DOI)000275422700002 ()19626260 (PubMedID)
    Tilgjengelig fra: 2010-04-22 Laget: 2010-04-22 Sist oppdatert: 2017-12-12bibliografisk kontrollert
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  • 253.
    Alenius, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Dahl, Marja-Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Hartvig, Per
    Lindström, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting2008Inngår i: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 42, nr 11, s. 884-893Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

  • 254.
    Alenkvist, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Epac2 signaling at the β-cell plasma membrane2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Secretion of appropriate amounts of insulin from pancreatic β-cells is crucial for glucose homeostasis. The β-cells release insulin in response to glucose and other nutrients, hormones and neurotransmitters, which trigger intracellular signaling cascades, that result in exocytotic fusion of insulin-containing vesicles with the plasma membrane. Increases of the intracellular concentration of calcium ions ([Ca2+]i) trigger exocytosis, whereas the messenger cyclic adenosine monophosphate (cAMP) amplifies various steps of the secretion process. The protein Epac2 mediates some effects of cAMP, but little is known about its regulation in β-cells. In this study, the spatio-temporal dynamics of Epac2 was investigated in insulin-secreting MIN6-cells and primary β-cells using various cell signaling biosensors and live-cell fluorescence microscopy approaches. Increases in the cAMP concentration triggered translocation of Epac2 from the cytoplasm to the plasma membrane. Oscillations of cAMP induced by glucose and the insulin-releasing hormone GLP-1 were associated with cyclic translocation of Epac2. Analyses of Epac2 mutants showed that the high-affinity cyclic nucleotide-binding domain and Ras-association domains were crucial for the translocation, whereas neither the DEP domain, nor the low-affinity cAMP-binding domain were required for membrane binding. However, the latter domain targeted Epac2 to insulin granules at the plasma membrane, which promoted their priming for exocytosis. Depolarization-induced elevations of [Ca2+]i also stimulated Epac2 translocation, but the effects were complex and in the presence of high cAMP concentrations, [Ca2+]i increases often reduced membrane binding. The stimulatory effect of Ca2+ was mediated by increased Ras activity, while the inhibitory effect reflected reduced concentrations of the membrane phospholipid PtdIns(4,5)P2. Anti-diabetic drugs of the sulfonylurea class, suggested to directly activate Epac2, induced translocation indirectly by depolarizing β-cells to increase [Ca2+]i. Epac2 is an activator of Rap GTPases, and its translocation increased Rap activity at the plasma membrane. It is concluded that the subcellular localization of Epac2 is controlled by a complex interplay between cAMP, Ca2+ and PtdIns(4,5)P2 and that the protein controls insulin release by binding to the exocytosis machinery. These results provide new insights into the regulation of β-cell function and may facilitate the development of new anti-diabetic drugs that amplify insulin secretion.

    Delarbeid
    1. Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic beta Cells
    Åpne denne publikasjonen i ny fane eller vindu >>Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic beta Cells
    2013 (engelsk)Inngår i: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 6, nr 273, s. ra29-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The cAMP (adenosine 3',5'-monophosphate)-activated guanine nucleotide exchange factor (GEF) Epac2 is an important mediator of cAMP-dependent processes in multiple cell types. We used real-time confocal and total internal reflection fluorescence microscopy to examine the spatiotemporal regulation of Epac2, which is a GEF for the guanosine triphosphatase (GTPase) Rap. We demonstrated that increases in the concentration of cAMP triggered the translocation of Epac2 from the cytoplasm to the plasma membrane in insulin-secreting beta cells. Glucose-induced oscillations of the submembrane concentration of cAMP were associated with cyclic translocation of Epac2, and this translocation could be amplified by increases in the cytoplasmic Ca2+ concentration. Analyses of Epac2 mutants identified the high-affinity cAMP-binding and the Ras association domains as crucial for the translocation. Expression of a dominant-negative Ras mutant reduced Epac2 translocation, and Ca2+-dependent oscillations in Ras activity synchronized with Epac2 translocation in single beta cells. The cyclic translocation of Epac2 was accompanied by oscillations of Rap GTPase activity at the plasma membrane, and expression of an inactive Rap1B mutant decreased insulin secretion. Thus, Epac2 localization is dynamically controlled by cAMP as well as by Ca2+-mediated activation of Ras. These results help to explain how oscillating signals can produce pulses of insulin release from pancreatic b cells.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-201253 (URN)10.1126/scisignal.2003932 (DOI)000318350100002 ()
    Tilgjengelig fra: 2013-06-10 Laget: 2013-06-10 Sist oppdatert: 2022-01-28bibliografisk kontrollert
    2. Two-step membrane recruitment of Epac2 primes secretory granules for exocytosis
    Åpne denne publikasjonen i ny fane eller vindu >>Two-step membrane recruitment of Epac2 primes secretory granules for exocytosis
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-284568 (URN)
    Tilgjengelig fra: 2016-04-19 Laget: 2016-04-18 Sist oppdatert: 2018-01-10
    3. Localization of Epac2 to the plasma membrane is controlled by an interplay between cAMP, Ca2+ and PtdIns(4,5)P2
    Åpne denne publikasjonen i ny fane eller vindu >>Localization of Epac2 to the plasma membrane is controlled by an interplay between cAMP, Ca2+ and PtdIns(4,5)P2
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-284580 (URN)
    Tilgjengelig fra: 2016-04-19 Laget: 2016-04-18 Sist oppdatert: 2018-01-10
    4. Sulfonylureas trigger Ca2+-dependent Epac2 recruitment and Rap activation at the plasma membrane in β-cells
    Åpne denne publikasjonen i ny fane eller vindu >>Sulfonylureas trigger Ca2+-dependent Epac2 recruitment and Rap activation at the plasma membrane in β-cells
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-284582 (URN)
    Tilgjengelig fra: 2016-04-19 Laget: 2016-04-18 Sist oppdatert: 2018-01-10
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  • 255.
    Alenkvist, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gandasi, Nikhil R
    Barg, Sebastian
    Tengholm, Anders
    Two-step membrane recruitment of Epac2 primes secretory granules for exocytosisManuskript (preprint) (Annet vitenskapelig)
  • 256.
    Alenkvist, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Idevall-Hagren, Olof
    Tengholm, Anders
    Localization of Epac2 to the plasma membrane is controlled by an interplay between cAMP, Ca2+ and PtdIns(4,5)P2Manuskript (preprint) (Annet vitenskapelig)
  • 257.
    Alenkvist, Ida
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Xu, Yunjian
    Tengholm, Anders
    Sulfonylureas trigger Ca2+-dependent Epac2 recruitment and Rap activation at the plasma membrane in β-cellsManuskript (preprint) (Annet vitenskapelig)
  • 258.
    Alexander, Michelle
    et al.
    Univ York, York YO10 5DD, N Yorkshire, England.;Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Ho, Simon Y. W.
    Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia..
    Molak, Martyna
    Polish Acad Sci, Museum & Inst Zool, PL-00679 Warsaw, Poland..
    Barnett, Ross
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Dorshorst, Ben
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Honaker, Christa
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Besnier, Francois
    Inst Marine Res, Sect Populat Genet, N-5024 Bergen, Norway..
    Wahlberg, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Dobney, Keith
    Univ Aberdeen, Sch Geosci, Dept Archaeol, Aberdeen AB24 3UF, Scotland..
    Siegel, Paul
    Virginia Tech, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Larson, Greger
    Palaeogen & Bioarchaeol Res Network, Res Lab Archaeol, Oxford OX1 3QY, England..
    Mitogenomic analysis of a 50-generation chicken pedigree reveals a rapid rate of mitochondrial evolution and evidence for paternal mtDNA inheritance2015Inngår i: Biology Letters, ISSN 1744-9561, E-ISSN 1744-957X, Vol. 11, nr 10, artikkel-id 20150561Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mitochondrial genomes represent a valuable source of data for evolutionary research, but studies of their short-term evolution have typically been limited to invertebrates, humans and laboratory organisms. Here we present a detailed study of 12 mitochondrial genomes that span a total of 385 transmissions in a well-documented 50-generation pedigree in which two lineages of chickens were selected for low and high juvenile body weight. These data allowed us to test the hypothesis of time-dependent evolutionary rates and the assumption of strict maternal mitochondrial transmission, and to investigate the role of mitochondrial mutations in determining phenotype. The identification of a non-synonymous mutation in ND4L and a synonymous mutation in CYTB, both novel mutations in Gallus, allowed us to estimate a molecular rate of 3.13 x 10(-7) mutations/site/year (95% confidence interval 3.75 x 10(-8)-1.12 x 10(-6)). This is substantially higher than avian rate estimates based upon fossil calibrations. Ascertaining which of the two novel mutations was present in an additional 49 individuals also revealed an instance of paternal inheritance of mtDNA. Lastly, an association analysis demonstrated that neither of the point mutations was strongly associated with the phenotypic differences between the two selection lines. Together, these observations reveal the highly dynamic nature of mitochondrial evolution over short time periods.

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  • 259.
    Alexander, Stephen P. H.
    et al.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Christopoulos, Arthur
    Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia.;Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia..
    Davenport, Anthony P.
    Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England..
    Kelly, Eamonn
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Mathie, Alistair A.
    Univ Suffolk, Sch EAST Engn Arts Sci & Technol, Ipswich IP4 1QJ, Suffolk, England..
    Peters, John A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Educ Inst, Neurosci Div, Dundee DD1 9SY, Angus, Scotland..
    Veale, Emma L.
    Univ Greenwich, Medway Sch Pharm, Anson Bldg,Cent Ave, Chatham ME4 4TB, Kent, England.;Univ Kent, Medway, Anson Bldg,Cent Ave, Chatham ME4 4TB, Kent, England..
    Armstrong, Jane F.
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Faccenda, Elena
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Harding, Simon D.
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Davies, Jamie A.
    Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh EH8 9XD, Midlothian, Scotland..
    Abbracchio, Maria Pia
    Univ Milan, Milan, Italy..
    Abraham, George
    Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England..
    Agoulnik, Alexander
    Florida Int Univ, Miami, FL 33199 USA..
    Alexander, Wayne
    Emory Univ, Atlanta, GA 30322 USA..
    Al-hosaini, Khaled
    King Saud Univ, Riyadh, Saudi Arabia..
    Baeck, Magnus
    Karolinska Univ Hosp, Stockholm, Sweden..
    Baker, Jillian G.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Barnes, Nicholas M.
    Univ Birmingham, Birmingham, Warwickshire, England..
    Bathgate, Ross
    Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia..
    Beaulieu, Jean-Martin
    Univ Toronto, Toronto, ON, Canada..
    Beck-Sickinger, Annette G.
    Univ Leipzig, Leipzig, Germany..
    Behrens, Maik
    Tech Univ Munich, Freising Weihenstephan, Germany..
    Bernstein, Kenneth E.
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Bettler, Bernhard
    Univ Basel, Basel, Switzerland..
    Birdsall, Nigel J. M.
    Francis Crick Inst, London, England..
    Blaho, Victoria
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Boulay, Francois
    Univ Grenoble Alpes, Grenoble, France..
    Bousquet, Corinne
    French Inst Hlth & Med Res INSERM, Toulouse, France..
    Braeuner-Osborne, Hans
    Univ Copenhagen, Copenhagen, Denmark..
    Burnstock, Geoffrey
    UCL, London, England..
    Calo, Girolamo
    Univ Padua, Padua, Italy..
    Castano, Justo P.
    Univ Cordoba, Cordoba, Spain..
    Catt, Kevin J.
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Ceruti, Stefania
    Univ Milan, Milan, Italy..
    Chazot, Paul
    Univ Durham, Durham, England..
    Chiang, Nan
    Harvard Univ, Boston, MA 02115 USA..
    Chini, Bice
    Univ Milano Bicocca, Vedano Al Lambro, Italy..
    Chun, Jerold
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Cianciulli, Antonia
    Univ Bari, Bari, Italy..
    Civelli, Olivier
    Univ Calif Irvine, Irvine, CA USA..
    Clapp, Lucie H.
    UCL, London, England..
    Couture, Rejean
    Univ Montreal, Montreal, PQ, Canada..
    Cox, Helen M.
    Kings Coll London, London, England..
    Csaba, Zsolt
    French Inst Hlth & Med Res INSERM, Paris, France..
    Dahlgren, Claes
    Univ Gothenburg, Gothenburg, Sweden..
    Dent, Gordon
    Keele Univ, Keele, Staffs, England..
    Douglas, Steven D.
    Univ Penn, Philadelphia, PA 19104 USA..
    Dournaud, Pascal
    French Inst Hlth & Med Res INSERM, Paris, France..
    Eguchi, Satoru
    Temple Univ, Philadelphia, PA 19122 USA..
    Escher, Emanuel
    Univ Sherbrooke, Sherbrooke, PQ, Canada..
    Filardo, Edward J.
    Univ Iowa, Iowa City, IA USA..
    Fong, Tung
    Labcorp Drug Dev, Somerset, NJ USA..
    Fumagalli, Marta
    Univ Milan, Milan, Italy..
    Gainetdinov, Raul R.
    St Petersburg State Univ, St Petersburg, Russia..
    Garelja, Michael L.
    Univ Otago, Dunedin, New Zealand..
    de Gasparo, Marc
    MG Consulting Co, Basel, Switzerland..
    Gerard, Craig
    Harvard Univ, Boston, MA 02115 USA..
    Gershengorn, Marvin
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Gobeil, Fernand
    Univ Sherbrooke, Sherbrooke, PQ, Canada..
    Goodfriend, Theodore L.
    Univ Wisconsin, Madison, WI USA..
    Goudet, Cyril
    French Natl Ctr Sci Res, Montpellier, France..
    Graetz, Lukas
    Karolinska Inst, Stockholm, Sweden..
    Gregory, Karen J.
    Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia.;Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia..
    Gundlach, Andrew L.
    Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia..
    Hamann, Joerg
    Univ Amsterdam, Amsterdam, Netherlands..
    Hanson, Julien
    Univ Liege, Liege, Belgium..
    Hauger, Richard L.
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Hay, Debbie L.
    Univ Otago, Dunedin, New Zealand..
    Heinemann, Akos
    Med Univ Graz, Graz, Austria..
    Herr, Deron
    San Diego State Univ, San Diego, CA 92182 USA..
    Hollenberg, Morley D.
    Univ Calgary, Calgary, AB, Canada..
    Holliday, Nicholas D.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Horiuchi, Mastgugu
    Ehime Univ, Matsuyama, Ehime, Japan..
    Hoyer, Daniel
    Univ Melbourne, Melbourne, Vic, Australia..
    Hunyady, Laszlo
    Semmelwe Univ, Budapest, Hungary..
    Husain, Ahsan
    Emory Univ, Atlanta, GA 30322 USA..
    Ijzerman, Adriaan P.
    Leiden Univ, Leiden, Netherlands..
    Inagami, Tadashi
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Jacobson, Kenneth A.
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Jensen, Robert T.
    NIH, Bldg 10, Bethesda, MD 20892 USA..
    Jockers, Ralf
    French Inst Hlth & Med Res INSERM, Paris, France..
    Jonnalagadda, Deepa
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Karnik, Sadashiva
    Lerner Res Inst, Cleveland, OH USA..
    Kaupmann, Klemens
    Novartis, Basel, Switzerland..
    Kemp, Jacqueline
    Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA..
    Kennedy, Charles
    Strathclyde Univ, Glasgow, Lanark, Scotland..
    Kihara, Yasuyuki
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Kitazawa, Takio
    Rakuno Gakuen Univ, Ebetsu, Hokkaido, Japan..
    Kozielewicz, Pawel
    Karolinska Inst, Stockholm, Sweden..
    Kreienkamp, Hans-Juergen
    Univ Hamburg, Hamburg, Germany..
    Kukkonen, Jyrki P.
    Univ Helsinki, Helsinki, Finland..
    Langenhan, Tobias
    Univ Leipzig, Leipzig, Germany..
    Larhammar, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Forskargrupp Dan Larhammar. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leach, Katie
    Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia.;Monash Univ, Dept Pharmacol, Parkville, Vic 3052, Australia..
    Lecca, Davide
    Univ Milan, Milan, Italy..
    Lee, John D.
    Univ Queensland, Brisbane, Qld, Australia..
    Leeman, Susan E.
    Boston Univ, Boston, MA 02215 USA..
    Leprince, Jerome
    Univ Rouen, Rouen, France..
    Li, Xaria X.
    Univ Queensland, Toowoomba, Qld, Australia..
    Lolait, Stephen J.
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Lupp, Amelie
    Friedrich Schiller Univ Jena, Jena, Germany..
    Macrae, Robyn
    Univ Cambridge, Cambridge, England..
    Maguire, Janet
    Univ Cambridge, Clin Pharmacol Unit, Cambridge CB2 0QQ, England..
    Malfacini, Davide
    Univ Padua, Padua, Italy..
    Mazella, Jean
    French Natl Ctr Sci Res CNRS, Valbonne, France..
    Mcardle, Craig A.
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Melmed, Shlomo
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Michel, Martin C.
    Johannes Gutenberg Univ Mainz, Mainz, Germany..
    Miller, Laurence J.
    Mayo Fdn Med Educ & Res, Scottsdale, AZ USA..
    Mitolo, Vincenzo
    Univ Bari, Bari, Italy..
    Mouillac, Bernard
    French Natl Ctr Sci Res, Montpellier, France..
    Mueller, Christa E.
    Univ Bonn, Bonn, Germany..
    Murphy, Philip M.
    Edge Hill Univ, Bethesda, MD USA..
    Nahon, Jean-Louis
    French Natl Ctr Sci Res CNRS, Valbonne, France..
    Ngo, Tony
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Norel, Xavier
    French Inst Hlth & Med Res INSERM, Paris, France..
    Nyimanu, Duuamene
    Univ Cambridge, Cambridge, England..
    O'Carroll, Anne-Marie
    Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol BS8 1TD, Avon, England..
    Offermanns, Stefan
    Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany..
    Panaro, Maria Antonietta
    Univ Bari, Bari, Italy..
    Parmentier, Marc
    Free Univ Brussels, Brussels, Belgium..
    Pertwee, Roger G.
    Univ Aberdeen, Aberdeen, Scotland..
    Pin, Jean-Philippe
    Univ Montpellier, Montpellier, France..
    Prossnitz, Eric R.
    Univ New Mexico, Albuquerque, NM 87131 USA..
    Quinn, Mark
    Montana State Univ, Bozeman, MT 59717 USA..
    Ramachandran, Rithwik
    Univ Calgary, Calgary, AB, Canada..
    Ray, Manisha
    Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA..
    Reinscheid, Rainer K.
    Friedrich Schiller Univ Jena, Jena, Germany..
    Rondard, Philippe
    Univ Montpellier, Montpellier, France..
    Rovati, G. Enrico
    Univ Milan, Milan, Italy..
    Ruzza, Chiara
    Univ Ferrara, Ferrara, Italy..
    Sanger, Gareth J.
    Queen Mary Univ London, London, England..
    Schoeneberg, Torsten
    Univ Leipzig, Leipzig, Germany..
    Schulte, Gunnar
    Karolinska Inst, Stockholm, Sweden..
    Schulz, Stefan
    Friedrich Schiller Univ Jena, Jena, Germany..
    Segaloff, Deborah L.
    Univ Iowa, Iowa City, IA USA..
    Serhan, Charles N.
    Harvard Univ, Boston, MA 02115 USA..
    Singh, Khuraijam Dhanachandra
    Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA..
    Smith, Craig M.
    Deakin Univ, Waurn Ponds, Australia..
    Stoddart, Leigh A.
    Univ Nottingham, Med Sch, Sch Life Sci, Nottingham NG7 2UH, England..
    Sugimoto, Yukihiko
    Kumamoto Univ, Kumamoto, Japan..
    Summers, Roger
    Monash Univ, Melbourne, Vic, Australia..
    Tan, Valerie P.
    Univ Calif San Diego, La Jolla, CA 92093 USA..
    Thal, David
    Monash Univ, Melbourne, Vic, Australia..
    Thomas, Walter ( Wally)
    Univ Queensland, Toowoomba, Qld, Australia..
    Timmermans, Pieter B. M. W. M.
    Kosan Biosci Inc, San Francisco, CA USA..
    Tirupula, Kalyan
    Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA..
    Toll, Lawrence
    Florida Atlantic Univ, Jupiter, FL USA..
    Tulipano, Giovanni
    Univ Brescia, Brescia, Italy..
    Unal, Hamiyet
    Cleveland Clin, Cleveland, OH 44106 USA..
    Unger, Thomas
    Maastricht Univ, Maastricht, Netherlands..
    Valant, Celine
    Monash Univ, Melbourne, Vic, Australia..
    Vanderheyden, Patrick
    Free Univ Brussels, Brussels, Belgium..
    Vaudry, David
    Univ Rouen, Rouen, France..
    Vaudry, Hubert
    Univ Rouen, Rouen, France..
    Vilardaga, Jean-Pierre
    Univ Pittsburgh, Pittsburgh, PA USA..
    Walker, Christopher S.
    Univ Auckland, Auckland, New Zealand..
    Wang, Ji Ming
    NCI, Frederick, MD 21701 USA..
    Ward, Donald T.
    Univ Manchester, Manchester, Lancs, England..
    Wester, Hans-Juergen
    Tech Univ Munich, Munich, Germany..
    Willars, Gary B.
    Univ Leicester, Leicester, Leics, England..
    Williams, Tom Lloyd
    Univ Cambridge, Cambridge, England..
    Woodruff, Trent M.
    Univ Queensland, Toowoomba, Qld, Australia..
    Yao, Chengcan
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Ye, Richard D.
    Chinese Univ Hong Kong, Shenzhen, Hong Kong, Peoples R China..
    The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors2023Inngår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 180, nr Suppl. 2, s. S23-S144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at . G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

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  • 260.
    Alexandra, Olivia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Potential Application of Multiplex Automated Genome Engineering (MAGE) and One-Step Curing Plasmid System for Environmental Cambodian Enterobacterial Isolates2021Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
    Abstract [en]

    Antimicrobial resistance (AMR) is concerning because it limits antimicrobial drug treatment options. AMR occurs by the overuse and misuse of antimicrobial drugs. In environmental settings, AMR can disseminate from places of high use, which leads to increased exposure to humans and animals. A previous study from our laboratory group showed extended-spectrum cephalosporinase-producing Escherichia coli/Klebsiella pneumoniae were isolated from fecal samples obtained in rural Cambodian community settings. Based on these isolates, this study has two aims. The first aim was characterization of selected Cambodian isolates with random amplification polymorphic DNA (RAPD) and antibiotic susceptibility test. From RAPD, the selected six isolates are diverse, except for C61 and C66 bacteria isolates with potential clonality. Additionally, the selected isolates are multidrug resistant (MDR) with reduced susceptibility to beta-lactams and fluoroquinolones. The second aim was to assess two developed methodologies, multiplex automated genome engineering (MAGE) and One-Step Curing Plasmid, by validation in bacteria laboratory strain and development for six Cambodian isolates. To modify AMR genetic elements, MAGE uses pMA7-SacB for homologous recombination with oligos for chromosomal gene disruption. Meanwhile, One-Step Curing Plasmid uses pFREE with the CRISPR/Cas9 system for plasmid and self-curing. Validation showed that MAGE can modify 8% of E. coli MG1655 with lacZ control screening oligos and almost 90% are cured from pFREE. Selected Cambodian isolates have antibiotic-resistance plasmids of IncR or IncFII replicon. For usage in Cambodian isolates, pFREE was modified to be pCAM-FREE by cloning IncR and IncFII plasmid as gRNA1 and gRNA5, respectively. Sequencing results showed pCAM-FREE have gRNA5. In conclusion, our study managed to characterize selected Cambodian isolates as MDR and diverse. In a laboratory strain, MAGE and One-Step Curing Plasmid are functional methods. Furthermore, pCAM-FREE was constructed to target IncFII and in the future, MAGE and pCAM-FREE could be tested in Cambodian isolates.  

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    fulltext
  • 261.
    Alffenaar, J. W. C.
    et al.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.
    Stocker, S. L.
    Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;St Vincents Hosp, Dept Clin Pharmacol & Toxicol, Sydney, NSW, Australia.;Univ NSW, St Vincents Clin Campus, Kensington, NSW, Australia.
    Forsman, L. Davies
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Solna, Sweden.
    Garcia-Prats, A.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.;Univ Wisconsin, Dept Pediat, Madison, WI USA.
    Heysell, S. K.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
    Aarnoutse, R. E.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Nijmegen, Netherlands.
    Akkerman, O. W.
    Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis & TB, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, TB Ctr Beatrixoord, Haren, Netherlands.
    Aleksa, A.
    Grodno State Med Univ, Educ Inst, Grodno, BELARUS.
    van Altena, R.
    Asian Harm Reduct Network AHRN, Yangon, Myanmar.;Med Act Myanmar MAM, Yangon, Myanmar.
    de Onata, W. Arrazola
    Belgian Sci Inst Publ Hlth, Belgian Lung & TB Assoc, Brussels, Belgium.
    Bhavani, P. K.
    Indian Council Med Res Natl Inst Res TB, Int Ctr Excellence Res, Chennai, Tamil Nadu, India.
    Van't Boveneind-Vrubleuskaya, N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.;Metropolitan Publ Hlth Serv, Dept Publ Hlth TB Control, The Hague, Netherlands.
    Carvalho, A. C. C.
    Fundacao Oswaldo Cruz, Lab Inovacoes Terapias Ensino & Bioprod LITEB, Inst Oswaldo Cruz, Rio De Janeiro, RJ, Brazil.
    Centis, R.
    Ist Ricovero & Cura Carattere Sci IRCCS, Ist Clin Sci Maugeri, Serv Epidemiol Clin Malattie Resp, Tradate, Italy.
    Chakaya, J. M.
    Kenyatta Univ, Dept Med Therapeut & Dermatol, Nairobi, Kenya.;Univ Liverpool Liverpool Sch Trop Med, Dept Clin Sci, Liverpool, Merseyside, England.
    Cirillo, D. M.
    IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Emerging Bacterial Pathogens Unit, Milan, Italy.
    Cho, J. G.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.;Parramatta Chest Clin, Parramatta, NSW, Australia.
    Ambrosio, L. D.
    Publ Hlth Consulting Grp, Lugano, Switzerland.
    Dalcolmo, M. P.
    Funda Oswaldo Cruz Fiocruz, Reference Ctr Helio Fraga, Rio De Janeiro, RJ, Brazil.
    Denti, P.
    Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa.
    Dheda, K.
    Univ Cape Town, Ctr Lung Infect & Immun, Div Pulmonol, Dept Med, Cape Town, South Africa.;Univ Cape Town, UCT Lung Inst, Cape Town, South Africa.;Univ Cape Town Lung Inst, Cape Town, South Africa.;South African MRC Ctr Study Antimicrobial Resista, Cape Town, South Africa.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Immunol & Infect, London, England.
    Fox, G. J.
    Univ Sydney, Fac Med & Hlth, Sydney Med Sch, Sydney, NSW, Australia.;Woolcock Inst Med Res, Glebe, NSW, Australia.
    Hesseling, A. C.
    Stellenbosch Univ, Desmond Tutu TB Ctr, Dept Paediat & Child Hlth, Tygerberg, South Africa.
    Kim, H. Y.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney, Sch Pharm, Fac Med & Hlth, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia.
    Koser, C. U.
    Univ Cambridge, Dept Genet, Cambridge, England.
    Marais, B. J.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Childrens Hosp Westmead, Dept Infect Dis & Microbiol, Westmead, NSW, Australia.
    Margineanu, I
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.
    Martson, A. G.
    Univ Liverpool, Inst Translat Med, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England.
    Torrico, M. Munoz
    Inst Nacl Enfermedades Resp, Clin TB, Ciudad De Mexico, Mexico.
    Nataprawira, H. M.
    Univ Padjadjaran, Hasan Sadikin Hosp, Fac Med, Dept Child Hlth,Div Paediat Respirol, Bandung, Indonesia.
    Ong, C. W. M.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Infect Dis Translat Res Programme, Singapore, Singapore.;Natl Univ Singapore, Inst Hlth Innovat & Technol iHealthtech, Singapore, Singapore.;Natl Univ Singapore Hosp, Dept Med, Div Infect Dis, Singapore, Singapore.
    Otto-Knapp, R.
    German Cent Comm TB DZK, Berlin, Germany.
    Peloquin, C. A.
    Univ Florida, Infect Dis Pharmacokinet Lab, Pharmacitherapy & Translat Res, Coll Pharm, Gainesville, FL USA.
    Silva, D. R.
    Univ Fed Rio Grande do Sul, Fac Med, Porto Alegre, RS, Brazil.
    Ruslami, R.
    Univ Padjadjaran, Fac Med, TB HIV Res Ctr, Bandung, Indonesia.;Univ Padjadjaran, Fac Med, Dept Biomed Sci, Div Pharmacol & Therapy, Bandung, Indonesia.
    Santoso, P.
    Univ Padjadjaran, Fac Med, Dept Internal Med, Div Respirol & Crit Care,Hasan Sadikin Gen Hosp, Bandung, Indonesia.
    Savic, R. M.
    Univ Calif San Francisco, Sch Pharm, Dept Bioengn & Therapeut Sci, Div Pulm & Crit Care Med, San Francisco, CA USA.;Univ Calif San Francisco, Sch Med, Div Pulm & Crit Care Med, Dept Bioengn & Therapeut Sci, San Francisco, CA USA.
    Singla, R.
    Natl Inst TB & Resp Dis, Dept TB & Resp Dis, New Delhi, India.
    Svensson, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboudumc Ctr Infect Dis, Nijmegen, Netherlands.
    Skrahina, A.
    Republican Res & Pract Ctr Pulmonol & TB, Minsk, BELARUS.
    van Soolingen, D.
    Natl Inst Publ Hlth & Environm, TB Reference Lab RIVM, Bilthoven, Netherlands.
    Srivastava, S.
    Univ Texas Hlth Sci Ctr Tyler, Dept Pulm Immunol, Tyler, TX USA.
    Tadolini, M.
    IRCCS Azienda Osped Univ Bologna, Infect Dis Unit, Bologna, Italy.;Alma Mater Studiorum Univ Bologna, Dept Med & Surg Sci, Bologna, Italy.
    Tiberi, S.
    Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London, England.
    Thomas, T. A.
    Univ Virginia, Div Infect Dis & Int Hlth, Charlottesville, VA USA.
    Udwadia, Z. F.
    PD Hinduja Natl Hosp & Med Res Ctr, Mumbai, Maharashtra, India.
    Vu, D. H.
    Hanoi Univ Pharm, Natl Drug Informat & Adverse Drug React Monitorin, Hanoi, Vietnam.
    Zhang, W.
    Fudan Univ, Huashan Hosp, Shanghai Med Coll,Shanghai Key Lab Infect Dis & B, Natl Med Ctr Infect Dis,Dept Infect Dis, Shanghai, Peoples R China.
    Mpagama, S. G.
    Kilimanjaro Christian Med Univ Coll, Moshi, Tanzania.;Kibongoto Infect Dis Hosp, Siha, Kilimanjaro, Tanzania.
    Schon, T.
    Linköping Univ Hosp, Dept Infect Dis, Linköping, Sweden.;Linköping Univ, Inst Biomed & Clin Sci, Div Infect & Inflammat, Linköping, Sweden.;Linköping Univ, Kalmar Cty Hosp, Dept Infect Dis, Linköping, Sweden.
    Migliori, G. B.
    Grodno State Med Univ, Educ Inst, Grodno, BELARUS.
    Clinical standards for the dosing and management of TB drugs2022Inngår i: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 26, nr 6, s. 483-+Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice' for dosing and management of TB drugs.

    Methods: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.

    Results: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.

    Conclusion: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.

  • 262.
    Alffenaar, Jan-Willem C.
    et al.
    Univ Sydney, Sydney Inst Infect Dis, Sydney, NSW, Australia.;Univ Sydney Fac Med & Hlth, Sch Pharm, Sydney, NSW, Australia.;Westmead Hosp, Sydney, NSW, Australia..
    de Steenwinkel, Jurriaan E. M.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands..
    Diacon, Andreas H.
    TASK, Cape Town, South Africa..
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Srivastava, Shashikant
    Univ Texas Hlth Sci Ctr Tyler, Dept Pulm Immunol, Tyler, TX USA..
    Wicha, Sebastian G.
    Univ Hamburg, Inst Pharm, Dept Clin Pharm, Hamburg, Germany..
    Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of in vitro, in vivo methodologies and human studies2022Inngår i: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, artikkel-id 1063453Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.

    Fulltekst (pdf)
    FULLTEXT01
  • 263. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, nr 4, s. 470-476Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

    Fulltekst (pdf)
    fulltext
  • 264. 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 levels2002Inngår i: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, nr 2, s. 225-34Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 265.
    Alfredsson, Jessica
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Molecular Studies of Mast Cell Migration and Apoptosis: Two Ways of Regulating Mast Cell Numbers at Sites of Inflammation2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Upon activation mast cells release numerous proinflammatory mediators. With this feature, mast cells play an important role in host defense against pathogens, and are involved in tissue remodeling and wound healing. However, in cases of excessive inflammation the effects of mast cells are detrimental. This is observed in allergy, asthma, rheumatoid arthritis, atherosclerosis, certain types of heart failure, and in several other chronic destructive inflammations. Mast cell numbers are typically increased at inflammatory sites. There they act both directly, as effector cells, and in a regulatory manner, secreting agents that recruit and activate other immune cells.

    The studies presented here investigated mechanisms regulating mast cell numbers at sites of inflammation, focusing on cell migration and regulation of survival/apoptosis. We report that SCF-induced mast cell migration requires p38 MAP kinase activity. Moreover, we found that SCF-mediated mast cell survival is regulated through downregulation of the proapoptotic Bcl-2 family member Bim, as well as through phoshorylation of Bim. SCF seems to control Bim protein levels via FOXO transcription factors, and to induce phosphorylation of Bim via the Mek/Erk and the PI3-kinase/Akt signaling pathways. Furthermore, mast cell death triggered by deprivation of SCF and/or IL-3 involves the Bim protein, as demonstrated using bim-/- mast cells. Additional studies revealed that IgE-receptor activation, which occurs in allergy, promotes both prosurvival and proapoptotic signaling events. This includes upregulation of Bim and the prosurvival Bcl-XL and A1, as well as phosphorylation of Akt, FOXO factors, GSK-3β, IκB-α, Bad, and Bim. The simultaneous stimulation of prosurvival and proapoptotic signaling events could be a way to fine-tune the fate of mast cells after IgE-receptor activation and degranulation.

    The new insights about mechanisms involved in mast cell migration and regulation of survival/apoptosis might prove useful for future efforts to design new drugs to be used for mast cell-associated diseases.

    Delarbeid
    1. Stem Cell Factor-Induced Migration of Mast Cells Requires p38 Mitogen-Activated Protein Kinase Activity
    Åpne denne publikasjonen i ny fane eller vindu >>Stem Cell Factor-Induced Migration of Mast Cells Requires p38 Mitogen-Activated Protein Kinase Activity
    2001 Inngår i: Experimental Cell Research, Vol. 267, nr 1, s. 144-151Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-92671 (URN)
    Tilgjengelig fra: 2005-03-11 Laget: 2005-03-11bibliografisk kontrollert
    2. Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
    Åpne denne publikasjonen i ny fane eller vindu >>Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
    Vise andre…
    Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Identifikatorer
    urn:nbn:se:uu:diva-92672 (URN)
    Tilgjengelig fra: 2005-03-11 Laget: 2005-03-11bibliografisk kontrollert
    3. Porapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation
    Åpne denne publikasjonen i ny fane eller vindu >>Porapoptotic Bcl-2 family member Bim is involved in the control of mast cell survival and is induced together with Bcl-XL upon IgE-receptor activation
    Vise andre…
    2005 Inngår i: Cell Death and Differentiation, Vol. 12, nr 2, s. 136-144Artikkel i tidsskrift (Fagfellevurdert) Published
    Identifikatorer
    urn:nbn:se:uu:diva-92673 (URN)
    Tilgjengelig fra: 2005-03-11 Laget: 2005-03-11bibliografisk kontrollert
    4. IgE-receptor activation of mast cells regulates phosphorylation and expression of forkhead and Bcl-2 family members
    Åpne denne publikasjonen i ny fane eller vindu >>IgE-receptor activation of mast cells regulates phosphorylation and expression of forkhead and Bcl-2 family members
    Manuskript (Annet vitenskapelig)
    Identifikatorer
    urn:nbn:se:uu:diva-92674 (URN)
    Tilgjengelig fra: 2005-03-11 Laget: 2005-03-11 Sist oppdatert: 2010-01-13bibliografisk kontrollert
    Fulltekst (pdf)
    FULLTEXT01
    Download (pdf)
    COVER01
  • 266.
    Alfredsson Timmins, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Functional organisation of the cell nucleus in the fission yeast, Schizosaccharomyces pombe2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In eukaryotes the genome adopts a non-random spatial organisation, which is important for gene regulation. However, very little is known about the driving forces behind nuclear organisation. In the simple model eukaryote fission yeast, Schizosaccharomyces pombe, it has been known for a long time that transcriptionally repressed heterochromatin localise to the nuclear membrane (NM); the centromeres attaches to spindle pole body (SPB), while the telomeres are positioned at the NM on the opposite side of the nucleus compared to the SPB. Studies presented in this thesis aimed at advancing our knowledge of nuclear organisation in Schizosaccharomyces pombe.

    We show that the heterochromatic mating-type region localises to the NM in the vicinity of the SPB. This positioning was completely dependent on Clr4, a histone methyl transferase crucial for the formation of heterochromatin. Additional factors important for localisation were also identified: the chromo domain protein Swi6, and the two boundary elements IR-L and IR-R surrounding this locus. We further identify two other chromo domain proteins; Chp1 and Chp2, as crucial factors for correct subnuclear localisation of this region. From these results we suggest that the boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Gene regulation can affect the subnuclear localisation of genes. Using nitrogen starvation in S. pombe as a model for gene induction we determined the subnuclear localisation of two gene clusters repressed by nitrogen: Chr1 and Tel1. When repressed these loci localise to the NM, and this positioning is dependent on the histone deacetylase Clr3. During induction the gene clusters moved towards the nuclear interior in a transcription dependent manner.

    The knowledge gained from work presented in this thesis, regarding nuclear organisation in the S. pombe model system, can hopefully aid to a better understanding of human nuclear organisation.

    Delarbeid
    1. The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    Åpne denne publikasjonen i ny fane eller vindu >>The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    2007 (engelsk)Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 120, nr 11, s. 1935-1943Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed due to the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase, Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain where the two boundary elements IR-L and IR-R had been deleted the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.

    Emneord
    fission yeast, heterochromatin, silencing, subnuclear localization
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-13023 (URN)10.1242/jcs.03457 (DOI)000246665300013 ()17504808 (PubMedID)
    Tilgjengelig fra: 2009-08-05 Laget: 2009-08-05 Sist oppdatert: 2022-01-28bibliografisk kontrollert
    2. Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    Åpne denne publikasjonen i ny fane eller vindu >>Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    (engelsk)Manuskript (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    The chromatin in the cell nucleus has a spatial organisation. For example, in the fission yeast, Schizosaccharomyces pombe, transcriptionally repressed heterochromatin is found at the nuclear membrane (NM). The centromeres and the mating-type region localise in the proximity of the spindle pole body (SPB), while the telomeres are found on the opposite side of the nucleus in the proximity of the nucleolus. In a previous study we used the mating-type region as a model to study the driving force behind nuclear organisation. We proposed two mutually exclusive models to explain what determines the localisation of the mating-type region. The first model suggests that solely the amount of heterochromatin in the region affects the localisation, while the other model stipulates that the boundary elements together with heterochromatin formation anchor the mating-type region in the NM in the vicinity of the SPB. Here, we present data that disproves the first model. We found that in a strain expressing tripled amounts of the chromodomain protein Swi6, a structural component of heterochromatin, the mating-type region was delocalised from the proximity of the SPB. A strain deleted of the histone deacetylase clr3+ also had a delocalised mating-type locus. Interestingly, a strain with a point-mutation in clr3-735 producing an enzymatically inactive protein in normal amounts showed an intermediate phenotype. Most importantly, we identify the chromodomain proteins, Chp1 and Chp2, as crucial factors for correct subnuclear localisation of the mating-type region. We suggest that boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Identifikatorer
    urn:nbn:se:uu:diva-107280 (URN)
    Tilgjengelig fra: 2009-08-04 Laget: 2009-08-04 Sist oppdatert: 2010-01-14bibliografisk kontrollert
    3. Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
    Åpne denne publikasjonen i ny fane eller vindu >>Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
    Vise andre…
    2009 (engelsk)Inngår i: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 118, nr 1, s. 99-112Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    There are several documented events of changes in subnuclear localization during gene activation. However, there are conflicting data on whether the nuclear periphery is a compartment for gene repression or activation, and whether genes are moved to the pores at the nuclear membrane (NM) or not during gene activation. Nitrogen starvation of fission yeast serves as a good model system for studying gene induction since it causes fast regulation of hundreds of genes. In this study the subnuclear localization of two gene clusters repressed by nitrogen was investigated. During normal growth conditions the gene clusters localized to the nuclear periphery at the opposite side of the nucleus as compared to the spindle pole body (SPB). This constrained localization was dependent on the histone deacetylase Clr3, known to transcriptionally repress genes in these clusters. Already 20 minutes after nitrogen depletion drastic changes in subnuclear localization of the two loci were observed, away from the NM towards the nuclear interior. At least for one of the clusters the movement was clearly transcription dependent. Data presented here illustrates how interconnected events of gene activation and nuclear reorganization are, as well as provides a suggestion of how nuclear organization might be maintained.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-107289 (URN)10.1007/s00412-008-0180-6 (DOI)000262504300009 ()
    Tilgjengelig fra: 2009-08-05 Laget: 2009-08-05 Sist oppdatert: 2022-01-28bibliografisk kontrollert
    Fulltekst (pdf)
    FULLTEXT01
  • 267. Alfstad, K Å
    et al.
    Lossius, M I
    Røste, G K
    Mowinckel, P
    Scheie, D
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Dept. of Laboratory medicine/Pathology, Umeå University, Umeå Sweden.
    Larsson, P G
    Nakken, K O
    Acute postoperative seizures after epilepsy surgery: a long-term outcome predictor?2011Inngår i: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, nr 1, s. 48-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors.

    MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up.

    RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using ≥ six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence.

    CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis.

  • 268.
    Algady, Walid
    et al.
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Louzada, Sandra
    Wellcome Sanger Inst, Cambridge CB10 1SA, England.
    Carpenter, Danielle
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Brajer, Paulina
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    Farnert, Anna
    Karolinska Inst, Dept Med Solna, Div Infect Dis, S-17176 Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, S-17176 Stockholm, Sweden.
    Rooth, Ingegerd
    Natl Inst Med Res, Nyamisati Malaria Res, Dar Es Salaam, Tanzania.
    Ngasala, Billy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH), Internationell barnhälsa och nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Yang, Fengtang
    Wellcome Sanger Inst, Cambridge CB10 1SA, England.
    Shaw, Marie-Anne
    Univ Leeds, Leeds Inst Med Res St Jamess, Leeds LS9 7TF, W Yorkshire, England.
    Hollox, Edward J.
    Univ Leicester, Dept Genet & Genome Biol, Leicester LE1 7RH, Leics, England.
    The Malaria-Protective Human Glycophorin Structural Variant DUP4 Shows Somatic Mosaicism and Association with Hemoglobin Levels2018Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, nr 5, s. 769-776Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycophorin A and glycophorin B are red blood cell surface proteins and are both receptors for the parasite Plasmodium falciparum, which is the principal cause of malaria in sub-Saharan Africa. DUP4 is a complex structural genomic variant that carries extra copies of a glycophorin A-glycophorin B fusion gene and has a dramatic effect on malaria risk by reducing the risk of severe malaria by up to 40%. Using fiber-FISH and Illumina sequencing, we validate the structural arrangement of the glycophorin locus in the DUP4 variant and reveal somatic variation in copy number of the glycophorin B-glycophorin A fusion gene. By developing a simple, specific, PCR-based assay for DUP4, we show that the DUP4 variant reaches a frequency of 13% in the population of a malaria-endemic village in southeastern Tanzania. We genotype a substantial proportion of that village and demonstrate an association of DUP4 genotype with hemoglobin levels, a phenotype related to malaria, using a family-based association test. Taken together, we show that DUP4 is a complex structural variant that may be susceptible to somatic variation and show that DUP4 is associated with a malarial-related phenotype in a longitudinally followed population.

    Fulltekst (pdf)
    fulltext
  • 269.
    Al-Hadad, Shahad Raad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Träningsprogram för vårdnadshavare försäker och korrekt hantering av oralaanticancerläkemedel i hemmet2020Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
  • 270.
    Alhaidan, Yazeid
    et al.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;King Abdullah Int Med Res Ctr, Dept Med Genom Res, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia..
    Larsen, Martin J.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark..
    Schou, Anders Jorgen
    Odense Univ Hosp, Hans Christian Andersen Childrens Hosp, DK-5000 Odense C, Denmark..
    Stenlid, Maria H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Al Balwi, Mohammed A.
    King Abdullah Int Med Res Ctr, Dept Med Genom Res, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia..
    Christesen, Henrik Thybo
    Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;Odense Pancreases Ctr, Www OPA Cnu, Uppsala, Sweden..
    Brusgaard, Klaus
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;Near East Univ, Nicosia, Cyprus..
    Exome sequencing revealed DNA variants in NCOR1, IGF2BP1, SGLT2 and NEK11 as potential novel causes of ketotic hypoglycemia in children2020Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikkel-id 2114Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Unexplained or idiopathic ketotic hypoglycemia (KH) is the most common type of hypoglycemia in children. The diagnosis is based on the exclusion of routine hormonal and metabolic causes of hypoglycemia. We aimed to identify novel genes that cause KH, as this may lead to a more targeted treatment. Deep phenotyping of ten preschool age at onset KH patients (boys, n = 5; girls, n = 5) was performed followed by trio exome sequencing and comprehensive bioinformatics analysis. Data analysis revealed four novel candidate genes: (1) NCOR1 in a patient with KH, iron deficiency and loose stools; (2) IGF2BP1 in a proband with KH, short stature and delayed bone age; (3) SLC5A2 in a proband with KH, intermittent glucosuria and extremely elevated p-GLP-1; and (4) NEK11 in a proband with ketotic hypoglycemia and liver affliction. These genes are associated with different metabolic processes, such as gluconeogenesis, translational regulation, and glucose transport. In conclusion, WES identified DNA variants in four different genes as potential novel causes of IKH, suggesting that IKH is a heterogeneous disorder that can be split into several novel diseases: NCOR1-KH, IGF2BP1-KH, SGLT2-KH or familial renal glucosuria KH, and NEK11-KH. Precision medicine treatment based on exome sequencing may lead to advances in the management of IKH.

    Fulltekst (pdf)
    FULLTEXT01
  • 271.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions2019Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, nr 1, s. 252-259Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).

    Fulltekst (pdf)
    FULLTEXT01
  • 272.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Kaialy, Waseem
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Computational predictions of glass-forming ability and crystallization tendency of drug molecules2014Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, nr 9, s. 3123-3132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.

  • 273.
    Alhalaweh, Amjad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alzghoul, Ahmad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, nr 1, s. 312-317Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.

    Fulltekst (pdf)
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  • 274.
    Alhalaweh, Amjad
    et al.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Taylor, Lynne S.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.2016Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, s. 172-182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.

  • 275.
    Alhamad, Dima W.
    et al.
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates..
    Elgendy, Sara M.
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates..
    Hersi, Fatema
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Med, Sharjah, U Arab Emirates..
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt..
    Omar, Hany A.
    Univ Sharjah, Sharjah Inst Med Res, Sharjah, U Arab Emirates.;Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates.;Beni Suef Univ, Fac Pharm, Dept Pharmacol & Toxicol, Bani Suwayf 62514, Egypt.;Univ Sharjah, Coll Pharm, Dept Pharm Practice & Pharmacotherapeut, Sharjah, U Arab Emirates..
    The inhibition of autophagy by spautin boosts the anticancer activity of fingolimod in multidrug-resistant hepatocellular carcinoma2022Inngår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 304, artikkel-id 120699Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The contribution of autophagy to drug resistance has been studied in several cancers. However, there is no clear evidence about the role of autophagy in the resistance to chemotherapy in cancers, such as hepatocellular carcinoma (HCC). HCC is characterized by a poor prognosis and limited therapeutic options. Moreover, the emergence of multidrug-resistance (MDR) hinders successful treatment. Therefore, understanding how autophagy is regulated in resistant HCC is essential for sensitizing this malignancy to chemotherapy. This work demonstrated that basal and induced autophagy differ between parental and resistant Hep3B cells. In optimum growth conditions, the basal level of autophagy was low in resistant Hep3B (Hep3B-R) cells compared to the wild-type Hep3B (Hep3B-P) cells. However, in metabolic or therapeutic stress conditions, the rate of autophagy flux was much faster in the resistant cells. The work also confirmed the pro-survival function of autophagy in HCC. Besides, it demonstrated that the autophagy inhibitor, spautin, acted synergistically with fingolimod (FTY720) to promote cell death. The combination treatment resulted in superior reactive oxygen species (ROS) production and significant induction of apoptosis. In addition, spautin potentiated the effect of FTY720 against cell survival pathways like the Akt and ERK. Interestingly, the results indicated that Hep3B-R cells were more sensitive to autophagy inhibition than their parental counterparts. Collectively, this work revealed that combining spautin with chemotherapeutic agents that induce cytoprotective autophagy such as FTY720 is a promising approach to overcome MDR in HCC.

  • 276.
    Alhanoun, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Elin Alhanoun.
    Vad har läkemedelskommittéerna för kunskaper omläkemedelspåverkan på miljön?: -En pilotstudie om kunskapsstöd2022Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [en]

    Background: The increased use of medicines in recent decades has affected the environmentand led to negative consequences. Environmental risk for a drug can be classified by using PBTindex and PEC / PNEC-ratio. Environmental risk information can be found on the knowledgesupport websites "medicines and the environment" at Janusinfo.se and in environmentalinformation at Fass.se. The Drug- and Therapeutics Committees (DTCs) ensure that medicinesare used in a correct and cost-effective manner and recommend medicines in annually updatedguidelines.

    Method: A survey was created and pilot-tested by 10 persons experienced from DTCs. Thequestionnaire consisted of four parts, general questions, questions about the use of theknowledge support "medicines and the environment" on janusinfo, questions about the use ofenvironmental information from Fass.se and other questions about environmental aspects.

    Result: In total, 9 out of 10 people who were included in the pilot study answered. Threerespondents had only positive feedback on the questionnaires. Some respondents thought thatthere were some questions and answers’ options that were not easy to understand and that somequestions could be answered only by people familiar with the subject.Conclusions:

    The conclusion is that the pilot study has led to many improvements in surveyquestions and approaches. In the future, further research is needed for knowledge about drugeffects in the environment. 

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  • 277.
    Alhariri, Batul
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Antipsykotiska läkemedel i relation till spel och impulskontrollstörningar i patienter med neurologiska sjukdomar2024Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Bakgrund: Det har visat sig under de senaste 20 åren att användning av aripiprazol ökar risken för spel- och impulskontrollstörningar. Aripiprazol är ett första generationens antipsykotiska läkemedel och fungerar som en partiell serotonin 5-HT1A-receptoragonist, en 5-HT2A-receptorantagonist och en specifik partiell dopamin D2/D3-agonist. 

    Syfte: Syftet är att studera hur förekomsten av spel- och impulskontrollstörningar skiljer sig mellan neurologiska patienter som får Aripiprazol respektive andra antipsykotiska läkemedel som komplement till behandling med Parkinsons sjukdom eller Restless Legs Syndrome. 

    Metoder: Detta är en retrospektiv registerstudie som analyserar läkemedelsdata som täcker åren 2005 till 2022 och patientdata som innehåller diagnoser för Parkinsons sjukdom och Restless Legs Syndrome samt spel- och impulskontrollstörningar. Data analyserades genom att mäta frekvensen av recept för att analysera antalet händelser av spelstörningar, impulskontrollstörningar och kontrollgrupper hos personer med Parkinsons sjukdom och Restless Legs Syndrome. 

    Resultat: Det finns en tydlig skillnad mellan de antipsykotiska läkemedlen. Första och andra generationens antipsykotika, inklusive litium, olanzapin, levomepromazin och aripiprazol, har visats vara associerade med störningar i spel och impulskontroll hos patienter med Parkinsons sjukdom och Restless Legs Syndrome. Aripiprazol visade sig ha det starkaste sambandet med störningar i impulskontroll och litium hade det starkaste sambandet med spelstörningar hos personer med Restless Legs Syndrome. Dessutom hade Levomepromazin det starkaste sambandet med störningar i impulskontroll och Olanzapin hade det starkaste sambandet med spelstörningar hos personer med Parkinsons sjukdom. 

    Slutsatser: Denna studie har konsekvenser för framtiden då den hjälper till att veta om det finns risk för spel- och impulskontrollstörningar vid användning av antipsykotiska läkemedel. Så det hjälper till att skapa maximal säkerhet för antipsykotiska läkemedel och hantera risken för spel- och impulskontrollstörningar på bästa möjliga sätt.

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  • 278. Alheim, K
    et al.
    Andersson, C
    Tingsborg, S
    Ziolkowska, M
    Schultzberg, M
    Bartfai, T
    Interleukin 1 expression is inducible by nerve growth factor in PC12 pheochromocytoma cells.1991Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 88, nr 20, s. 9302-6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Expression of the cytokine interleukin 1 alpha (IL-1 alpha) was demonstrated in the rat PC12 pheochromocytoma cell line by (i) immunohistochemistry using rabbit polyclonal antisera raised against the recombinant murine IL-1 alpha, (ii) an ELISA, and (iii) a specific cell conversion bioassay based on the use of LBRM33-1A5 cells. IL-1 alpha mRNA was demonstrated in the PC12 cells, by PCR amplification. Constitutive expression of IL-1 alpha in PC12 cells was demonstrated in all experiments, although the cellular levels of IL-1 alpha-like immunoreactivity varied. The expression of IL-1 alpha, as studied at the mRNA level, was inducible by mouse nerve growth factor (7S NGF), and the gene product level was inducible in a dose- and time-dependent fashion by 7S NGF. The maximum induction corresponds to a 600% increase in IL-1 alpha-like immunoreactivity above the expression level found in noninduced cells and occurred after a 3-day incubation of the cells with NGF at 0.75 micrograms/ml of culture medium. The significance of the ability of NGF to induce IL-1 expression lies in the fact that IL-1 itself also acts as a growth factor that promotes glial proliferation and, even more importantly, IL-1 itself induces the expression of NGF at peripheral nerve injury [Lindholm, D., Heumann, R., Meyer, M. & Thoenen, H. (1987) Nature (London) 330, 658-659].

  • 279. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 5, artikkel-id 13312Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

    Fulltekst (pdf)
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  • 280.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015Inngår i: BMC Complementary and Alternative Medicine, E-ISSN 1472-6882, Vol. 15, artikkel-id 419Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

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  • 281. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 9, nr 11, artikkel-id e111118Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

    Fulltekst (pdf)
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  • 282.
    Alhomsi, Jezeel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Influence of a common pharmaceutical excipient on BCS-based biowaivers for oral drug products2024Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
  • 283.
    Ali, Arwa
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Gao, Menghan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Iskantar, Alexandros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wang, Hai
    Chinese Acad Sci, CAS Ctr Excellence Nanosci, Natl Ctr Nanosci & Technol, Key Lab Biomed Effects Nanomat & Nanosafety, Beijing, Peoples R China.;Univ Chinese Acad Sci, Beijing, Peoples R China..
    Karlsson-Parra, Alex
    Mendus AB, Stockholm, Sweden..
    Yu, Di
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Jin, Chuan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment2023Inngår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, artikkel-id 1146413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic a4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of a4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFN?(+) CD8(+) T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T-RM) CD8(+) T cells (CD103(+)CD49a(+)CD69(+)). The combination treatment also led to increased infiltration of CD39(+)CD103(+) tumor-specific CD8(+) T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic a4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

    Fulltekst (pdf)
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  • 284.
    Ali, Ehood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Harvard Medical school / Boston Children's Hospital.
    The Role of the Glycine Receptor’s Alpha 2Subunit in the Behavior of Mice2014Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
  • 285.
    Ali, Ersin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Framtida läkemedel bör rikta sig mot väldigt tidiga stadier av Alzheimers sjukdom2012Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
  • 286.
    Ali Haj, Mahmoud
    et al.
    United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Amir, Nahid
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nicholls, Gary M.
    Otago University .
    Adem, Abdu
    United Arab Emirates University.
    Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel2013Inngår i: BMC Veterinary Research, E-ISSN 1746-6148, Vol. 9, s. 232-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our objectives were to document and compare plasma levels of Catecholamines, Cortisol,Glutathione and Malondialdehyde in camels after long term dehydration (20 days) in the presenceor absence of angiotensin II AT1 receptor blocker (Losartan) versus levels in non-dehydratedcamels; and to record the effects on glutathione and malondialdehyde activity in liver and kidneyhomogenate in the one-humped camel. Eighteen male camels were used in this study, sixcontrols, six dehydrated and treated with losartan (5mg/kg daily) and six were dehydrated withouttreatment. Our results revealed significant decrease (P<0.05) in plasma epinephrine level in bothtreated and dehydrated camels; while, Plasma norepinephrine showed significant increase in bothdehydrated groups (P< 0.01). Levels of plasma dopamine were also significantly increased (P<0.01) in both dehydrated groups compared to control camels.Plasma levels of cortisol increased significantly across dehydration with or without losartanadministration (P<0.01) compared with time-matched levels in control camels. Losartan had nosignificant modulating effect on the cortisol response to dehydration.Plasma, liver and kidney homogenates revealed significant increase (P<0.05) in glutathione levelsin both dehydrated groups compared to control.Plasma, liver and kidney homogenates for malondialdehyde levels in both treated and dehydratedcamels also showed significant increase (P<0.05 & P<0.01) compared to controls.In conclusion, our study demonstrates that the effect of dehydration with or without losartaninduced oxidative stress in these camels, leading to significant changes in plasma catecholaminesand cortisol levels, together with significant increments in glutathione and malondialdehydeactivities in plasma, liver and kidney homogenate to counter act the damaging effect of the freeradicals in the dehydrated camels.

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  • 287.
    Ali, Lana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Formulation development of novel antimicrobial peptides to be used in rapid antimicrobial susceptibility testing (AST)2023Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    Emerging resistance to antimicrobials is a global crisis driven by the overuse of antibiotics and diagnostic uncertainty, therefore reliable assays for rapid identification of bacteria and antimicrobial susceptibility testing are important. 

    In this study, five antimicrobial peptides (AMPs) received from the Pharmacognosy research group were tested in rapid antimicrobial susceptibility testing, ASTar®. The aim was to study the stability of these peptides and develop a formulation intended for AST Disc to be used in ASTar. The stability of the peptides were investigated using high- performance liquid chromatography at different temperatures over time. Antibacterial assays with various approaches were performed to evaluate the antibacterial activity and use as a reference for ASTar. This was followed by AST Disc manufacturing loaded with AMPs in various concentrations. 

    Antimicrobial susceptibility testing by ASTar resulted in a minimum inhibitory concentration (MIC) of 40 μM of LRS-21 against E. coli using the algorithm. However, the algorithm was not applicable to all AMPs and once the normalization formula was applied it resulted in MIC of 20 μM of LL-37 against E. coli and 80 μM against S. aureus. No antibacterial activity was exhibited in ASTar for the three remaining peptides (MIC>160 μM) against E. coli and S. aureus. 

    These findings show that antimicrobial peptides can be tested using ASTar however the current algorithm is not applicable to all AMPs. The results of the thesis could be used for time-effective research of other AMPs, to understand their effectiveness against different bacterial strains, as they are of pharmaceutical interest, especially since the emergence of antibiotic resistance. 

  • 288.
    Ali, Muhammad Akhtar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Understanding Cancer Mutations by Genome Editing2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Mutational analyses of cancer genomes have identified novel candidate cancer genes with hitherto unknown function in cancer. To enable phenotyping of mutations in such genes, we have developed a scalable technology for gene knock-in and knock-out in human somatic cells based on recombination-mediated construct generation and a computational tool to design gene targeting constructs. Using this technology, we have generated somatic cell knock-outs of the putative cancer genes ZBED6 and DIP2C in human colorectal cancer cells. In ZBED6-/- cells complete loss of functional ZBED6 was validated and loss of ZBED6 induced the expression of IGF2. Whole transcriptome and ChIP-seq analyses revealed relative enrichment of ZBED6 binding sites at upregulated genes as compared to downregulated genes. The functional annotation of differentially expressed genes revealed enrichment of genes related to cell cycle and cell proliferation and the transcriptional modulator ZBED6 affected the cell growth and cell cycle of human colorectal cancer cells. In DIP2C-/-cells, transcriptome sequencing revealed 780 differentially expressed genes as compared to their parental cells including the tumour suppressor gene CDKN2A. The DIP2C regulated genes belonged to several cancer related processes such as angiogenesis, cell structure and motility. The DIP2C-/-cells were enlarged and grew slower than their parental cells. To be able to directly compare the phenotypes of mutant KRAS and BRAF in colorectal cancers, we have introduced a KRASG13D allele in RKO BRAFV600E/-/-/ cells. The expression of the mutant KRAS allele was confirmed and anchorage independent growth was restored in KRASG13D cells. The differentially expressed genes both in BRAF and KRAS mutant cells included ERBB, TGFB and histone modification pathways. Together, the isogenic model systems presented here can provide insights to known and novel cancer pathways and can be used for drug discovery.

    Delarbeid
    1. Computational and molecular tools for scalable rAAV mediated genome editing
    Åpne denne publikasjonen i ny fane eller vindu >>Computational and molecular tools for scalable rAAV mediated genome editing
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The rapid discovery of potential driver mutations through large scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV) mediated gene targeting is particularly suited to knock-in of single nucleotide substitutions. However, the generation of gene targeting constructs and the targeting process is time consuming and labor-intense. To facilitate rAAV mediated gene targeting, we developed the first software and complementary automation friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing ~72% of bases in protein-coding exons were designed. Similarly, ~81% of genes were predicted to be targetable by rAAV mediated knock-out. A Gateway based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-235563 (URN)
    Tilgjengelig fra: 2014-11-05 Laget: 2014-11-05 Sist oppdatert: 2018-01-11
    2. The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Åpne denne publikasjonen i ny fane eller vindu >>The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cells
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-235564 (URN)
    Tilgjengelig fra: 2014-11-05 Laget: 2014-11-05 Sist oppdatert: 2018-01-11
    3. DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Åpne denne publikasjonen i ny fane eller vindu >>DIP2C regulates expression of the tumor suppressor gene CDKN2A
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized candidate

    breast and lung cancer gene. The gene contains a DMAP1 binding domain, pointing to

    potential involvement in DNMT1-dependent methylation. To study the role of DIP2C in

    tumor development, we engineered human DIP2C knockout cell systems by rAAV-mediated

    gene targeting. Homo- and heterozygous RKO DIP2C knockout cells displayed enlarged cells

    and growth retardation. This phenotype was most pronounced in DIP2C-/- knockouts, and

    these cells also displayed a significant decrease in DIP2C mRNA levels. RNA sequencing

    revealed 780 genes affected by the loss of DIP2C, including the cellular senescence marker

    P16INK4a. Functional annotation of the regulated genes shows enrichment of genes involved

    with cell death processes, cell structure and motility. Furthermore, KEGG pathway analysis

    shows association of 19 genes with pathways in cancer. In conclusion, the phenotypic data

    and expression changes induced by loss of DIP2C indicate that the gene function may be

    important for several biological processes implicated in cancer, and that loss of gene function

    may be a trigger of cellular senescence.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-235565 (URN)
    Tilgjengelig fra: 2014-11-05 Laget: 2014-11-05 Sist oppdatert: 2018-01-11
    4. Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    Åpne denne publikasjonen i ny fane eller vindu >>Core Ras Pathway Signaling in Human Colorectal Cancers Revealed by Isogenic Modeling of NF1, KRAS and BRAF Mutations
    2012 (engelsk)Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, nr Suppl.5, s. S118-S118Artikkel i tidsskrift, Meeting abstract (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-194476 (URN)10.1016/S0959-8049(12)71162-0 (DOI)000313036501006 ()
    Konferanse
    22nd Biennial Congress of the European-Association-for-Cancer-Research, JUL 07-10, 2012, Barcelona, SPAIN
    Tilgjengelig fra: 2013-02-15 Laget: 2013-02-14 Sist oppdatert: 2017-12-06bibliografisk kontrollert
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  • 289.
    Ali, Muhammad Akhtar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Younis, Shady
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wallerman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gupta, Rajesh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tobias Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The transcriptional modulator ZBED6 regulates cell cycle and growth of human colorectal cancer cellsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The transcription factor ZBED6 is a repressor of IGF2 whose action impacts development, cell proliferation and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Transcriptome analyses revealed enrichment of cell cycle-related processes among differentially expressed genes in both cell lines. Chromatin immunoprecipitation sequencing analyses displayed enrichment of ZBED6 binding at genes upregulated in ZBED6-/- knockout clones. Ten differentially expressed genes were identified as putative direct gene targets and their downregulation by ZBED6 was experimentally validated. Eight of these genes were linked to the Wnt, Hippo, TGF-b, EGFR or PI3K pathways, all involved in colorectal cancer development. Ablation of ZBED6 affected the cell cycle and led to increased growth rate of ZBED6-/- RKO cells. These observations support a role for transcriptional modulation by ZBED6 in cell cycle regulation and growth of colorectal cancers.

  • 290.
    Ali, Muhammad Ilyas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Characterization of binding kinetics of TetraSynO2 and HexaSynO2 to α-synuclein oligomers2022Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
    Abstract [en]

    α-synuclein is a 140 amino acid protein, abundant in the brain and its physiological concentration regulates neurotransmitter release. The disturbance in balance between generation and clearance of α-synuclein lead to aggregation of α-synuclein monomers into oligomers which play a key role in pathogenesis and progression of Parkinson’s disease (PD). PD is the second most common neurodegenerative disease and is estimated to affect 2% of the population at the age of 60 and above.  Immunotherapy is one of the promising approaches to treat PD and various monoclonal antibodies have been developed to target α-synuclein oligomers. SynO2, an IgG antibody is one such antibody which showed high binding affinity towards α-synuclein oligomers and fibrils. To treat the disease in early phase small α-synuclein oligomer is a potential target to prevent them from further aggregation. But bivalent IgG antibodies, because of a large spatial distance between their two arms, are unable to bind to small α-synuclein oligomers with avidity. To enhance the avidity and binding potential of the bivalent antibody SynO2, multivalent antibodies were designed where two and four single chain fragment variables (scFv) were fused on the binding site of the antibody to produce TetraSynO2 and HexaSynO2, respectively. Purpose of this study was to characterize the binding kinetics of TetraSynO2 and HexaSynO2 to α-synuclein oligomers. Recombinant Antibodies were produced using Expi293 system and were purified via affinity purification using Protein G column. Size of purified SynO2, TetraSynO2 and HexaSynO2 were 150 kDa, 201 kDa and 250 kDa, respectively and were stable when analysed via thermal stability assay. α-synuclein oligomers for usage in various binding assays were prepared and characterized. Different ELISA setups and real time interaction studies using LigandTracer were applied to study the avidity of SynO2 and binding kinetics of TetraSynO2 and HexaSynO2. The results showed that SynO2 binds much stronger than SynO2 Fab indicating that SynO2 binds with avidity. Cross reactivity with other amyloid proteins showed that SynO2 and HexaSynO2 had mild cross reactivity to amyloid beta. Furthermore, binding kinetics revealed that HexaSynO2 had increased binding strength with avidity to α-synuclein oligomers than SynO2 and TetraSynO2, which was attributed to the lower dissociation rate of HexaSynO2. In conclusion, multivalent antibodies showed stronger binding potential with avidity to α-synuclein oligomers compared to the bivalent antibody and provides a promising design for future intervention in diagnosis and treatment of PD. 

    Fulltekst tilgjengelig fra 2044-06-30 14:17
  • 291.
    Ali, Suzann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of lithium and clozapine on tryptophan membrane transport in human fibroblasts in the presence of proinflammatory cytokines2021Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Neuropsychiatry is a medical field including a range of disorders that are associated with an impairment of the serotonergic and dopaminergic pathways, amongst others schizophrenia, bipolar- and major depressive disorder. Serotonin synthesis depends on cerebral availability of its amino acid precursor tryptophan, which is transported through the blood-brain barrier by isoforms of system-L and system-A. Variability of tryptophan transport is proposed as a cause for the monoamine synthesis alteration. Furthermore, a reduced amino acid uptake into different cerebral regions in presence of proinflammatory cytokines is among the suggested mechanisms causing major depressive disorder.   

    Lithium and clozapine are used in the treatment of schizophrenia and bipolar disorder. Clozapine is an atypical antipsychotic drug, often clinically combined with the mood stabilizer lithium, whose mechanism of action is incompletely elucidated. The aim of the study was to examine the effect of lithium and clozapine, separately and in combination- on tryptophan uptake into fibroblast cell-lines from healthy volunteers, in presence of proinflammatory cytokines, specifically IL-1β.

    Fibroblast cell-lines from healthy volunteers were utilized as an experimental model for the blood-brain barrier. The cells were treated with IL-Iβ, IL-1Ra (IL-Iβ antagonist), lithium, and clozapine in various constellations. Uptake of 14C-L-tryptophan across fibroblast cellular membranes was measured using the cluster tray method. Obtained results demonstrate an anti-inflammatory effect caused by lithium administration in fibroblast cell-lines from healthy individuals. Further investigations are required to draw a definitive conclusion about lithium's anti-inflammatory effect in healthy cell lines, and in patient cell lines.

  • 292.
    Ali, Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ullah, Farid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Khan, Ayaz
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Abdullah, Uzma
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features2017Inngår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 18, nr 1, artikkel-id 144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.

    CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.

    CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

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  • 293.
    Al-Ibraheemi, Selvana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    En litteraturgenomgång av kodningsmanualer för patient-farmaceutkommunikation2022Independent thesis Basic level (professional degree), 180 hpOppgave
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    fulltext
  • 294.
    Al-ikabi, Mohammed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Developing Inhibitors Against the SARS-CoV-2 Main Protease (MPro)2022Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    COVID-19, the disease caused by the SARS-CoV-2 virus, was first identified in 2019 and spread rapidly, leading to a global pandemic. Over 528,7 million cases have been reported worldwide, alongside 6.2 million deaths. There have been two earlier coronavirus outbreaks; SARS in 2002, and MERS in 2012, but treatment for these diseases remains limited. This shows a clear need for the development of treatments, not only for the current, but also possible future coronavirus outbreaks. While vaccines exist for the current coronavirus, many individuals cannot take them, so the preparation of antiviral agents remains important.

    Small molecule drugs are an attractive alternative for when vaccines are not available or feasible. An appealing target is the coronavirus main protease (MPro). MPro’s biological role is to cleave the viruses two non-functional polyproteins and is therefore important for viral proliferation. Furthermore, it has different selectivity than any known human protease enzymes making it a promising drug target. It was discovered that the Mpro of SARS-CoV and SARS-CoV-2 share 96% sequence identity, making previously explored SARS-CoV Mpro inhibitors a good starting point for drug development.

    ML188 is an Mpro inhibitor that can be synthesized by the Ugi reaction, and a range of analogues have been evaluated in the Moodie group by changing the P1’, P1, P2, and P3 positions. While there were improvements to ML188, there became a problem with the molecules becoming too lipophilic. At the P3 position, there was a plan to include heterocycles to increase polarity and potency, but the corresponding isocyanides needed for the Ugi reaction proved difficult to synthesize. The strategy in this project was to use a dummy isocyanide, which could be removed after the Ugi reaction to unveil a carboxylic acid group at P3. Then standard amide couplings could be used to explore previously inaccessible P3 analogues. Due to the unexplored nature of the chemistry of the synthesis, an optimization process was used at every step. Different conditions, including solvents, temperature, reagent, work up conditions, and reaction durations were investigated. Inividual reactions were evaluated and compared by documenting yields and comparing purity in NMR and LC-MS.

    The first main target for the optimization was the cleavable ugi product. The required dummy 6-bromo-2-isocyanopyridine was made in two steps. First by N-formylation, and then dehydration with POCl3 to create the isocyanide group. The Ugi reaction was then conducted to make an analogue with the same P1, P1l and P2 groups as ML188. During the optimization of this reaction, it was found that using the solvent 2,2,2-trifluoroethanol resulted in a productof increased purity. Cleavage of the dummy group was performed with different reaction durations and temperatures, and a range of purification conditions were explored. This method provides high purity carboxylic acid that will be used for amide coupling to create new P3 analogues. Developing methodology to alter the largely unexplored P3 group of ML188 is a crucial step to synthesize new ML188 analogues. This work could potentially lead to drugs with stronger inhibitory effects on Mpro and therefore coronavirus viralproliferation. Because of the similarities between coronavirus Mpro’s, these compounds may also be effective against future coronaviruses.

  • 295.
    Alim, Abdul
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin. Public Health and Caring Sciences.
    Mechanisms in Tendon Healing: Pain, Biomarkers and the Role of Mast Cells2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Tendon injuries and tendinopathy are common disorders, but the underlying mechanisms are not well understood. The overall aim of this thesis was to better understand the mechanisms underlying tendon healing, pain, and inflammation.

    The aim of the first study was to assess biomarkers of tendon healing, including procollagen type I (PINP) and type III (PIIINP) in relation to patient outcome in 65 patients with Achilles tendon rupture (ATR). At two weeks post-ATR, PINP and PIIINP-levels were quantified using microdialysis followed by ELISA. At one-year post-ATR patient outcome was assessed using the validated Achilles tendon Total Rupture Score. We found that higher ratio of PINP and PIIINP to total protein were significantly associated with less pain but more fatigue in the affected limb.

    In the second study, we applied Intermittent Pneumatic Compression (IPC) therapy for two weeks to stimulate tendon healing. The patients received either adjuvant IPC treatment or treatment-as-usual in a plaster cast without IPC. We observed that IPC therapy significantly increased PINP levels in the injured tendon, suggesting enhanced healing response.

    In our third study, we investigated healing response and the role of mast cells (MCs) in-vivo using an ATR rat model. Three weeks postoperatively, we demonstrated an increased number of MCs and a higher proportion of degranulated MCs in the injured tendon compared to the control. We further established that MCs in the injured tendon were positive for the glutamate receptor NMDAR1.

    In our final study, we assessed the effect of glutamate stimulation on in-vitro-derived mouse bone marrow MCs. Mast cell degranulation was quantified through β-hexosaminidase release, immunofluorescence was used to quantify NMDARs at the protein level, and RT-qPCR/microarray was used to study the expression of NMDARs and associated genes. Glutamate induced a robust upregulation of glutamate receptors of both ionotropic and metabotropic type, both at the mRNA and at protein level. NMDAR1 co-localized with glutamate in the membrane of MCs, thereby confirming an interaction between glutamate and its receptor. Glutamate also induced expression of pro-inflammatory compounds such as IL-6 and CCL2 and transcription factors such as Egr2, Egr3 and FosB. Moreover, the NMDA-channel blocker MK-801 completely abrogated the response of MCs to glutamate, supporting a functional glutamate–glutamate receptor axis in MCs.

    Together, findings presented in this dissertation reveal possible mechanisms of tendon healing in relation to pain and function, and establish a novel principle for how immune cells can communicate with nerve cells after ATR.

    Delarbeid
    1. Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture.
    Åpne denne publikasjonen i ny fane eller vindu >>Procollagen markers in microdialysate can predict patient outcome after Achilles tendon rupture.
    2016 (engelsk)Inngår i: BMJ open sport & exercise medicine, ISSN 2055-7647, Vol. 2, nr 1, artikkel-id e000114Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: Patients who sustain acute Achilles tendon rupture (ATR) exhibit variable and mostly impaired long-term functional, and patient-reported outcomes. However, there exists a lack of early predictive markers of long-term outcomes to facilitate the development of improved treatment methods. The aim of this study was to assess markers of tendon callus production in patients with ATR in terms of outcome, pain, and fatigue.

    STUDY DESIGN AND SETTING: Prospective cohort study; level of evidence 2. Outpatient orthopaedic/sports medicine department.

    PATIENTS: A total of 65 patients (57 men, 8 women; mean age 41±7 years) with ATR were prospectively assessed.

    ASSESSMENTS: Markers of tendon callus production, procollagen type I N-terminal propeptide (PINP) and procollagen type III N-terminal propeptide (PIIINP), were assessed 2 weeks postoperatively using microdialysis followed by enzymatic quantification. Normalised procollagen levels (n-PINP and n-PIIINP) were calculated as the ratio of procollagen to total protein content. Pain and fatigue were assessed at 1 year using reliable questionnaires Achilles tendon Total Rupture Score (ATRS).

    RESULTS: Patients exhibited fatigue (77.6%) and pain (44.1%) to some extent. Higher levels of n-PINP (R=0.38, p=0.016) and n-PIIINP (R=0.33, p=0.046) were significantly associated with less pain in the limb. Increased concentrations of PINP (R=-0.47, p=0.002) and PIIINP (R=-0.37, p=0.024) were related to more self-reported fatigue in the leg. The results were corroborated by multiple linear regression analyses.

    CONCLUSIONS: Assessment of procollagen markers in early tendon healing can predict long-term patient-reported outcomes after ATR. These novel findings suggest that procollagen markers could be used to facilitate the development of improved treatment methods in patients who sustain ATR.

    TRIAL REGISTRATION NUMBERS: NCT01317160: Results. NCT02318472: Pre-results.

    sted, utgiver, år, opplag, sider
    London, UK: , 2016
    Emneord
    Achilles, Chronic, Collagen, Injuries, Tendon
    HSV kategori
    Forskningsprogram
    Ortopedi
    Identifikatorer
    urn:nbn:se:uu:diva-395018 (URN)10.1136/bmjsem-2016-000114 (DOI)27900179 (PubMedID)
    Tilgjengelig fra: 2019-10-11 Laget: 2019-10-11 Sist oppdatert: 2020-02-19bibliografisk kontrollert
    2. Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis
    Åpne denne publikasjonen i ny fane eller vindu >>Achilles tendon rupture healing is enhanced by intermittent pneumatic compression upregulating collagen type I synthesis
    Vise andre…
    2018 (engelsk)Inngår i: Knee Surgery, Sports Traumatology, Arthroscopy, ISSN 0942-2056, E-ISSN 1433-7347, Vol. 26, nr 7, s. 2021-2029Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    PURPOSE AND HYPOTHESIS: Adjuvant intermittent pneumatic compression (IPC) during leg immobilization following Achilles tendon rupture (ATR) has been shown to reduce the risk of deep venous thrombosis. The purpose of this study was to investigate whether IPC can also promote tendon healing.

    METHODS: One hundred and fifty patients with surgical repair of acute ATR were post-operatively leg immobilized and prospectively randomized. Patients were allocated for 2 weeks of either adjuvant IPC treatment (n = 74) or treatment-as-usual (n = 74) in a plaster cast without IPC. The IPC group received 6 h daily bilateral calf IPC applied under an orthosis on the injured side. At 2 weeks post-operatively, tendon healing was assessed using microdialysis followed by enzymatic quantification of tendon callus production, procollagen type I (PINP) and type III (PIIINP) N-terminal propeptide, and total protein content. 14 IPC and 19 cast patients (control group) consented to undergo microdialysis. During weeks 3-6, all subjects were leg-immobilized in an orthosis without IPC. At 3 and 12 months, patient-reported outcome was assessed using reliable questionnaires (ATRS and EQ-5D). At 12 months, functional outcome was measured using the validated heel-rise test.

    RESULTS: At 2 weeks post-rupture, the IPC-treated patients exhibited 69% higher levels of PINP in the ruptured Achilles tendon (AT) compared to the control group (p = 0.001). Interestingly, the IPC-treated contralateral, intact AT also demonstrated 49% higher concentrations of PINP compared to the non-treated intact AT of the plaster cast group (p = 0.002). There were no adverse events observed associated with IPC. At 3 and 12 months, no significant (n.s.) differences between the two treatments were observed using patient-reported and functional outcome measures.

    CONCLUSIONS: Adjuvant IPC during limb immobilization in patients with ATR seems to effectively enhance the early healing response by upregulation of collagen type I synthesis, without any adverse effects. Whether prolonged IPC application during the whole immobilization period can also lead to improved long-term clinical healing response should be further investigated. The healing process during leg immobilization in patients with Achilles tendon rupture can be improved through adjuvant IPC therapy, which additionally prevents deep venous thrombosis.

    LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

    Emneord
    Achilles tendon rupture, Intermittent pneumatic compression devices, Microdialysis, Procollagen, Regeneration
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-395017 (URN)10.1007/s00167-017-4621-8 (DOI)28668970 (PubMedID)
    Tilgjengelig fra: 2019-10-11 Laget: 2019-10-11 Sist oppdatert: 2020-02-19bibliografisk kontrollert
    3. Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
    Åpne denne publikasjonen i ny fane eller vindu >>Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture
    Vise andre…
    2017 (engelsk)Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 451-460Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

    sted, utgiver, år, opplag, sider
    Berlin Heidelberg: , 2017
    Emneord
    Achilles tendon healing, Mast cells, NMDA, Rats, Tryptase
    HSV kategori
    Forskningsprogram
    Ortopedi; Immunologi
    Identifikatorer
    urn:nbn:se:uu:diva-395522 (URN)10.1007/s00441-017-2684-y (DOI)000416358400010 ()28975451 (PubMedID)
    Tilgjengelig fra: 2019-10-20 Laget: 2019-10-20 Sist oppdatert: 2020-02-06bibliografisk kontrollert
    4. Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
    Åpne denne publikasjonen i ny fane eller vindu >>Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells
    Vise andre…
    2021 (engelsk)Inngår i: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 18, nr 10, s. 2383-2392Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

    sted, utgiver, år, opplag, sider
    Springer Nature, 2021
    Emneord
    Glutamate, Glutamate receptors, Mast cells, NMDA receptors, Tryptase
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-434116 (URN)10.1038/s41423-020-0421-z (DOI)000527501500001 ()32313211 (PubMedID)
    Forskningsfinansiär
    AFA InsuranceSwedish Research CouncilSwedish Cancer SocietyThe Swedish Heart and Lung AssociationKnut and Alice Wallenberg Foundation
    Tilgjengelig fra: 2021-02-05 Laget: 2021-02-05 Sist oppdatert: 2023-07-14bibliografisk kontrollert
    Fulltekst (pdf)
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    presentationsbild
  • 296.
    Alim, Abdul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Grujic, Mirjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ackerman, Paul W
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Kristiansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Eliasson, Pernilla
    Department of Orthopedics and Sports Medicine, Linköping University, Linköping, Sweden.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells2021Inngår i: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 18, nr 10, s. 2383-2392Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate-glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate-glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

    Fulltekst (pdf)
    fulltext
  • 297.
    Alim, Abdul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin. Acad Primary Hlth Care, Reg Uppsala, Uppsala, Sweden..
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75651 Uppsala, Sweden..
    Do Mast Cells Have a Role in Tendon Healing and Inflammation?2020Inngår i: Cells, E-ISSN 2073-4409, Vol. 9, nr 5, artikkel-id 1134Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Understanding the links between the tendon healing process, inflammatory mechanisms, and tendon homeostasis/pain after tissue damage is crucial in developing novel therapeutics for human tendon disorders. The inflammatory mechanisms that are operative in response to tendon injury are not fully understood, but it has been suggested that inflammation occurring in response to nerve signaling, i.e., neurogenic inflammation, has a pathogenic role. The mechanisms driving such neurogenic inflammation are presently not clear. However, it has recently been demonstrated that mast cells present within the injured tendon can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling and thereby modulate neurogenic inflammation following tissue injury. In this review, we discuss the role of mast cells in the communication with peripheral nerves, and their emerging role in tendon healing and inflammation after injury.

    Fulltekst (pdf)
    FULLTEXT01
  • 298.
    Alim, Md Abdul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin. Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Ackermann, Paul W
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.
    Eliasson, Pernilla
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Blomgran, Parmis
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Kristiansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Increased mast cell degranulation and co-localization of mast cells with the NMDA receptor-1 during healing after Achilles tendon rupture2017Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 370, nr 3, s. 451-460Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of inflammation and the mechanism of tendon healing after rupture has historically been a matter of controversy. The purpose of the present study is to investigate the role of mast cells and their relation to the NMDA receptor-1 (a glutamate receptor) during healing after Achilles tendon rupture. Eight female Sprague Dawley rats had their right Achilles tendon transected. Three weeks after rupture, histological quantification of mast cell numbers and their state of degranulation was assessed by histochemistry. Co-localization of mast cell tryptase (a mast cell marker) and NMDA receptor-1 was determined by immunofluorescence. The intact left Achilles tendon was used as control. An increased number of mast cells and a higher proportion of degranulated mast cells were found in the healing Achilles tendon compared to the intact. In addition, increased co-localization of mast cell tryptase and NMDA receptor-1 was seen in the areas of myotendinous junction, mid-tendon proper and bone tendon junction of the healing versus the intact tendon. These findings introduce a possible role for mast cells in the healing phase after Achilles tendon rupture.

    Fulltekst (pdf)
    fulltext
  • 299.
    Alimohammadi, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Molecular Targets in Autoimmune Polyendocrine Syndrome Type1 and Their Clinical Implications2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Autoimmunity is known to cause a wide range of disorders, and is suspected to be responsible for many more. Most autoimmune disorders are chronic and cause severe morbidity for the patients, and are also costly for society. A majority of these disorders are today considered as complex diseases with incompletely known etiology. Hence, model systems for studying the pathogenesis of autoimmunity are important to unravel its causes.

    Autoimmune Polyendocrine Syndrome Type 1 (APS-1), (OMIM 240300), is a rare autoimmune disorder. Patients with APS-1 progressively develop multiple organ-specific autoimmune lesions involving both endocrine and non endocrine tissues. Typical autoimmune disease components in APS-1 are hypoparathyroidism, Addison’s disease, vitiligo, alopecia and type 1 diabetes. The gene preventing APS-1 has been identified and designated Autoimmune Regulator (AIRE). It has been shown that mutations of AIRE cause loss of tolerance to self-structures, resulting in organ-specific autoimmunity.

    Although APS-1 is a rare syndrome occurring mainly in genetically isolated populations, the disease components of APS-1 are, in isolated forms, not unusual in the general population and affect many patients. Hence, APS-1 is an attractive model disease for studies of molecular mechanisms underlying organ-specific autoimmunity.

    This thesis concerns investigations in which two novel autoantigens are identified in APS-1 and used in serological diagnosis of the disease. NALP5, is identified as a parathyroid autoantigen - an important finding since autoimmune hypoparathyroidism is one of the cardinal symptoms of APS-1. Additionally, KCNRG is identified as a bronchial autoantigen in APS-1 patients with respiratory symptoms. Finally, studies that compare the immune response in APS-1 patients and the mouse model for APS-1 are presented.

    Delarbeid
    1. Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients
    Åpne denne publikasjonen i ny fane eller vindu >>Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients
    Vise andre…
    2006 (engelsk)Inngår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, nr 2, s. 96-104Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.

    Emneord
    APS1, Autoantigen, Autoimmune regulator, Knock-out mouse
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98037 (URN)10.1016/j.jaut.2006.06.001 (DOI)000241661500004 ()16820279 (PubMedID)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2020-11-04bibliografisk kontrollert
    2. Autoimmune Polyendocrine Syndrome Type 1: NALP5 in Autoimmune Polyendocrine Syndrome Type 1
    Åpne denne publikasjonen i ny fane eller vindu >>Autoimmune Polyendocrine Syndrome Type 1: NALP5 in Autoimmune Polyendocrine Syndrome Type 1
    Vise andre…
    2006 (engelsk)Inngår i: The New England Journal of Medicine, Vol. 358, nr 10, s. 1018-28Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients with APS-1, the autoantigen responsible for hypoparathyroidism, a hallmark of APS-1 and its most common autoimmune endocrinopathy, has not yet been identified.

    Methods We performed immunoscreening of a human parathyroid complementary DNA library, using serum samples from patients with APS-1 and hypoparathyroidism, to identify patients with reactivity to the NACHT leucine-rich-repeat protein 5 (NALP5). Subsequently, serum samples from 87 patients with APS-1 and 293 controls, including patients with other autoimmune disorders, were used to determine the frequency and specificity of autoantibodies against NALP5. In addition, the expression of NALP5 was investigated in various tissues.

    Results NALP5-specific autoantibodies were detected in 49% of the patients with APS-1 and hypoparathyroidism but were absent in all patients with APS-1 but without hypoparathyroidism, in all patients with other autoimmune endocrine disorders, and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells.

    Conclusions NALP5 appears to be a tissue-specific autoantigen involved in hypoparathyroidism in patients with APS-1. Autoantibodies against NALP5 appear to be highly specific and may be diagnostic for this prominent component of APS-1.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98038 (URN)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2009-09-29bibliografisk kontrollert
    3. NALP5 - a Target for Autoantibodies in AIRE Deficient Mice Reflecting the Autoimmune Status
    Åpne denne publikasjonen i ny fane eller vindu >>NALP5 - a Target for Autoantibodies in AIRE Deficient Mice Reflecting the Autoimmune Status
    Vise andre…
    (engelsk)Manuskript (Annet vitenskapelig)
    Identifikatorer
    urn:nbn:se:uu:diva-98039 (URN)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2020-11-04bibliografisk kontrollert
    4. Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen
    Åpne denne publikasjonen i ny fane eller vindu >>Pulmonary Autoimmunity as a Feature of Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial Autoantigen
    Vise andre…
    2009 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 11, s. 4396-4401Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Patients with autoimmune polyendocrine syndrome type 1 (APS-1) suffer from multiple organ-specific autoimmunity with autoantibodies against target tissue-specific autoantigens. Endocrine and nonendocrine organs such as skin, hair follicles, and liver are targeted by the immune system. Despite sporadic observations of pulmonary symptoms among APS-1 patients, an autoimmune mechanism for pulmonary involvement has not been elucidated. We report here on a subset of APS-1 patients with respiratory symptoms. Eight patients with pulmonary involvement were identified. Severe airway obstruction was found in 4 patients, leading to death in 2. Immunoscreening of a cDNA library using serum samples from a patient with APS-1 and obstructive respiratory symptoms identified a putative potassium channel regulator (KCNRG) as a pulmonary autoantigen. Reactivity to recombinant KCNRG was assessed in 110 APS-1 patients by using immunoprecipitation. Autoantibodies to KCNRG were present in 7 of the 8 patients with respiratory symptoms, but in only 1 of 102 APS-1 patients without respiratory symptoms. Expression of KCNRG messenger RNA and protein was found to be predominantly restricted to the epithelial cells of terminal bronchioles. Autoantibodies to KCNRG, a protein mainly expressed in bronchial epithelium, are strongly associated with pulmonary involvement in APS-1. These findings may facilitate the recognition, diagnosis, characterization, and understanding of the pulmonary manifestations of APS-1.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-98040 (URN)10.1073/pnas.0809986106 (DOI)000264278800062 ()19251657 (PubMedID)
    Tilgjengelig fra: 2009-02-11 Laget: 2009-02-11 Sist oppdatert: 2022-01-28bibliografisk kontrollert
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    FULLTEXT01
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    COVER01
  • 300.
    Alimohammadi, Mohammad
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Rostedt Punga, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Neurophysiological Measures of Efficacy and Safety for Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations2017Inngår i: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 9, nr 11, artikkel-id 352Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.

    Fulltekst (pdf)
    fulltext
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