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  • 201. Abrahamsson, B
    et al.
    Lennernas, H
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Application of the biopharmaceutic classification system now and in the future2003Ingår i: Drug Bioavailability – Estimation of Solubility, Permeability, Absorption and Bioavailability, Wiley , 2003Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 202.
    Abrahamsson, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för forskning om funktionshinder.
    Ihop eller isär?: samarbete mellan personal i skola och boende för barn med autism: en förundersökning1993Rapport (Övrigt vetenskapligt)
  • 203.
    Abrahamsson, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Biopharmaceutical aspects of extended release tablets based on the hydrophilic matrix principle 1997Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 204. Abrahamsson, Christina
    et al.
    Ahlund, Catherine
    Nordlander, Margareta
    Lind, Lars
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A method for heart rate-corrected estimation of baroreflex sensitivity.2003Ingår i: J Hypertens, ISSN 0263-6352, Vol. 21, nr 11, s. 2133-40Artikel i tidskrift (Refereegranskat)
  • 205.
    Abrahamsson, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Logopedi.
    Quick, Linnéa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Logopedi.
    Datorbaserad fonologisk lästräning för barn med hörselnedsättning: En undersökning av fonologisk medvetenhet och ordavkodning2015Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Randomized controlled trials evaluating the effect of various forms of literacy training with reliable tests are lacking in Sweden today. The aim of the present study was to investigate whether a cross-over design and the use of phonologically matched wordlists specifically designed to detect transfer, would yield a more thorough method and reliable results. Six children with hearing impairment using hearing aids between 7 and 9 years of age took part in the study. The schools in which the children had their education were randomized into either an intervention group that started to practice phonics by means of a computer-assisted program after the first testing, or a control group that, continued as usual in school. Children were informed to practice daily with the program during four weeks in school. Children were tested with a battery of tests for phonological awareness, letter knowledge and word decoding at three occasions separated by four weeks. Results showed that the wordlists seemed reliable in establishing children’s decoding strategies as well as how word length affected reading speed. Both children who took part in the intervention and the control group improved their scores at the second testing. Thus, the computer-assisted reading intervention did not prove to be more effective than usual school activities. Due to a small number of participants, a large heterogeneity of the group and insufficient practice time, effects were difficult to detect. The present investigation should be considered a pilot study towards the use of more careful testing methods with adapted wordlists that enables the detection of transfer. But, to accomplish this, it is crucial to use a larger number of participants.

    Randomiserade kontrollerade studier som utvärderar effekten av olika former av läs- och skrivträning med tillförlitliga tester saknas i Sverige idag. Syftet med denna undersökning var att genomföra en interventionsstudie med cross-over design och använda fonologiskt matchade ordlistor specifikt utformade för att upptäcka transfer, för att ge utdelning för en mer grundlig metod och reliabla resultat. Sex barn mellan 7 och 9 års ålder som använde hörapparat deltog i studien. Skolorna som barnen gick i randomiserades till att antingen utgöra en interventionsgrupp, som började träna med ett ljudbaserat lästräningsprogram via dator efter första testningen, eller kontrollgrupp som fortsatte med vanlig skolundervisning. Barnen informerades att träna med programmet under fyra veckor dagligen i skolan. Barnen utförde ett testbatteri innehållande tester för fonologisk medvetenhet, bokstavskännedom och ordavkodning vid tre tillfällen med fyra veckors mellanrum. Resultaten visade att ordlistorna på ett reliabelt sätt kunde fastställa barns avkodningsstrategier samt hur ordlängd påverkade läshastigheten. Både interventions- och kontrollgruppen påvisade förbättring vid andra testningen. Dock kunde det inte påvisas att den datorbaserade lästräningen var mer effektiv än sedvanlig skolundervisning. Då deltagarantalet var litet, spridningen stor och träningstiden vid datorn var låg kan detta ha bidragit till att effekterna uteblev. Studien bör ses som en pilotstudie som går mot en noggrannare form av testmetod där användandet av anpassade ordlistor möjliggör upptäckt av transfer. För att åstadkomma detta är det emellertid avgörande att det ingår ett större deltagarantal.

  • 206. Abrahamsson, Hasse
    et al.
    Ostlund-Lindqvist, Ann-Margret
    Nilsson, Ralf
    Simren, Magnus
    Gillberg, Per-Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation2008Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 43, nr 12, s. 1483-1488Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation. Material and methods. Female patients with constipation (23 IBS-C, 4 functional constipation (FC)) were studied and compared with non-constipated subjects (16 IBS-D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro-anal transit time (OATT), reference=4.3 days) and stool frequency were measured. C4 (7--hydroxy-4-cholesten-3-one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h. Results. When all the groups of constipated and non-constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p 0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p 0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels. Conclusions. Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.

  • 207.
    Abrahamsson, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten.
    Characterization of calcium transport in mouse and clonal rat pancreatic ß-cells 1985Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 208.
    Abrahamsson, Jonas
    et al.
    Queen Silvia Children’s Hospital, Gothenburg.
    Forestier, Erik
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jónsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Zeller, Bernward
    Hasle, Henrik
    Aarhus University Hospital Skejby, Aarhus.
    Response-Guided Induction Therapy in Pediatric Acute Myeloid Leukemia With Excellent Remission Rate2011Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, nr 3, s. 310-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose

    To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.

    Patients and Methods

    All Nordic children with AML younger than 15 years (n = 151) were treated on the Nordic Society for Pediatric Hematology and Oncology (NOPHO) AML 2004 protocol. After the first course of idarubicin, cytarabine, etoposide, and 6-thioguanin, patients with good response were allowed hematologic recovery before the second course, whereas patients with a poor (>= 15% blasts) or intermediate (5% to 14.9% blasts) were recommended to proceed immediately with therapy. Patients not in remission after the second course received fludarabine, cytarabine, and granulocyte colony-stimulating factor. Poor responders received allogeneic stem-cell transplantation (SCT) as consolidation.

    Results

    Seventy-four percent of patients had good response, 17% had intermediate response, and 7% had poor response after the first course. The overall remission frequency was 97.4%, with 92% in remission after the second course. The rate of induction death was 1.3%. Patients with an intermediate response had a lower event-free survival of 35% compared with good (61%) and poor responders (82%).

    Conclusion

    The NOPHO-AML 2004 induction strategy gives an excellent remission rate with low toxic mortality in an unselected population. Outcome is worse in patients with intermediate response but may be improved by intensifying consolidation in this group using SCT.

  • 209.
    Abrahamsson, Lillemor
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för hushållsvetenskap (IHV).
    Andersson, Agneta
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för hushållsvetenskap (IHV). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Principles of nutritional assessment2006Ingår i: Scandinavian Journal of Food and Nutrition, ISSN 1748-2976, E-ISSN 1748-2984, Vol. 50, nr 4, s. 177-177Artikel, recension (Övrig (populärvetenskap, debatt, mm))
  • 210.
    Abrahamsson, Lillemor
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för hushållsvetenskap (IHV). kost.
    Andersson, Agneta
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för hushållsvetenskap (IHV). Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Becker, Wulf
    Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap. Klinisk nutrition och metabolism.
    Nilsson, Gerd
    Näringslära för högskolan2006Bok (Övrig (populärvetenskap, debatt, mm))
  • 211.
    Abrahamsson, Lotta
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Logopedi.
    Ljung, Ida-Karin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Logopedi.
    Bliss i interaktion: - En samtalsanalytisk fallstudie av hur blissanvändare och tolkare tillsammans bygger upp yttranden2008Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats
  • 212.
    Abrahamsson, Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    On the Impact of Bariatric Surgery on Glucose Homeostasis2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI>50 kg/m2.

    In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery.

    In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS).

    In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day <3.3mmol/l and 20 and 40 minutes < 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms.

    In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response.

    In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.

    Delarbeten
    1. Gastric Bypass Surgery Elevates NT-ProBNP Levels
    Öppna denna publikation i ny flik eller fönster >>Gastric Bypass Surgery Elevates NT-ProBNP Levels
    2013 (Engelska)Ingår i: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 23, nr 9, s. 1421-1426Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background

    Brain natriuretic peptide (BNP) is produced in the heart in response to stretching of the myocardium. BNP levels are negatively correlated to obesity, and in obese subjects, a reduced BNP responsiveness has been described. Diet-induced weight loss has been found to lower or to have no effect on BNP levels, whereas gastric banding and gastric bypass have reported divergent results. We studied obese patients undergoing gastric bypass (GBP) surgery during follow-up of 1 year.

    Methods

    Twenty patients, 18 women, mean 41 (SD 9.5) years old, with a mean preoperative BMI of 44.6 (SD 5.5) kg/m2 were examined. N-terminal pro-brain natriuretic peptide (NT-ProBNP), glucose and insulin were measured preoperatively, at day 6 and months 1, 6 and 12. In 14 of the patients, samples were also taken at days 1, 2 and 4.

    Results

    The NT-ProBNP levels showed a marked increase during the postoperative week (from 54 pg/mL preop to 359 pg/mL on day 2 and fell to 155 on day 6). At 1 year, NT-ProBNP was 122 pg/mL (125 % increase, p = 0.01). Glucose, insulin and HOMA indices decreased shortly after surgery without correlation to NT-ProBNP change. Mean BMI was reduced from 44.6 to 30.5 kg/m2 at 1 year and was not related to NT-ProBNP change.

    Conclusions

    The data indicate that GBP surgery rapidly alters the tone of BNP release, by a mechanism not related to weight loss or to changes in glucometabolic parameters. The GBP-induced conversion of obese subjects, from low to high NT-ProBNP responders, is likely to influence the evaluation of cardiac function in GBP operated individuals.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-199870 (URN)10.1007/s11695-013-0889-z (DOI)000322494800011 ()23456799 (PubMedID)
    Tillgänglig från: 2013-05-17 Skapad: 2013-05-17 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?
    Öppna denna publikation i ny flik eller fönster >>GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?
    2013 (Engelska)Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 169, nr 6, s. 885-889Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia. Design: We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms. Results: Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements. Conclusion: These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-213465 (URN)10.1530/EJE-13-0504 (DOI)000327539100021 ()
    Tillgänglig från: 2014-01-02 Skapad: 2013-12-23 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    3. Hypoglycemia in everyday life after gastric bypass and duodenal switch
    Öppna denna publikation i ny flik eller fönster >>Hypoglycemia in everyday life after gastric bypass and duodenal switch
    2015 (Engelska)Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 173, nr 1, s. 91-100Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Design: Gastric bypass (GBP) and duodenal switch (DS) in morbid obesity are accompanied by marked metabolic improvements, particularly in glucose control. In recent years, episodes of severe late postprandial hypoglycemia have been increasingly described in GBP patients; data in DS patients are scarce. We recruited three groups of subjects; 15 GBP, 15 DS, and 15 non-operated overweight controls to examine to what extent hypoglycemia occurs in daily life. Methods: Continuous glucose monitoring (CGM) was used during 3 days of normal activity. The glycemic variability was measured by mean amplitude of glycemic excursion and continuous overall net glycemic action. Fasting blood samples were drawn, and the patients kept a food and symptom log throughout the study. Results: The GBP group displayed highly variable CGM curves, and 2.9% of their time was spent in hypoglycemia (< 3.3 mmol/l, or 60 mg/dl). The DS group had twice as much time in hypoglycemia (5.9%) and displayed CGM curves with little variation as well as lower HbA1c levels (29.3 vs 35.9 mmol/mol, P < 0.05). Out of a total of 72 hypoglycemic episodes registered over the 3-day period, 70 (97%) occurred in the postprandial state and only about one-fifth of the hypoglycemic episodes in the GBP and DS groups were accompanied by symptoms. No hypoglycemias were seen in controls during the 3-day period. Conclusion: Both types of bariatric surgery induce marked, but different, changes in glucose balance accompanied by frequent, but mainly unnoticed, hypoglycemic episodes. The impact and mechanism of hypoglycemic unawareness after weight-reduction surgery deserves to be clarified.

    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-261313 (URN)10.1530/EJE-14-0821 (DOI)000358947700018 ()25899582 (PubMedID)
    Tillgänglig från: 2015-09-03 Skapad: 2015-09-01 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
    4. Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
    Öppna denna publikation i ny flik eller fönster >>Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
    Visa övriga...
    2016 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 9, s. 2667-2675Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

    Nyckelord
    Gastric bypass, hypoglycemia
    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-276380 (URN)10.2337/db16-0341 (DOI)000382099800021 ()27313315 (PubMedID)
    Forskningsfinansiär
    Diabetesförbundet
    Tillgänglig från: 2016-02-12 Skapad: 2016-02-12 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
  • 213.
    Abrahamsson, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ahlund, Lovisa
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Ahrin, Elsa
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Alfonsson, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Klinisk psykologi i hälso- och sjukvård.
    Video-based CBT-E improves eating patterns in obese patients with eating disorder: A single case multiple baseline study2018Ingår i: Journal of Behavior Therapy and Experimental Psychiatry, ISSN 0005-7916, E-ISSN 1873-7943, Vol. 61, s. 104-112Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND OBJECTIVES:

    Cognitive Behavioral Therapy (CBT) is effective for treating eating disorders but it may be difficult to reach patients living far from urban centers. Mobile video-based psychotherapy may potentially improve service reach but has not yet been evaluated. The purpose of this study was to investigate the effects of mobile video-based CBT for eating disorder and to explore the feasibility to use this technology in clinical care.

    METHODS:

    A controlled single case multiple baseline design was used which allowed for statistical analyses with randomization tests and non-overlap of all pairs (NAP). Five patients in the first stage of eating disorder treatment were included and the main outcome variable was daily meal frequency. Secondary outcome variables included eating disorder symptoms, psychological distress and treatment satisfaction.

    RESULTS:

    The treatment resulted in a significant (p < .01) increase in daily meal frequency with medium to large effect sizes (combined NAP = .89). Four participants reported reliable improvements in eating disorder symptoms and three reported improvements in mood. The participants reported high satisfaction with the treatment and with the mobile video-application despite some technical problems.

    LIMITATIONS:

    Self-reported data on eating behavior is prone to be biased and the results of single case studies may have limited generalizability.

    CONCLUSION:

    CBT can be delivered effectively via a mobile video application and, despite some technological issues, can be well received by patients. All participants in this study had previous low access to mental health services and reported high satisfaction with the treatment format.

  • 214.
    Abrahamsson, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Engström, Britt Edén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Sundbom, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Karlsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Gastric Bypass Surgery Elevates NT-ProBNP Levels2013Ingår i: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 23, nr 9, s. 1421-1426Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Brain natriuretic peptide (BNP) is produced in the heart in response to stretching of the myocardium. BNP levels are negatively correlated to obesity, and in obese subjects, a reduced BNP responsiveness has been described. Diet-induced weight loss has been found to lower or to have no effect on BNP levels, whereas gastric banding and gastric bypass have reported divergent results. We studied obese patients undergoing gastric bypass (GBP) surgery during follow-up of 1 year.

    Methods

    Twenty patients, 18 women, mean 41 (SD 9.5) years old, with a mean preoperative BMI of 44.6 (SD 5.5) kg/m2 were examined. N-terminal pro-brain natriuretic peptide (NT-ProBNP), glucose and insulin were measured preoperatively, at day 6 and months 1, 6 and 12. In 14 of the patients, samples were also taken at days 1, 2 and 4.

    Results

    The NT-ProBNP levels showed a marked increase during the postoperative week (from 54 pg/mL preop to 359 pg/mL on day 2 and fell to 155 on day 6). At 1 year, NT-ProBNP was 122 pg/mL (125 % increase, p = 0.01). Glucose, insulin and HOMA indices decreased shortly after surgery without correlation to NT-ProBNP change. Mean BMI was reduced from 44.6 to 30.5 kg/m2 at 1 year and was not related to NT-ProBNP change.

    Conclusions

    The data indicate that GBP surgery rapidly alters the tone of BNP release, by a mechanism not related to weight loss or to changes in glucometabolic parameters. The GBP-induced conversion of obese subjects, from low to high NT-ProBNP responders, is likely to influence the evaluation of cardiac function in GBP operated individuals.

  • 215.
    Abrahamsson, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Engström, Britt Edén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Sundbom, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Karlsson, Anders F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?2013Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 169, nr 6, s. 885-889Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia. Design: We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms. Results: Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements. Conclusion: These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

  • 216.
    Abrahamsson, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Engström, Britt Edén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Sundbom, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Karlsson, Anders F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Hypoglycemia in everyday life after gastric bypass and duodenal switch2015Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 173, nr 1, s. 91-100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Design: Gastric bypass (GBP) and duodenal switch (DS) in morbid obesity are accompanied by marked metabolic improvements, particularly in glucose control. In recent years, episodes of severe late postprandial hypoglycemia have been increasingly described in GBP patients; data in DS patients are scarce. We recruited three groups of subjects; 15 GBP, 15 DS, and 15 non-operated overweight controls to examine to what extent hypoglycemia occurs in daily life. Methods: Continuous glucose monitoring (CGM) was used during 3 days of normal activity. The glycemic variability was measured by mean amplitude of glycemic excursion and continuous overall net glycemic action. Fasting blood samples were drawn, and the patients kept a food and symptom log throughout the study. Results: The GBP group displayed highly variable CGM curves, and 2.9% of their time was spent in hypoglycemia (< 3.3 mmol/l, or 60 mg/dl). The DS group had twice as much time in hypoglycemia (5.9%) and displayed CGM curves with little variation as well as lower HbA1c levels (29.3 vs 35.9 mmol/mol, P < 0.05). Out of a total of 72 hypoglycemic episodes registered over the 3-day period, 70 (97%) occurred in the postprandial state and only about one-fifth of the hypoglycemic episodes in the GBP and DS groups were accompanied by symptoms. No hypoglycemias were seen in controls during the 3-day period. Conclusion: Both types of bariatric surgery induce marked, but different, changes in glucose balance accompanied by frequent, but mainly unnoticed, hypoglycemic episodes. The impact and mechanism of hypoglycemic unawareness after weight-reduction surgery deserves to be clarified.

  • 217.
    Abrahamsson, Niclas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Lau Börjesson, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sundbom, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Wiklund, Urban
    Umea Univ, Biomed Engn, Dept Radiat Sci, Umea, Sweden.
    Karlsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gastric bypass reduces symptoms and hormonal responses to hypoglycemia2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 9, s. 2667-2675Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

  • 218. Abrahamsson, P
    et al.
    Andersen, K
    Grip, L
    Wallentin, L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Dellborg, M
    Early assessment of long-term risk with continuous ST-segment monitoringamong patients with unstable coronary syndromes. Results from 1-yearfollow-up in the TRIM study.2001Ingår i: J Electrocardiol, Vol. 34, s. 103-Artikel i tidskrift (Refereegranskat)
  • 219.
    Abrahamsson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Post Authorization Safety Studies (PASS) & Patient Support Programs (PSP): Läkemedelsföretagens säkerhetsverktyg efter lansering2015Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: I juli 2012 uppdaterades regelverken för farmakovigilans inom Europa och flera förändringar gjordes i de bestämmelser som rör säkerhetsstudier på godkända läkemedel. En sammanställning av dessa behövdes för att lyfta fram viktiga bestämmelser och ge en tydligare överblick av de myndighetskrav som berör PASS (Post-Authorization Safety Studies) och PSP (Patient Support Programs).

     

    Syfte: Projektet syftar till att analysera och tolka regelverk och riktlinjer gällande PASS och PSP inom Europa samt utreda vad som gäller för PASS i de skandinaviska länderna. Detta för att lyfta fram viktiga bestämmelser och underlätta tolkningen för berörda företag.

     

    Material och metoder: Huvuddelen av projektet bestod av en litteraturstudie där fokus låg på lagar och riktlinjer inom Europa. Informationsinhämtning skedde även genom intervjuer med personal på Bayer AB och Läkemedelsverket. Jämförelser har sedan gjorts mellan svenska, norska och danska regelverk.

     

    Resultat: Myndighetskraven för PASS och PSP skiljer sig åt i vissa avseenden. Etikgodkännande krävs för PASS men inte för PSP och slutrapporten från en PASS granskas av läkemedelsmyndighet medan PSP inte ger någon slutrapport. För PASS krävs i Sverige och Norge ett etikgodkännande vilket inte krävs i Danmark. I Danmark ska dokumentation om studien skickas till läkemedelsmyndigheten om Danmark är referensland eller rapportör för produkten. I Sverige och Norge krävs ingen kommunikation med läkemedelsmyndigheten.

     

    Konklusion: PASS syftar till att studera säkerheten hos läkemedel medan PSP primärt är ett stöd för patientvården i vilket vissa säkerhetsaspekter kan fångas upp sekundärt. Trots att regelverken rörande farmakovigilans gäller för samtliga EU-länder har olika tolkningar gjorts i de skandinaviska länderna och de lokala regelverken skiljer sig åt i vissa avseenden.

  • 220. Abramczyk, Olga
    et al.
    Zien, Piotr
    Zielinski, Rafał
    Pilecki, Marek
    Hellman, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Szyszka, Ryszard
    The protein kinase 60S is a free catalytic CK2alpha' subunit and forms an inactive complex with superoxide dismutase SOD12003Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 307, nr 1, s. 31-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The 60S ribosomes from Saccharomyces cerevisiae contain a set of acidic P-proteins playing an important role in the ribosome function. Reversible phosphorylation of those proteins is a mechanism regulating translational activity of ribosomes. The key role in regulation of this process is played by specific, second messenger-independent protein kinases. The PK60S kinase was one of the enzymes phosphorylating P-proteins. The enzyme has been purified from yeast and characterised. Pure enzyme has properties similar to those reported for casein kinase type 2. Peptide mass fingerprinting (PMF) has identified the PK60S as a catalytic alpha(') subunit of casein kinase type 2 (CK2alpha(')). Protein kinase activity is inhibited by SOD1 and by highly specific CK2 inhibitor-4,5,6,7-tetrabromo-benzotriazole (TBBt). The possible mechanism of regulation of CK2alpha(') activity in stress conditions, by superoxide dismutase in regulation of 80S-ribosome activity, is discussed.

  • 221.
    Abramenkovs, Andris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Induction and repair of clustered DNA damage sites after exposure to ionizing radiation2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The mechanisms that maintain genomic stability safeguard cells from constant DNA damage produced by endogenous and external stressors. Therefore, this thesis aimed to specifically address questions regarding the requirement and involvement of DNA repair proteins in the repair of various types of radiation-induced DNA damage.

    The first aim was to determine whether the phosphorylation of DNA-PKcs, a major kinase involved in non-homologous end joining pathway, can be utilized to score the DNA double-strand break (DSB) content in cells. DNA-PKcs phosphorylated (pDNA-PKcs) at T2609 was more sensitive to the cellular DSB content than ɣH2AX, as analyzed by flow cytometry. Further, pDNA-PKcs at T2609 could discriminate between DSB repair-compromised and normal cells, confirming that the pDNA-PKcs can be used as a DSB repair marker. In paper II, the DSB repair was assessed in cells with reduced levels of DNA-PKcs. The reduction in DNA-PKcs resulted in decreased cell survival and unaffected DSB repair. These results clearly indicate that DNA-PKcs plays an additional role in promoting cell survival in addition to its function in DSB repair.

    The second part of the thesis focused on the characterization of complex DNA damage. DNA damage was investigated after exposure to α-particles originating from Ra-223. The Ra-223 treatment induced a nonrandom DSB distribution consistent with damage induced by high-linear energy transfer radiation. The exposure to Ra-223 significantly reduced cell survival in monolayers and 3D cell structures. The last paper unraveled the fate of heat-sensitive clustered DNA damage site (HSCS) repair in cells. HSCS repair was independent of DSB repair, and these lesions did not contribute to the generation of additional DSBs during repair. Prolonged heating of DNA at relatively low temperatures induced structural changes in the DNA that contributed to the production of DNA artifacts.

    In conclusion, these results demonstrate that DNA-PKcs can be used to monitor DSB repair in cells after exposure to ionizing radiation. However, the functions of DNA-PKcs are not limited to DSB repair, as it can promote cell survival through other mechanisms. The complexity of the DNA damage produced by high-LET radiation is a major contributor to cell death. However, not all clusters produced in irradiated cells are converted into DSBs during repair.

    Delarbeten
    1. Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    Öppna denna publikation i ny flik eller fönster >>Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity
    2017 (Engelska)Ingår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, nr 6, s. 597-604Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

    Ort, förlag, år, upplaga, sidor
    RADIATION RESEARCH SOC, 2017
    Nationell ämneskategori
    Biofysik
    Identifikatorer
    urn:nbn:se:uu:diva-343567 (URN)10.1667/RR14693.1 (DOI)000416744600001 ()
    Forskningsfinansiär
    CancerfondenStrålsäkerhetsmyndigheten
    Tillgänglig från: 2018-03-02 Skapad: 2018-03-02 Senast uppdaterad: 2019-03-08Bibliografiskt granskad
    2. Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    Öppna denna publikation i ny flik eller fönster >>Suppression of DNA-dependent protein kinase sensitize cells to radiation without affecting DSB repair
    2014 (Engelska)Ingår i: Mutation research, ISSN 0027-5107, E-ISSN 1873-135X, Vol. 769, s. 1-10Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Efficient and correct repair of DNA double-strand break (DSB) is critical for cell survival. Defects in the DNA repair may lead to cell death, genomic instability and development of cancer. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is an essential component of the non-homologous end joining (NHEJ) which is the major DSB repair pathway in mammalian cells. In the present study, by using siRNA against DNA-PKcs in four human cell lines, we examined how low levels of DNA-PKcs affected cellular response to ionizing radiation. Decrease of DNA-PKcs levels by 80-95%, induced by siRNA treatment, lead to extreme radiosensitivity, similar to that seen in cells completely lacking DNA-PKcs and low levels of DNA-PKcs promoted cell accumulation in G2/M phase after irradiation and blocked progression of mitosis. Surprisingly, low levels of DNA-PKcs did not affect the repair capacity and the removal of 53BP1 or gamma-H2AX foci and rejoining of DSB appeared normal. This was in strong contrast to cells completely lacking DNA-PKcs and cells treated with the DNA-PKcs inhibitor NU7441, in which DSB repair were severely compromised. This suggests that there are different mechanisms by which loss of DNA-PKcs functions can sensitize cells to ionizing radiation. Further, foci of phosphorylated DNA-PKcs (T2609 and S2056) co-localized with DSB and this was independent of the amount of DNA-PKcs but foci of DNA-PKcs was only seen in siRNA-treated cells. Our study emphasizes on the critical role of DNA-PKcs for maintaining survival after radiation exposure which is uncoupled from its essential function in DSB repair. This could have implications for the development of therapeutic strategies aiming to radiosensitize tumors by affecting the DNA-PKcs function.

    Nyckelord
    DNA repair, DNA-PKcs, Ionizing radiation, DNA-PK deficiency, NU7441
    Nationell ämneskategori
    Medicinsk genetik
    Identifikatorer
    urn:nbn:se:uu:diva-237292 (URN)10.1016/j.mrfmmm.2014.06.004 (DOI)000343625700001 ()
    Tillgänglig från: 2014-12-03 Skapad: 2014-12-01 Senast uppdaterad: 2019-03-08Bibliografiskt granskad
    3. The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    Öppna denna publikation i ny flik eller fönster >>The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survival
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

    Nyckelord
    Prostate cancer, ARv7, DNA damage, Ra-223, high-LET
    Nationell ämneskategori
    Radiologi och bildbehandling
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-378720 (URN)
    Tillgänglig från: 2019-03-08 Skapad: 2019-03-08 Senast uppdaterad: 2019-03-08
    4. Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    Öppna denna publikation i ny flik eller fönster >>Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair
    2018 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikel-id e0209594Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-374120 (URN)10.1371/journal.pone.0209594 (DOI)000454621900032 ()30592737 (PubMedID)
    Forskningsfinansiär
    Cancerfonden, CAN2014/661Cancerfonden, CAN2016/649Strålsäkerhetsmyndigheten, SSM2017-2374Strålsäkerhetsmyndigheten, SSM2018-2181
    Tillgänglig från: 2019-01-23 Skapad: 2019-01-23 Senast uppdaterad: 2019-03-08Bibliografiskt granskad
  • 222.
    Abramenkovs, Andris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Spiegelberg, Diana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Nilsson, Sten
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survivalManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

  • 223.
    Abramenkovs, Andris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Spiegelberg, Diana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Öron-, näs- och halssjukdomar.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression2018Ingår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, s. S634-S635Artikel i tidskrift (Övrigt vetenskapligt)
  • 224.
    Abramenkovs, Andris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Measurement of DNA-Dependent Protein Kinase Phosphorylation Using Flow Cytometry Provides a Reliable Estimate of DNA Repair Capacity2017Ingår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 188, nr 6, s. 597-604Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Uncontrolled generation of DNA double-strand breaks (DSBs) in cells is regarded as a highly toxic event that threatens cell survival. Radiation-induced DNA DSBs are commonly measured by pulsed-field gel electrophoresis, microscopic evaluation of accumulating DNA damage response proteins (e.g., 53BP1 or gamma-H2AX) or flow cytometric analysis of gamma-H2AX. The advantage of flow cytometric analysis is that DSB formation and repair can be studied in relationship to cell cycle phase or expression of other proteins. However, gamma-H2AX is not able to monitor repair kinetics within the first 60 min postirradiation, a period when most DSBs undergo repair. A key protein in non-homologous end joining repair is the catalytic subunit of DNA-dependent protein kinase. Among several phosphorylation sites of DNA-dependent protein kinase, the threonine at position 2609 (T2609), which is phosphorylated by ataxia telangiectasia mutated (ATM) or DNA-dependent protein kinase catalytic subunit itself, activates the end processing of DSB. Using flow cytometry, we show here that phosphorylation at T2609 is faster in response to DSBs than gamma-H2AX. Furthermore, flow cytometric analysis of T2609 resulted in a better representation of fast repair kinetics than analysis of gamma-H2AX. In cells with reduced ligase IV activity, and wild-type cells where DNA-dependent protein kinase activity was inhibited, the reduced DSB repair capacity was observed by T2609 evaluation using flow cytometry. In conclusion, flow cytometric evaluation of DNA-dependent protein kinase T2609 can be used as a marker for early DSB repair and gives a better representation of early repair events than analysis of gamma-H2AX.

  • 225.
    Abramenkovs, Andris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Stenerlöw, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Removal of heat-sensitive clustered damaged DNA sites is independent of double-strand break repair2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikel-id e0209594Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA double-strand breaks (DSBs) are the most deleterious lesions that can arise in cells after ionizing radiation or radiometric drug treatment. In addition to prompt DSBs, DSBs may also be produced during repair, evolving from a clustered DNA damaged site, which is composed of two or more distinct lesions that are located within two helical turns. A specific type of cluster damage is the heat-sensitive clustered site (HSCS), which transforms into DSBs upon treatment at elevated temperatures. The actual lesions or mechanisms that mediate the HSCS transformation into DSBs are unknown. However, there are two possibilities; either these lesions are transformed into DSBs due to DNA lesion instability, e.g., transfer of HSCS into single-strand breaks (SSBs), or they are formed due to local DNA structure instability, e.g., DNA melting, where two SSBs on opposite strands meet and transform into a DSB. The importance of these processes in living cells is not understood, but they significantly affect estimates of DSB repair capacity. In this study, we show that HSCS removal in human cells is not affected by defects in DSB repair or inhibition of DSB repair. Under conditions where rejoining of prompt DSBs was almost completely inhibited, heat-sensitive DSBs were successfully rejoined, without resulting in increased DSB levels, indicating that HSCS do not transfer into DSB in cells under physiological conditions. Furthermore, analysis by atomic force microscopy suggests that prolonged heating of chromosomal DNA can induce structural changes that facilitate transformation of HSCS into DSB. In conclusion, the HSCS do not generate additional DSBs at physiological temperatures in human cells, and the repair of HSCS is independent of DSB repair.

  • 226.
    Abramov, Sergei
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    Dahlqvist, Johanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    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. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018Ingår i: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, nr 12, s. A44-A44Artikel i tidskrift (Övrigt vetenskapligt)
  • 227. Abrams, P
    et al.
    Cardozo, L
    Fall, M
    Griffiths, D
    Rosier, P
    Ulmsten, U
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Van Kerrebroeck, P
    Victor, A
    Wein, A
    The standardisation of terminology in lower urinary tract function: reportfrom the standardisation sub-committee of the International ContinenceSociety.2003Ingår i: Urology, Vol. 61, s. 37-Artikel i tidskrift (Refereegranskat)
  • 228. Abrams, P
    et al.
    Cardozo, L
    Fall, M
    Griffiths, D
    Rosier, P
    Ulmsten, U
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    van Kerrebroeck, P
    Victor, A
    Wein, A
    The standardisation of terminology of lower urinary tract function: Report from the standardistation sub-committee of the International Continence Society.2002Ingår i: Neurourology and Urodynamics, Vol. 21, s. 167-Artikel i tidskrift (Refereegranskat)
  • 229. Abrams, Pascale
    et al.
    Boquete, Hugo
    Fideleff, Hugo
    Feldt-Rasmussen, Ulla
    Jonsson, J
    Koltowska-Häggström, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Wilton, Patrick
    Abs, Roger
    GH replacement in hypopituitarism improves lipid profile and quality of life independently of changes in obesity variables2008Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, nr 6, s. 825-832Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: GH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL. Design and methods: Adult GHD Subjects from the Pfizer International Metabolic Database were grouped according to BMI (n = 291 with BMI < 25 kg/m(2), n = 372 with BMI 25-30 kg/m(2), n = 279 with BMI > 30 kg/m(2)), WG (n = 508 with normal WG, n = 434 with increased WG) and FM (n = 357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-1 concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment. Results: At baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups. Conclusions: Variables of obesity adversely affect the already unfavourable lipid profile in GHD Subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.

  • 230. Abramsson, Alexandra
    et al.
    Kurup, Sindhulakshmi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Yamada, Shuhei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lindblom, Per
    Schallmeiner, Edith
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ledin, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ringvall, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kjellén, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bondjers, Göran
    Li, Jin-Ping
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lindahl, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Spillmann, Dorothe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Gerhardt, Holger
    Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development2007Ingår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, nr 3, s. 316-331Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.

  • 231. Abramsson-Zetterberg, L
    et al.
    Zetterberg, G
    Bergqvist, Michael
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Grawe, J
    Human cytogenetic biomonitoring using flow-cytometric analysis ofmicronuclei in transferrin-positive immature peripheral bloodreticulocytes.2000Ingår i: Environ Mol Mutagen, Vol. 36, s. 22-Artikel i tidskrift (Refereegranskat)
  • 232.
    Abramsson-Zetterberg, Lilianne
    et al.
    National Food Administration, Uppsala.
    Durling, Louise J.K.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Yang-Wallentin, Fan
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för informationsvetenskap.
    Rytter, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Vessby, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes2006Ingår i: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 603, nr 1, s. 33-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Folic acid has a well-documented stabilising effect on chromosomes. A correlation between folate status and chromosome stability in humans has been reported in studies that were restricted to certain subpopulations, e.g., folate-deficient persons. The goal of the present investigation was to clarify if there also is a correlation between folate status and chromosome stability among individuals without any folate deficiency.

    The method used here is the recently developed flow cytometry-based micronucleus assay in human transferrin-positive reticulocytes (MN-Trf-Ret). In a blood sample, separation of the very young reticulocytes from the mature erythrocytes makes this micronucleus assay possible.

    This investigation comprises three studies (cross-sectional, giving baseline data), two of which are connected to an intervention study. In the three cross-sectional studies (total number of subjects, 99) the frequency of MN-Trf-Ret (fMN-Trf-Ret) was measured and compared with the serum folate status. In two of the studies also serum homocysteine and Vitamin B12 were measured and compared with the baseline fMN-Trf-Ret. Combining the results from the three cross-sectional studies, a negative correlation between folate status and fMN-Trf-Ret was obtained (p < 0.05).

    The goal of the intervention studies was to clarify if different nutritional supplementations had any effect on the fMN-Trf-Ret and the cell proliferation (percentage polychromatic erythrocytes, PCE). Each of the two studies involved two groups, one placebo and one supplemented group. In one of the studies the supplementation was folic acid, 1000 μg/day during 1 week (n = 30, both sexes); in the other intervention study, folic acid (800 μg/day), B12 (20 μg/day) and B6 (4 mg/day) were taken during 1 week (n = 29, both sexes). No significant difference in %PCE or fMN-Trf-Ret between the two groups was found in either of the two intervention studies.

  • 233. Abramsson-Zetterberg, Lilianne
    et al.
    Ilbäck, Nils-Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013Ingår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, s. 86-89Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 234.
    Abrantes, João A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacometric Approaches to Improve Dose Individualization Methods in Hemophilia A2019Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Hemophilia A is a bleeding disorder caused by the lack of functional coagulation factor VIII (FVIII). The overall aim of this thesis was to improve dose individualization of FVIII replacement therapy in hemophilia A using pharmacometric approaches.

    A population pharmacokinetic (PK) model of FVIII activity following the administration of moroctocog alfa was developed based on data from a large heterogeneous cohort of moderate to severe hemophilia A patients. Body weight, age, neutralizing anti-FVIII inhibitors, race, and analytical assay were found to be significant predictors of FVIII activity PK. In addition, large inter-individual variability (IIV) and inter-occasion variability (IOV) was identified highlighting the need for dose individualization.

    High magnitudes of IOV are known to impair model-based therapeutic drug monitoring. Using a population PK model of FVIII activity, several approaches to handle IOV in Bayesian forecasting of individual PK parameters were assessed across a wide range of features. Considering IOV in Bayesian forecasting, but ignoring IOV in dose calculation, led to the most precise individualized doses, in particular, when sparse data was used.

    The dose-exposure-response relationship of FVIII replacement therapy remains unclear. A parametric repeated time-to-categorical event (RTTCE) model was developed to characterize the relationship between the dose of octocog alfa, plasma FVIII activity, bleeding frequency and severity, and covariates, using data from clinical trials. The bleeding hazard was found to decrease throughout time and to be affected by plasma FVIII activity and number of previous bleeds. Unexplained IIV in the bleeding hazard was found to be large.

    Bayesian forecasting based on the RTTCE model was used to predict the future occurrence of bleeds, and to contrast the predicted outcome using individual i) PK, ii) bleeding, and iii) PK, bleeding and covariate information, from data collected in clinical trials. The results support that individual bleed information can inform the optimization of prophylactic dosing regimens in severe hemophilia A patients.

    In summary, the pharmacometric approaches presented provide a valuable quantitative framework to improve dose individualization in hemophilia A. Furthermore, enhanced dosing has the potential to reduce bleeding frequency and to lower the high costs associated to treatment.

    Delarbeten
    1. Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
    Öppna denna publikation i ny flik eller fönster >>Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
    Visa övriga...
    2017 (Engelska)Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, nr 6, s. 977-988Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

    Nationell ämneskategori
    Farmakologi och toxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-342208 (URN)10.1002/cpt.716 (DOI)000414921800026 ()28437834 (PubMedID)
    Tillgänglig från: 2018-02-20 Skapad: 2018-02-20 Senast uppdaterad: 2019-04-05Bibliografiskt granskad
    2. Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
    Öppna denna publikation i ny flik eller fönster >>Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
    2019 (Engelska)Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, nr 6, s. 1326-1336Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.

    METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.

    RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.

    CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2019
    Nyckelord
    NONMEM, pharmacokinetics, population analysis, therapeutic drug monitoring
    Nationell ämneskategori
    Farmakologi och toxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-381215 (URN)10.1111/bcp.13901 (DOI)000468974200029 ()30767254 (PubMedID)
    Tillgänglig från: 2019-04-05 Skapad: 2019-04-05 Senast uppdaterad: 2019-06-24Bibliografiskt granskad
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    Öppna denna publikation i ny flik eller fönster >>Relationship between factor VIII activity, bleeds and individual characteristics in severe hemophilia A patients