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  • 1. A Molarius, A
    et al.
    Granström, F
    Feldman, Inna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Kalander Blomqvist, M
    Pettersson, H
    Ello, S
    Can financial insecurity and condescending treatment explain the higher prevalence of poor self-rated health in women than in men? A population-based cross-sectional study in Sweden2012Konferensbidrag (Övrigt vetenskapligt)
  • 2. Aahlin, Kristofer
    et al.
    Arvidsson, Per I.
    Huerta, Fernando
    Yngve, Ulrika.
    Preparation of 1-(4-(5-amino-6-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-yl)benzoyl)piperazine derivatives as glycogen synthase kinase 3 inhibitors.2011Patent (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    Title compds. I [R1 = H or Me], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by cyclization of 3-amino-N-(4-hydroxypyridin-3-yl)pyrazine-2-carboxamide (prepn. given) to get intermediate 3-(oxazolo[4,5-c]pyridin-2-yl)pyrazin-2-amine, which underwent bromination followed by Suzuki reaction with (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone. Compds. of the invention were tested for their selective inhibitory activity of GSK3β, e.g., II exhibited Ki value of 2.3 nM. The invention compds. are useful for the treatment of cognitive disorders, diabetes, cancer, etc. [on SciFinder(R)]

  • 3.
    Aalto, Heidi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Föräldrars upplevelser av omvårdnaden av sitt sent underburna barn på BB: En intervjustudie2014Självständigt arbete på avancerad nivå (magisterexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund: Sent underburna barn vårdas ofta på BB-avdelning för fullgångna barn. De har högre frekvens av återinläggningar på sjukhus än fullgångna barn. De flesta studier kring underburna barns vistelse på sjukhus är inte gjorda specifikt på sent underburna barn. Syfte: Syftet är att utforska föräldrars upplevelser av omvårdnaden av sent underburna barn på en BB-avdelning i Sverige. I analysen användes det teoretiska begreppet empowerment. Metod: Studien är deskriptiv med en kvalitativ ansats. Telefonintervjuer användes som datainsamlingsmetod. Fem mammor och två pappor deltog i studien. Intervjuerna analyserades med innehållsanalys. Resultat/Slutsats: Föräldrarna upplevde att personalen antingen förmedlade empowerment eller inte. Omvårdnadsåtgärder kring barnet som gjorde föräldrarna mer delaktiga upplevdes mer positivt och omvårdnadsåtgärder som orsakade en separation mellan föräldrar och barn upplevdes mer negativt. Föräldrarna hade svårt att ifrågasätta personal, även om de upplevde att något kring omvårdnadsåtgärden kändes fel. Omvårdnadsåtgärder, utfördes inte alltid i enlighet med vetenskap och beprövad erfarenhet. Personalen kan utbildas mer i att främja empowerment i föräldrarollen och därmed även öka föräldradelaktigheten i barnets omvårdnad och möjligheten att se varje familjs unika behov. Mer forskning behövs om hur detta ska ske.

  • 4. Aaltonen, Kirsimari
    et al.
    Ahlin, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Salonen, Laura
    Fjällskog, Marie Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Heikkilä, Pävi
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides2006Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, nr 11, s. 1697-1702Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.

  • 5. Aaltonen, Kirsimari
    et al.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Heikkilä, Päivi
    Aittomäki, Kristiina
    Tamminen, A.
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    High cyclin B1 expression is associated with poor survival in breast cancer2009Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, nr 7, s. 1055-60Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclin B1 regulates the G(2)-M transition of the cell cycle. Cyclin B1 expression is higher in premalignant and malignant than normal breast lesions. Correlation of cyclin B1 expression with other histopathological variables and prognostic role in breast cancer are not fully understood. Traditionally used prognostic criteria identify large subset of patients to receive adjuvant chemotherapy and to be exposed to adverse effects. A reliable and simple method helping prognostic evaluation in breast cancer is needed. We analysed cyclin B1 expression on 1348 invasive breast cancers and studied correlations with other histopathological variables and survival. High cyclin B1 correlated with high tumour grade, large tumour size and positive nodal status, oestrogen and progesterone receptor negativity, positive HER2 and p53 status, young age at diagnosis, and high cyclin E, cyclin A and Ki67 expression. Among patients not given adjuvant chemotherapy high cyclin B1 was a strong predictor of shorter overall and metastasis-free survival (RR 3.74, P<0.0005 and RR 3.51, P<0.0005, respectively), and remained as an independent prognostic factor also in multivariate analysis (RR 1.80, P=0.04 and RR 2.31, P=0.02, respectively). This study suggests high cyclin B1 associates with aggressive phenotype and is an independent prognostic factor in breast cancer.

  • 6. Aaltonen, Kirsimari
    et al.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Landberg, Göran
    Eerola, Hannaleena
    Aittomäki, Kristiina
    Heikkilä, Päivi
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer2009Ingår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 113, nr 1, s. 75-82Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclins D1 and E play an important role in breast carcinogenesis. High cyclin E expression is common in hormone receptor negative and high grade aggressive breast cancer, whereas cyclin D1 in hormone receptor positive and low grade breast cancer. Experimental data has suggested that cyclin D1 and E mediate cell proliferation by different mechanisms in estrogen receptor (ER) positive and negative breast cancer. To test this hypotheses in large breast cancer material and to clarify the histopathological correlations of cyclin E and D1, especially the association with proliferation, we analyzed cyclin E and D1 immunohistochemical expression on breast tumour microarrays consisting of 1348 invasive breast cancers. High cyclin D1 expression was associated with high grade (P<0.0005), high cyclin A (P<0.0005) and Ki67 (P<0.0005) expression among ER positive but with low grade (P=0.05) and low Ki67 (P=0.01) expression among ER negative breast cancers. Cyclin E and D1 expression correlated positively in ER positive (P<0.0005) but had a negative correlation in ER negative tumours (P=0.004). Cyclin E associated with high grade among all tumours (P<0.0005). In conclusion, the findings of this study show that cyclin D1 has separate roles, and proliferation is driven by different mechanisms in ER positive and negative breast cancers.

  • 7. Aaltonen, Kirsimari
    et al.
    Blomqvist, Carl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eerola, Hannaleena
    Aittomäki, Kristiina
    Heikkilä, Päivi
    Nevanlinna, Heli
    Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers2008Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 14, nr 7, s. 1976-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.

  • 8. Aaltonen, Minna
    et al.
    Soukka, Hanna
    Halkola, Lauri
    Jalonen, Jarmo
    Kalimo, Hannu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Holopainen, Irma E
    Kääpä, Pekka O
    Inhaled nitric oxide treatment inhibits neuronal injury after meconium aspiration in piglets2007Ingår i: Early Human Development, ISSN 0378-3782, E-ISSN 1872-6232, Vol. 83, nr 2, s. 77-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Meconium aspiration-induced hypertensive lung injury is frequently associated with neuronal damage. Inhaled nitric oxide (iNO) is widely used in the treatment of pulmonary hypertension, but its effects on the brain are poorly known. Aims: The aim of this study was to determine the effects of iNO treatment on the neuronal tissue after meconium aspiration. Study design: 71 anesthetized, catheterized and ventilated newborn piglets were studied for 6 h. Thirty-five piglets were instilled with a bolus of human meconium intratracheally and 36 piglets with saline instillation served as controls. Nineteen meconium piglets and 17 control piglets were continuously treated with 20 ppm of iNO, started at 30 min after the insult. The extent of neuronal injury was analysed histologically, and the levels of brain tissue lipid peroxidation products, reduced glutathione (GSH), myeloperoxidase activity and oxidized DNA were analysed as indicators of oxidative stress. Results: iNO treatment diminished the pulmonary hypertensive response caused by meconium aspiration, but did not change systemic or carotid hemodynamics. NO administration was associated with reduced neuronal injury and diminished amount of oxidized DNA in the hippocampus of the meconium piglets. Further, iNO treatment was associated with decreased level of GSH in the cortex, but no change in lipid peroxidation production or myeloperoxidase activity was detected in any of the studied brain areas. Conclusions: Our results suggest that iNO treatment may inhibit DNA oxidation and neuronal injury in the hippocampus, associated with newborn meconium aspiration.

  • 9. Aalto-Setälä, Katriina
    et al.
    Palomäki, Heikki
    Miettinen, Helena
    Vuorio, Alpo
    Kuusi, Timo
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Salonen, Oili
    Kaste, Markku
    Kontula, Kimmo
    Genetic risk factors and ischemic cerebrovascular disease: role of common variation of the genes encoding apolipoproteins and angiotensin-converting enzyme1998Ingår i: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 30, nr 2, s. 224-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA polymorphisms in genes encoding apolipoproteins (apo) A-I, C-III, B and E and angiotensin-converting enzyme (ACE) have been proposed to be associated with the risk of coronary artery disease (CAD). We studied whether the same genetic markers would also be associated with the occurrence and extent of atherosclerosis in cervical arteries. DNA samples from 234 survivors of stroke or a transient ischaemic attack aged 60 years or less were examined. The presence of atherosclerosis was assessed using aortic arch angiograms. The SstI polymorphism of apoA-I/C-III gene locus, the XbaI polymorphism of apoB gene, common apoE phenotypes and the insertion/deletion polymorphism of the ACE gene were analysed. The allele frequencies of the apoA-I/C-III, apoB, apoE or ACE gene did not differ between the groups with (n = 148) or without (n = 85) cervical atherosclerosis. However, when patients with at least one apoE4 allele and one X2 allele of apoB were combined and compared with those without either of them (E2E3 or E3E3 and X1X1), a significant association with the presence of cervical atherosclerosis was found (P = 0.03). The patients having the E2E3 phenotype had a significantly elevated serum triglyceride level compared with those with the E3E3 phenotype (P = 0.03). Serum high-density lipoprotein (HDL) cholesterol was lower in the patients with the E2E3 phenotype than in those with the E3E3 and E3E4 (P = 0.01 and P = 0.06, respectively). The apoB or ACE genotypes were not significantly associated with serum lipid or lipoprotein levels. There was no association between the ACE gene polymorphism and the occurrence of hypertension. In conclusion, the interaction of common apoB and apoE alleles may increase the risk of atherosclerosis in cervical arteries.

  • 10.
    Aanestad, Øystein
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Quantitative electromyographic studies of the perineal muscles in normal subjects and patients suffering from anal or urinary incontinence1998Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The aims of the study were to characterize the interference pattern in perineal muscles in healthy subjects with the use of quantitative EMG techniques, to evaluate if prostatic surgery had any effect on the interference pattern and furthermore to examine the interference pattern in the perineal muscles in patients suffering from urinary or anal incontinence.

    The interference pattern in the perineal muscles was examined with a computerized analysis, the Turns and Amplitude (T/A) analysis, and the innervation pattern of the muscles was examined with single fiber electromyography measuring the fiber density. Reference values were collected from 30 normal subjects. The patient material consisted of 20 males subjected to transurethral prostatectomy (TUR-P), 10 males who underwent radical retropubic prostatectomy (RRP), 20 patients suffering from anal incontinence and 24 women withurinary incontinence.

    T/A analysis of the interference pattern in the perineal muscles in normal subjects showed a significant increase in number of turns/sec and mean amplitude correlating to increasing force but no age-related changes.

    TUR-P and RRP did effect the innervation of the distal urethral sphincter muscle as shown by increased fiber density indicating a peripheral nerve lesion. T/A analysis did not shown any increased activation of the distal urethral sphincter as a compensation for the loss in bladder neck sphincter function but rather signs of decreasedcentral activation.

    Patients with idiopathic faecal incontinence showed signs of impaired innervation of the external anal sphincter muscle. A decreased interference pattern at maximal contraction indicated a reduced central activation of perineal muscles, in particular for patients with partial rupture of the external anal sphincter muscle. The reduced central activation could play a role for the aetiology of faecal incontinence.

    Patients with urinary stress incontinence also showed signs of impaired innervation of the external anal sphincter muscle as well as reduced interference pattern at maximal contraction and during continuous recording of the EMG activity during cystometry. A reduced central activation of the motor units was predicted as one factor involved in the aetiology.

  • 11. Aapro, Matti
    et al.
    Beguin, Yves
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Gascon, Pere
    Hedenus, Michael
    Österborg, Anders
    Too-Low Iron Doses and Too Many Dropouts in Negative Iron Trial?2011Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, nr 17, s. E525-E526Artikel i tidskrift (Refereegranskat)
  • 12. Aapro, Matti S.
    et al.
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bokemeyer, Carsten
    Cornes, Paul
    Foubert, Jan
    Gascon, Pere
    Glaspy, John
    Hellström-Lindberg, Eva
    Link, Hartmut
    Ludwig, Heinz
    Österborg, Anders
    Repetto, Lazzaro
    Soubeyran, Pierre
    Erythropoietins should be used according to guidelines2008Ingår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 9, nr 5, s. 412-3Artikel i tidskrift (Refereegranskat)
  • 13.
    Aare, Sudhakar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Ochala, Julien
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Norman, Holly S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Radell, Peter
    Eriksson, Lars I
    Göransson, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Chen, Yi-Wen
    Hoffman, Eric P
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model2011Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, nr 24, s. 1334-1350Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

  • 14.
    Aare, Sudhakar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Radell, Peter
    Department of anesthesiology, Karolinska Inistitute.
    Eriksson, Lars
    Department of anesthesiology, Karolinska Inistitute.
    Akkad, Hazem
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Chen, Yi-Wen
    Research center for genetic medicine.
    Hoffman, Eric
    Research center for genetic medicine.
    Lars, Larsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model2013Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, nr 8, s. 312-320Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

     

  • 15.
    Aare, Sudhakar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Radell, Peter
    Department of anesthesiology, Karolinska Inistitute.
    Eriksson, Lars
    Department of anesthesiology, Karolinska Inistitute.
    Chen, Yi-Wen
    Research center for genetic medicine.
    Hoffman, Eric P
    Research center for genetic medicine.
    Larsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model2012Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 18, s. 865-877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

  • 16.
    Aare, Sudhakar Reddy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Intensive Care Unit Muscle Wasting: Skeletal Muscle Phenotype and Underlying Molecular Mechanisms2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.

    The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

    Delarbeten
    1. Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
    Öppna denna publikation i ny flik eller fönster >>Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model
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    2011 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, nr 24, s. 1334-1350Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

    Nationell ämneskategori
    Neurologi
    Identifikatorer
    urn:nbn:se:uu:diva-164317 (URN)10.1152/physiolgenomics.00116.2011 (DOI)000298403600002 ()22010006 (PubMedID)
    Tillgänglig från: 2011-12-19 Skapad: 2011-12-19 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    2. The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
    Öppna denna publikation i ny flik eller fönster >>The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model
    Visa övriga...
    2012 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 18, s. 865-877Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

    Nyckelord
    Sepsis, porcine, muscle wasting, intensive care
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-180380 (URN)10.1152/physiolgenomics.00031.2012 (DOI)000309109100001 ()
    Tillgänglig från: 2012-09-05 Skapad: 2012-09-05 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    3. Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
    Öppna denna publikation i ny flik eller fönster >>Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
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    2013 (Engelska)Ingår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, nr 8, s. 312-320Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

     

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-180375 (URN)10.1152/physiolgenomics.00123.2012 (DOI)000317662000002 ()23429211 (PubMedID)
    Tillgänglig från: 2012-09-05 Skapad: 2012-09-05 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    4. Diaphragm muscle weakness in an experimental porcine intensive care unit model
    Öppna denna publikation i ny flik eller fönster >>Diaphragm muscle weakness in an experimental porcine intensive care unit model
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    2011 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 6, artikel-id e20558Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In critically ill patients, mechanisms underlying diaphragm muscle remodeling and resultant dysfunction contributing to weaning failure remain unclear. Ventilator-induced modifications as well as sepsis and administration of pharmacological agents such as corticosteroids and neuromuscular blocking agents may be involved. Thus, the objective of the present study was to examine how sepsis, systemic corticosteroid treatment (CS) and neuromuscular blocking agent administration (NMBA) aggravate ventilator-related diaphragm cell and molecular dysfunction in the intensive care unit. Piglets were exposed to different combinations of mechanical ventilation and sedation, endotoxin-induced sepsis, CS and NMBA for five days and compared with sham-operated control animals. On day 5, diaphragm muscle fibre structure (myosin heavy chain isoform proportion, cross-sectional area and contractile protein content) did not differ from controls in any of the mechanically ventilated animals. However, a decrease in single fibre maximal force normalized to cross-sectional area (specific force) was observed in all experimental piglets. Therefore, exposure to mechanical ventilation and sedation for five days has a key negative impact on diaphragm contractile function despite a preservation of muscle structure. Post-translational modifications of contractile proteins are forwarded as one probable underlying mechanism. Unexpectedly, sepsis, CS or NMBA have no significant additive effects, suggesting that mechanical ventilation and sedation are the triggering factors leading to diaphragm weakness in the intensive care unit.

    Nationell ämneskategori
    Fysiologi
    Forskningsämne
    Klinisk neurofysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-155622 (URN)10.1371/journal.pone.0020558 (DOI)000291730000014 ()21698290 (PubMedID)
    Tillgänglig från: 2011-06-27 Skapad: 2011-06-27 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
  • 17.
    Aarnio, Mikko
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).

    To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.

    To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.

    To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.

    This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.

    Delarbeten
    1. High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
    Öppna denna publikation i ny flik eller fönster >>High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
    Visa övriga...
    2016 (Engelska)Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 152, s. 231-237Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aims: D-deprenyl is a useful positron emission tomography tracer for visualization of inflammatory processes. Studies with [C-11]-D-deprenyl showed robust uptake in peripheral painful sites of patients with rheumatoid arthritis or chronic whiplash injury. The mechanism of preferential D-deprenyl uptake is not yet known, but the existence of a specific binding site was proposed. Thus, in the present study, we sought to identify the binding site for D-deprenyl and verify the hypothesis about the possibility of monoamine oxidase enzymes as major targets for this molecule. Main methods: A high-throughput analysis of D-deprenyl activity towards 165 G-protein coupled receptors and 84 enzyme targets was performed. Additionally, binding studies were used to verify the competition of [H-3]D-deprenyl with ligands specific for targets identified in the high-throughput screen. Key findings: Our high-throughput investigation identified monoamine oxidase-B, monoamine oxidase-A and angiotensin converting enzyme as potential targets for D-deprenyl. Further competitive [3H] D-deprenyl binding studies with specific inhibitors identified monoamine oxidase-B as the major binding site. No evident high-affinity hits were identified among G-protein coupled receptors. Significance: Our study was the first to utilize a high-throughput screening approach to identify putative D-deprenyl targets. It verified 249 candidate proteins and confirmed the role of monoamine oxidase - B in D-deprenyl binding. Our results add knowledge about the possible mechanism of D-deprenyl binding, which might aid in explaining the increased uptake of this compound in peripheral inflammation. Monoamine oxidase-B will be further investigated in future studies utilizing human inflamed synovium.

    Nyckelord
    D-deprenyl High-throughput screening Binding site
    Nationell ämneskategori
    Farmaceutiska vetenskaper Klinisk medicin
    Identifikatorer
    urn:nbn:se:uu:diva-291492 (URN)10.1016/j.lfs.2016.03.058 (DOI)000375728500028 ()27058977 (PubMedID)
    Forskningsfinansiär
    Berzelii Centre EXSELENT, 2013-01495
    Tillgänglig från: 2016-05-03 Skapad: 2016-05-03 Senast uppdaterad: 2018-04-09Bibliografiskt granskad
    2. Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
    Öppna denna publikation i ny flik eller fönster >>Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
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    2018 (Engelska)Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 194, s. 26-33Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.

    Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.

    Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.

    Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.

    Nyckelord
    Arthritis, Binding target, Monoamine oxidase B, Synovium, d-Deprenyl
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmaceutisk biokemi; Medicinsk biokemi
    Identifikatorer
    urn:nbn:se:uu:diva-347601 (URN)10.1016/j.lfs.2017.12.003 (DOI)000425052000004 ()29221756 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 9459
    Tillgänglig från: 2018-04-04 Skapad: 2018-04-04 Senast uppdaterad: 2018-04-18Bibliografiskt granskad
    3. Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
    Öppna denna publikation i ny flik eller fönster >>Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
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    2017 (Engelska)Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, s. 418-424Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

    Nyckelord
    Ankle injuries, Carbon-11, Deprenyl, Inflammation, PET, Pain
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-333782 (URN)10.1016/j.sjpain.2017.10.008 (DOI)000419851500070 ()29126847 (PubMedID)
    Tillgänglig från: 2017-11-16 Skapad: 2017-11-16 Senast uppdaterad: 2018-04-09Bibliografiskt granskad
    4. Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
    Öppna denna publikation i ny flik eller fönster >>Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
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    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The understanding of etiological mechanisms of whiplash associated disorder is still inadequate. Objective visualization and quantification of peripheral musculoskeletal injury and possible painful inflammation in whiplash associated disorder would facilitate diagnosis, strengthen patients’ subjective pain reports and aid clinical decisions eventually leading to better treatments. In the current study, we further evaluated the potential to use [11C]D-deprenyl PET/CT to visualize inflammation after whiplash injury. Sixteen patients with whiplash injury grade II were recruited at the emergency department and underwent [11C]D-deprenyl PET/CT in the acute phase and at 6 months after injury. Subjective pain levels, self rated neck disability and active cervical range of motion were recorded at each imaging session. Results showed that the molecular aspects of inflammation and possible tissue injuries after acute whiplash injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. An altered [11C]D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self rated disability during both imaging occasions. These findings may contribute to a better understanding of affected peripheral structures in whiplash injury and strengthens the idea that PET/CT detectable organic lesions in peripheral tissue may be relevant for the development of persistent pain and disability in whiplash injury.

    Perspective: This article presents a novel way of objectively visualizing possible structural damage and inflammation that cause pain and disability in whiplash injury. This PET method can bring an advance in pain research and eventually would facilitate the clinical management of patients in pain.

    Nyckelord
    Whiplash; deprenyl; inflammation; pain; PET; carbon-11
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Molekylär medicin; Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-347602 (URN)
    Tillgänglig från: 2018-04-04 Skapad: 2018-04-04 Senast uppdaterad: 2018-04-12
    5. Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
    Öppna denna publikation i ny flik eller fönster >>Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.

    Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used.

    Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

    Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

    Nyckelord
    deprenyl; inflammation; pain; PET; carbon-11
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Anestesiologi och intensivvård
    Identifikatorer
    urn:nbn:se:uu:diva-347604 (URN)
    Tillgänglig från: 2018-04-04 Skapad: 2018-04-04 Senast uppdaterad: 2018-04-12
  • 18.
    Aarnio, Mikko
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Hall, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Ängeby-Möller, Kristina
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.

    Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used.

    Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

    Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

  • 19.
    Aarnio, Mikko
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Fredriksson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Wolf, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Peterson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Linnman, Clas
    Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.2017Ingår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, s. 418-424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

  • 20.
    Aarnio, Mikko
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Linnman, Clas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Lampa, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Gordh, Torsten
    Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CTManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The understanding of etiological mechanisms of whiplash associated disorder is still inadequate. Objective visualization and quantification of peripheral musculoskeletal injury and possible painful inflammation in whiplash associated disorder would facilitate diagnosis, strengthen patients’ subjective pain reports and aid clinical decisions eventually leading to better treatments. In the current study, we further evaluated the potential to use [11C]D-deprenyl PET/CT to visualize inflammation after whiplash injury. Sixteen patients with whiplash injury grade II were recruited at the emergency department and underwent [11C]D-deprenyl PET/CT in the acute phase and at 6 months after injury. Subjective pain levels, self rated neck disability and active cervical range of motion were recorded at each imaging session. Results showed that the molecular aspects of inflammation and possible tissue injuries after acute whiplash injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. An altered [11C]D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self rated disability during both imaging occasions. These findings may contribute to a better understanding of affected peripheral structures in whiplash injury and strengthens the idea that PET/CT detectable organic lesions in peripheral tissue may be relevant for the development of persistent pain and disability in whiplash injury.

    Perspective: This article presents a novel way of objectively visualizing possible structural damage and inflammation that cause pain and disability in whiplash injury. This PET method can bring an advance in pain research and eventually would facilitate the clinical management of patients in pain.

  • 21.
    Aarnio, Pauliina
    et al.
    Dept for International Health, Medical School, University of Tampere, Finland.
    Olsson, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Chimbiri, Agnes
    Kulmala, Teija
    Male involvement in antenatal HIV counseling and testing: exploring men's perceptions in rural Malawi2009Ingår i: AIDS Care, ISSN 0954-0121, E-ISSN 1360-0451, Vol. 21, nr 12, s. 1537-1546Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antenatal care can act as an excellent tool to improve access to HIV counseling and testing services. This paper investigates an issue that may weaken its potential, namely lack of male involvement. We explored married men's perceptions of HIV in pregnancy and male involvement in antenatal HIV testing and counseling in Southern Malawi through 11 focus group discussions and a cross-sectional survey (n=388). The main findings were that men were largely unaware of available antenatal HIV testing and counseling services, and perceived it overall problematic to attend female-oriented health care. Most men supported provision of antenatal HIV testing. They perceived husbands to participate in the process indirectly through spousal communication, being faithful during pregnancy, and supporting the wife if found HIV-positive. Involvement of husbands was compromised by men's reluctance to learn their HIV status and the threat that HIV poses on marriage. Men stressed the importance of prior spousal agreement of antenatal HIV testing and considered HIV testing without their consent a valid reason for divorce. We suggest that male involvement in antenatal HIV testing requires refocusing of information and health services to include men. To avoid negative social outcomes for women, comprehensive and early involvement of men is essential.

  • 22.
    Aarts, Clara
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Exclusive breastfeeding-Does it make a difference?: A longitudinal, prospective study of daily feeding practices, health and growth in a sample of Swedish infants2001Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The concept of exclusive breastfeeding in relation to daily feeding practices and to health and growth of infants in an affluent society was examined. In a descriptive longitudinal prospective study 506 mother-infant pairs were followed from birth through the greater part of the first year. Feeding was recorded daily, and health and growth were recorded fortnightly.

    Large individual variations were seen in breastfeeding patterns. A wide discrepancy between the exclusive breastfeeding rates obtained from "current status" data and data "since birth" was found.

    Using a strict definition of exclusive breastfeeding from birth and taking into account the reasons for giving complementary feeding, the study showed that many exclusively breastfed infants had infections early in life, the incidence of which increased with age, despite continuation of exclusive breastfeeding. However, truly exclusively breastfed infants seem less likely to suffer infections than infants who receive formula in addition to breast milk. Increasing formula use was associated with an increasing likelihood of suffering respiratory illnesses. The growth of exclusively breastfed infants was similar to that of infants who were not exclusively breastfed.

    The health of newborn infants during the first year of life was associated with factors other than feeding practices alone. Some of these factors may be prenatal, since increasing birth weight was associated with an increasing likelihood of having respiratory symptoms, even in exclusively breastfed infants. However, exclusive breastfeeding was shown to be beneficial for the health of the infant even in an affluent society.

  • 23.
    Aarts, Clara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Vårdvetenskap.
    Greiner, Ted
    Regarding the review article by Erlanson-Albertsson and Zetterström, Acta Paediatr 2005;94:1523-312006Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 95, nr 5, s. 623-624Artikel i tidskrift (Refereegranskat)
  • 24.
    Aarts, Clara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Holm, Marta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Barnhälsoteam: ett exempel på framgångsfaktorer för god samverkan kring förebyggande arbete för barn2010Ingår i: Socialmedicinsk Tidskrift, ISSN 0037-833X, Vol. 87, nr 4, s. 274-281Artikel i tidskrift (Refereegranskat)
  • 25.
    Aarts, Clara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Kylberg, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Hofvander, Yngve
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Gebre-Medhin, Meharigm
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Growth under privileged conditions of healthy Swedish infants exclusively breastfed from birth to 4-6 months:  a longitudinal prospective study based on daily records of feeding2003Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 92, nr 2, s. 145-151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim:

    In most studies the methodology used to study growth in relation to breastfeeding patterns cannot ensure that exclusive breastfeeding has in fact occurred since birth. The aim of this study was to investigate the growth of healthy infants in Sweden in whom exclusive breastfeeding for the first 4–6 mo was ascertained through daily feeding records and to compare the results with the World Health Organization (WHO) “12-month breastfed pooled data set” and the Euro-Growth references for exclusively breastfed infants, as well as with the National Center for Health Statistics (NCHS)/WHO reference.

    Methods:

    147 exclusively breastfed infants and 325 non-exclusively breastfed Swedish infants, with a birthweight of ≥3 kg, were included. The mothers had previous breastfed at least one infant for at least 4 mo. Weight was recorded fortnightly and length monthly.

    Results:

    Infants exclusively breastfed since birth showed similar growth in weight and height to that of the non-exclusively breastfed infants. During the first 6 mo of life the growth of exclusively breastfed infants was also similar to that of the infants regularly receiving formula at 12–16 wk of age, mostly in addition to breast milk. The monthly growth increments were fairly similar to those of the “WHO pooled breastfed data set” and the Euro-Growth references for exclusively breastfed infants.

    Conclusion:

    In an affluent society truly exclusively breastfed infants seem to have the same growth during the first half year of life as non-exclusively breastfed infants with a high breastfeeding rate.

  • 26.
    Aarts, Clara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Kylberg, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Hornell, A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Hofvander, Yngve
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Gebre-Medhin, Mehari
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    Greiner, Ted
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Internationell mödra- och barnhälsovård (IMCH).
    How exclusive is exclusive breastfeeding? A comparison of data since birth with current status data:  2000Ingår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 29, nr 6, s. 1041-1046Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND:

    There is no accepted and widely used indicator for exclusive breastfeeding since birth. Indeed, the difference between 'current status' data on exclusive breastfeeding and data on 'exclusive breastfeeding since birth' is rarely recognized. We used data from a longitudinal study to examine this issue.

    METHODS:

    A descriptive longitudinal, prospective study design was used in which 506 mother-infant pairs were included. The mothers completed daily recordings on infant feeding during the first nine months after birth. A research assistant conducted fortnightly home visits with structured interviews. The resulting data on breastfeeding patterns are presented in two different ways: analysis of 'current status' data based on a single 24-hour recording of infant feeding at 2, 4 and 6 months of age, and analysis of data 'since birth', i.e. data on infant feeding for every day, starting from birth until the ages of 2, 4 and 6 months.

    RESULTS:

    A wide discrepancy between the results obtained from the two analyses was found. The difference in the exclusive breastfeeding rate was over 40 percentage points at both 2 and 4 months of age (92% versus 51% at 2 months and 73% versus 30% at 4 months) and 9 percentage points at 6 months (11% versus 1.8%).

    CONCLUSIONS:

    Current status indicators based on a 24-hour period may be inadequate and even misleading for many purposes. We propose that in many studies an indicator called 'exclusive breastfeeding since birth' could be added.

  • 27.
    Aarts, Clara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Nordstrom, P. M.
    Koskinen, L.
    Juhansoo, T.
    Mitchell, M. P.
    Marquis, F.
    Chasse, F.
    Critchley, K.
    Campbell, B.
    Hemingway, A.
    Enabling nursing students to focus on the Ottawa Charter and the nurses role in tackling inequalities in health through international exchange2010Ingår i: Nurse Education Today, ISSN 0260-6917, E-ISSN 1532-2793, Vol. 30, nr 5, s. 448-452Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Student nurses in a transatlantic exchange program explored the role of registered nurses in five countries' public health systems. The Ottawa Charter provided a framework for students to examine the nurse's responsibilities in public health. Students took practice placements in geographically rural areas on another continent and explored inequalities in health care. If nurses are to understand their role in the health care system then they must be taught the scope of their practice including their role in health promotion, public health practice and community development. For this project nursing instructors developed an assignment relevant to the aims and suitable for students in all five nursing programs. Only three of 48 students offered an assignment which focused on building healthy public policy. Nurse educators need to explore this further to ensure nurses of the future are aware of their role and responsibilities in this area and have skills to work effectively to influence and build healthy policy. The international student exchange supported the students' developing understanding of the breadth of initiatives around the globe where nurses are actively engaged in addressing inequalities of health. Findings from an analysis of their assignments are presented in this evaluative report.

  • 28.
    Aase, Karin
    et al.
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Ernkvist, Mira
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Ebarasi, Lwaki
    Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Jakobsson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Majumdar, Arindam
    Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Yi, Chunling
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
    Birot, Olivier
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Ming, Yue
    Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institutet, St Erik’s Hospital, SE-11284 Stockholm, Sweden.
    Kvanta, Anders
    Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institutet, St Erik’s Hospital, SE-11284 Stockholm, Sweden.
    Edholm, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Aspenström, Pontus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Kissil, Joseph
    Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Shimono, Akihiko
    Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, Chuou-ku, Kobe 650-0047, Japan.
    Holmgren, Lars
    Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
    Angiomotin regulates endothelial cell migration during embryonic angiogenesis2007Ingår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 21, nr 16, s. 2055-2068Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.

  • 29. Aavik, Einari
    et al.
    Lumivuori, Henri
    Leppänen, Olli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Wirth, Thomas
    Hakkinen, Sanna-Kaisa
    Braesen, Jan-Hinrich
    Beschorner, Ulrich
    Zeller, Thomas
    Braspenning, Maarten
    van Criekinge, Wim
    Makinen, Kimmo
    Yla-Herttuala, Seppo
    Global DNA methylation analysis of human atherosclerotic plaques reveals extensive genomic hypomethylation and reactivation at imprinted locus 14q32 involving induction of a miRNA cluster2015Ingår i: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, nr 16, s. 993-U23Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims Genetics can explain just above 10% of the observed heritability in cardiovascular diseases. Epigenetics is about to provide some further explanations, but the information needed for that is in the accumulation phase. Genome-wide DNA methylation analysis has revealed thousands of genes, which are epigenetically differentially regulated in atherosclerotic plaques. Our results point to an additional level of complexity that needs to be integrated into the aetiology of atherogenesis.We conducted a genome-wide analysis to identify differentially methylated genes in atherosclerotic lesions. Methods DNA methylation at promoters, exons and introns was identified by massive parallel sequencing. Gene expression was analysed by microarrays, qPCR, immunohistochemistry and western blots. Results Globally, hypomethylation of chromosomal DNA predominates in atherosclerotic plaques and two-thirds of genes showing over 2.5-fold differential in DNA methylation are up-regulated in comparison to healthy mammary arteries. The imprinted chromatin locus 14q32 was identified for the first time as an extensively hypomethylated area in atherosclerosis with highly induced expression of miR127, -136, -410, -431, -432, -433 and capillary formation-associated gene RTL1. The top 100 list of hypomethylated promoters exhibited over 1000-fold enrichment for miRNAs, many of which mapped to locus 14q32. Unexpectedly, also gene body hypermethylation was found to correlate with stimulated mRNA expression. Conclusion Significant changes in genomic methylation were identified in atherosclerotic lesions. The most prominent gene cluster activated via hypomethylation was detected at imprinted chromosomal locus 14q32 with several clustered miRNAs that were up-regulated. These results suggest that epigenetic changes are involved in atherogenesis and may offer new potential therapeutic targets for vascular diseases.

  • 30.
    Abadpour, Shadab
    et al.
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Göpel, Sven O.
    AstraZeneca R&D Gothenburg, Dept CVMD Biosci, Gothenburg, Sweden..
    Schive, Simen W.
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Foss, Aksel
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Scholz, Hanne
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 1575Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.

  • 31.
    Abadpour, Shadab
    et al.
    Oslo University Hospital, Oslo, Norway.
    Halvorsen, Bente
    Oslo University Hospital, Oslo, Norway.
    Sahraoui, Afaf
    University of Oslo, Oslo, Norway.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Aukrust, Pål
    Oslo University Hospital, Oslo, Norway.
    Scholz, Hanne
    Oslo University Hospital, Oslo, Norway.
    Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT2018Ingår i: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, artikel-id JME-17-0182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found up-regulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20mM glucose) + LIGHT in vitro and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by up-regulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.

  • 32. Abarca-Gómez, L.
    et al.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lytsy, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Socialmedicinsk epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Yngve, Agneta
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för kostvetenskap.
    Ezzati, M
    Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.2017Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, nr 10113, s. 2627-2642Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults.

    METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity).

    FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m(2) per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m(2) per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m(2) per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m(2) per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m(2) per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese.

    INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults.

  • 33.
    Abbasi, Mina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Translational aspects of unbound brain to plasma concentration ratios2012Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction:  The unbound brain-to-plasma concentration ratio (Kp,uu,brain) is one of the most important indicators for brain penetration in the area of CNS drug discovery and development. Kp,uu,brain can be calculated by combining the total brain-to-plasma concentration ratio (Kp,brain),  the brain free fraction (fu,brain) and  the plasma free fraction (fu,p).

    Aim:  This study has three purposes, to calculate Kp,uu,brain from publications in humans,  to collect data regarding species differences in Kp,uu,brain and to see whether Kp,uu,brain in humans differs in different  brain regions or not.

    Materials and Methods:  The values of Kp, brain were derived from positron emission tomography (PET), MRS (Magnetic Resonance Spectroscopy), and brain surgery for tumor removal. fu,brain and fu,p were collected from brain homogenate, equilibrium dialysis and ultrafiltration studies.

    Results:  Data on Kp,brain was sparse in the literature. Kp,uu,brain was calculated for sixteen different drugs in humans. According to the calculation, nine of these sixteen compounds were found to be actively influxed into the brain, six were actively effluxed from the BBB and one had a passive diffusion. Depending on the compound, Kp,uu,brain was higher or smaller in humans compared to mice and rats.  Kp,uu,brain for five compounds were calculated for different brain regions. Four compounds had a higher Kp,uu,brain value in almost all other regions than the cerebellum and one had a higher Kp,uu,brain in cerebellum than in the other regions.

    Conclusions:  No definite conclusion on Kp,uu,brain in humans, species differences in Kp,uu,brain  or Kp,uu,brain  in different human brain regions could be reached in this study. In view of the importance of Kp,uu,brain  in CNS drug discovery and development, more studies on Kp,uu,brain in humans and in the other species are required.

  • 34.
    Abbasinejad Enger, Shirin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Dosimetry Studies of Different Radiotherapy Applications using Monte Carlo Radiation Transport Calculations2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations.

    In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing.

    In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles.

    In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.

    Delarbeten
    1. Monte Carlo calculations of thermal neutron capture in gadolinium: a comparison of GEANT4 and MCNP with measurements.
    Öppna denna publikation i ny flik eller fönster >>Monte Carlo calculations of thermal neutron capture in gadolinium: a comparison of GEANT4 and MCNP with measurements.
    2006 Ingår i: Medical Physics, ISSN 0094-2405, Vol. 33, nr 2, s. 337-341Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-97526 (URN)
    Tillgänglig från: 2008-09-19 Skapad: 2008-09-19Bibliografiskt granskad
    2. Gadolinium neutron capture brachytherapy (GdNCB), a new treatment method for intravascular brachytherapy.
    Öppna denna publikation i ny flik eller fönster >>Gadolinium neutron capture brachytherapy (GdNCB), a new treatment method for intravascular brachytherapy.
    2006 Ingår i: Medical Physics, ISSN 0094-2405, Vol. 33, nr 1, s. 46-51Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-97527 (URN)
    Tillgänglig från: 2008-09-19 Skapad: 2008-09-19Bibliografiskt granskad
    3. Dosimetry for gadolinium neutron capture therapy (GdNCT)
    Öppna denna publikation i ny flik eller fönster >>Dosimetry for gadolinium neutron capture therapy (GdNCT)
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-97528 (URN)
    Tillgänglig från: 2008-09-19 Skapad: 2008-09-19 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    4. Cross-fire doses from β-emitting radionuclides in targeted radiotherapy: A theoretical study based on experimentally measured tumor characteristics
    Öppna denna publikation i ny flik eller fönster >>Cross-fire doses from β-emitting radionuclides in targeted radiotherapy: A theoretical study based on experimentally measured tumor characteristics
    2008 (Engelska)Ingår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 53, nr 7, s. 1909-1920Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A mathematical model based upon histological findings of cell cluster distributions in primary breast cancers and lymph node metastases was developed. The model is unique because it accounts for tumor cell cluster formations within both primary tumors and metastases. The importance of inter-cell cluster cross-fire radiation dose for beta-emitting radionuclides of different energies was studied. The cell clusters were simulated as spheres with 15, 25 and 50 microm radii having a homogeneous radioactivity distribution. The self-dose as well as the dose distribution around the spheres was calculated for seven radionuclides, (90)Y, (188)Re, (32)P, (186)Re, (159)Gd, (131)I and (177)Lu using the GEANT4 Monte Carlo code. Generally, the self-dose was decreasing with increasing energy of the emitted beta particles. An exception was (188)Re which, compared to (32)P, had higher beta energy as well as higher self-dose. This was due to the higher emission of conversion and Auger electrons in the (188)Re-decay. When the cell clusters had a mean distance that was shorter than the maximum range of beta-particles, then the inter-cluster cross-fire radiation contributed significantly to the absorbed dose. Thus, high-energy beta-particles may, in spite of a low self-dose to single clusters, still be favorable to use due to the contribution of inter-cluster cross-fire radiation.

    Nyckelord
    Cancer, tumor, radiation, therapy
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-97529 (URN)10.1088/0031-9155/53/7/007 (DOI)000254175900007 ()18364546 (PubMedID)
    Tillgänglig från: 2008-09-19 Skapad: 2008-09-19 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    5. Determination of self perturbations of spectra in detectors in photon fields
    Öppna denna publikation i ny flik eller fönster >>Determination of self perturbations of spectra in detectors in photon fields
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-97530 (URN)
    Tillgänglig från: 2008-09-19 Skapad: 2008-09-19 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
  • 35.
    Abberud, Madelene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Time to first antibiotic administration in The Alfred Emergency and Trauma Centre for suspected febrile neutropenia: a retrospective chart review2012Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Introduction: Febrile neutropenia (FN) is a frequent complication of chemotherapy use in cancer patients. There is evidence to suggest that the time to antibiotic administration is associated with increase survival and effective clinical outcome. The Australian consensus guidelines for the management of FN in adult cancer patients recommends treatment within 30 minutes to patients with features of systemic compromise. A study performed at The Alfred Hospital in 2010 revealed a median time of 145 minutes to first antibiotic administration. A new guideline was therefore developed and education was implemented. This study was conducted to evaluate the intervention. Aim: To determine time to first antibiotic prescribing and administration for patients with suspected FN presenting to the Alfred Emergency and Trauma centre. Materials and Methods: The electronic medical record of 112 episodes of suspected FN presenting between March and August 2012 were reviewed.  Data were retrospective collected according to a FN data spreadsheet. An observational study were also performed at  The Alfred Emergency and Trauma centre during October and November 2012 to determine time to first antimicrobial prescribing, because this data could not be collected from the electronic medical record. Results: The median time from presentation to antibiotic prescribing was 68 minutes. The median time from presentation to antibiotic administration was 121 minutes. Conclusions: The implementation of the new guidelines has reduced the time with 16.6%, but the target first antibiotic administration within 30 minutes has not been reached.

  • 36. Abbott, A. L.
    et al.
    Adelman, M. A.
    Alexandrov, A. V.
    Barnett, H. J. M.
    Beard, J.
    Bell, P.
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Blacker, D.
    Buckley, C. J.
    Cambria, R. P.
    Comerota, A. J.
    Connolly, E. S., Jr.
    Davies, A. H.
    Eckstein, H. H.
    Faruqi, R.
    Fraedrich, G.
    Gloviczki, P.
    Hankey, G. J.
    Harbaugh, R. E.
    Heldenberg, E.
    Kittner, S. J.
    Kleinig, T. J.
    Mikhailidis, D. P.
    Moore, W. S.
    Naylor, R.
    Nicolaides, A.
    Paraskevas, K. I.
    Pelz, D. M.
    Prichard, J. W.
    Purdie, G.
    Ricco, J. B.
    Riles, T.
    Rothwell, P.
    Sandercock, P.
    Sillesen, H.
    Spence, J. D.
    Spinelli, F.
    Tan, A.
    Thapar, A.
    Veith, F. J.
    Zhou, W.
    Why the United States Center for Medicare and Medicaid Services (CMS) Should not Extend Reimbursement Indications for Carotid Artery Angioplasty/Stenting2012Ingår i: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 43, nr 3, s. 247-251Artikel i tidskrift (Refereegranskat)
  • 37. Abbott, A. L.
    et al.
    Adelman, M. A.
    Alexandrov, A. V.
    Barnett, H. J. M.
    Beard, J.
    Bell, P.
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Blacker, D.
    Buckley, C. J.
    Cambria, R. P.
    Comerota, A. J.
    Connolly, E. Sander
    Davies, A. H.
    Eckstein, H. -H
    Faruqi, R.
    Fraedrich, G.
    Gloviczki, P.
    Hankey, G. J.
    Harbaugh, R. E.
    Heldenberg, E.
    Kittner, S. J.
    Kleinig, T. J.
    Mikhailidis, D. P.
    Moore, W. S.
    Naylor, R.
    Nicolaides, A.
    Paraskevas, K. I.
    Pelz, D. M.
    Prichard, J. W.
    Purdie, G.
    Ricco, J. -B
    Riles, T.
    Rothwell, P.
    Sandercock, P.
    Sillesen, H.
    Spence, J. D.
    Spinelli, F.
    Tan, A.
    Thapar, A.
    Veith, F. J.
    Zhou, Wei
    Why the United States Center for Medicare and Medicaid Services (CMS) should not extend reimbursement indications for carotid artery angioplasty/stenting2012Ingår i: International Journal of Angiology, ISSN 0392-9590, E-ISSN 1827-1839, Vol. 31, nr 1, s. 85-89Artikel i tidskrift (Refereegranskat)
  • 38. Abbott, Anne L.
    et al.
    Adelman, Mark A.
    Alexandrov, Andrei V.
    Barber, P. Alan
    Barnett, Henry J. M.
    Beard, Jonathan
    Bell, Peter
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Blacker, David
    Bonati, Leo H.
    Brown, Martin M.
    Buckley, Clifford J.
    Cambria, Richard P.
    Castaldo, John E.
    Comerota, Anthony J.
    Connolly, E. Sander, Jr.
    Dalman, Ronald L.
    Davies, Alun H.
    Eckstein, Hans-Henning
    Faruqi, Rishad
    Feasby, Thomas E.
    Fraedrich, Gustav
    Gloviczki, Peter
    Hankey, Graeme J.
    Harbaugh, Robert E.
    Heldenberg, Eitan
    Hennerici, Michael G.
    Hill, Michael D.
    Kleinig, Timothy J.
    Mikhailidis, Dimitri P.
    Moore, Wesley S.
    Naylor, Ross
    Nicolaides, Andrew
    Paraskevas, Kosmas I.
    Pelz, David M.
    Prichard, James W.
    Purdie, Grant
    Ricco, Jean-Baptiste
    Ringleb, Peter A.
    Riles, Thomas
    Rothwell, Peter M.
    Sandercock, Peter
    Sillesen, Henrik
    Spence, J. David
    Spinelli, Francesco
    Sturm, Jonathon
    Tan, Aaron
    Thapar, Ankur
    Veith, Frank J.
    Wijeratne, Tissa
    Zhou, Wei
    Why Calls for More Routine Carotid Stenting Are Currently Inappropriate An International, Multispecialty, Expert Review and Position Statement2013Ingår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 44, nr 4, s. 1186-1190Artikel i tidskrift (Refereegranskat)
  • 39. Abbott, Anne L
    et al.
    Adelman, Mark A
    Alexandrov, Andrei V
    Barnett C C, Henry J M
    Beard, Jonathan
    Bell, Peter
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Blacker, David
    Buckley, Clifford J
    Cambria, Richard P
    Comerota, Anthony J
    Connolly, E Sander
    Davies, Alun H
    Eckstein, Hans-Henning
    Faruqi, Rishad
    Fraedrich, Gustav
    Gloviczki, Peter
    Hankey, Graeme J
    Harbaugh, Robert E
    Heldenberg, Eitan
    Kittner, Steven J
    Kleinig, Timothy J
    Mikhailidis, Dimitri P
    Moore, Wesley S
    Naylor, Ross
    Nicolaides, Andrew
    Paraskevas, Kosmas I
    Pelz, David M
    Prichard, James W
    Purdie, Grant
    Ricco, Jean-Baptiste
    Riles, Thomas
    Rothwell, Peter
    Sandercock, Peter
    Sillesen, Henrik
    Spence, J David
    Spinelli, Francesco
    Tan, Aaron
    Thapar, Ankur
    Veith, Frank J
    Zhou, Wei
    Why the US Center for Medicare and Medicaid Services Should Not Extend Reimbursement Indications for Carotid Artery Angioplasty/Stenting2012Ingår i: Angiology, ISSN 0003-3197, E-ISSN 1940-1574, Vol. 63, nr 8, s. 639-644Artikel i tidskrift (Refereegranskat)
  • 40. Abbott, Anne L.
    et al.
    Adelman, Mark A.
    Alexandrov, Andrei V.
    Barnett, Henry J. M.
    Beard, Jonathan
    Bell, Peter
    Björck, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kärlkirurgi.
    Blacker, David
    Buckley, Clifford J.
    Cambria, Richard P.
    Comerota, Anthony J.
    Connolly, E. Sander
    Davies, Alun H.
    Eckstein, Hans-Henning
    Faruqi, Rishad
    Fraedrich, Gustav
    Gloviczki, Peter
    Hankey, Graeme J.
    Harbaugh, Robert E.
    Heldenberg, Eitan
    Kittner, Steven J.
    Kleinig, Timothy J.
    Mikhailidis, Dimitri P.
    Moore, Wesley S.
    Naylor, Ross
    Nicolaides, Andrew
    Paraskevas, Kosmas I.
    Pelz, David M.
    Prichard, James W.
    Purdie, Grant
    Ricco, Jean-Baptiste
    Riles, Thomas
    Rothwell, Peter
    Sandercock, Peter
    Sillesen, Henrik
    Spence, J. David
    Spinelli, Francesco
    Tan, Aaron
    Thapar, Ankur
    Veith, Frank J.
    Zhou, Wei
    Why the United States Center for Medicare and Medicaid Services should not extend reimbursement indications for carotid artery angioplasty/stenting2012Ingår i: VASCULAR, ISSN 1708-5381, Vol. 20, nr 1, s. 1-7Artikel i tidskrift (Övrigt vetenskapligt)
  • 41. Abbud-Filho, Mario
    et al.
    Adams, Patricia L
    Alberú, Josefina
    Cardella, Carl
    Chapman, Jeremy
    Cochat, Pierre
    Cosio, Fernando
    Danovitch, Gabriel
    Davis, Connie
    Gaston, Robert S
    Humar, Atul
    Hunsicker, Lawrence G
    Josephson, Michelle A
    Kasiske, Bertram
    Kirste, Günter
    Leichtman, Alan
    Munn, Stephen
    Obrador, Gregorio T
    Tibell, Annika
    Wadström, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Zeier, Martin
    Delmonico, Francis L
    A report of the Lisbon Conference on the care of the kidney transplant recipient2007Ingår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 83, nr 8, s. S1-S22Artikel, forskningsöversikt (Refereegranskat)
  • 42.
    Abdeldaim, Guma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Korsgaard, J.
    Köpenhamns Universitet.
    Olcén, P.
    Örebro Universitet, klinisk mikrobiologi.
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Strålin, Kristoffer
    Örebro Universitet, klinisk mikrobiologi.
    Is quantitative PCR for the pneumolysin (ply) gene useful for detection of pneumococcal lower respiratory tract infection?2009Ingår i: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 15, nr 6, s. 565-570Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pneumolysin (ply) gene is widely used as a target in PCR assays for Streptococcus pneumoniae in respiratory secretions. However, false-positive results with conventional ply-based PCR have been reported. The aim here was to study the performance of a quantitative ply-based PCR for the identification of pneumococcal lower respiratory tract infection (LRTI). In a prospective study, fibreoptic bronchoscopy was performed in 156 hospitalized adult patients with LRTI and 31 controls who underwent bronchoscopy because of suspicion of malignancy. Among the LRTI patients and controls, the quantitative ply-based PCR applied to bronchoalveolar lavage (BAL) fluid was positive at >/=10(3) genome copies/mL in 61% and 71% of the subjects, at >/=10(5) genome copies/mL in 40% and 58% of the subjects, and at >/=10(7) genome copies/mL in 15% and 3.2% of the subjects, respectively. Using BAL fluid culture, blood culture, and/or a urinary antigen test, S. pneumoniae was identified in 19 LRTI patients. As compared with these diagnostic methods used in combination, quantitative ply-based PCR showed sensitivities and specificities of 89% and 43% at a cut-off of 10(3) genome copies/mL, of 84% and 66% at a cut-off of 10(5) genome copies/mL, and of 53% and 90% at a cut-off of 10(7) genome copies/mL, respectively. In conclusion, a high cut-off with the quantitative ply-based PCR was required to reach acceptable specificity. However, as a high cut-off resulted in low sensitivity, quantitative ply-based PCR does not appear to be clinically useful. Quantitative PCR methods for S. pneumoniae using alternative gene targets should be evaluated.

  • 43.
    Abdeldaim, Guma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Mölling, Paula
    Holmberg, Hans
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Olcén, Per
    Strålin, Kristoffer
    Usefulness of real-time PCR for lytA, ply, and Spn9802 on plasma samples for the diagnosis of pneumococcal pneumonia2010Ingår i: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 16, nr 8, s. 1135-1141Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study, we evaluated rapid real-time PCR assays for ply, Spn9802, and lytA applied to plasma samples for the detection of Streptococcus pneumoniae in patients with community-acquired pneumonia (CAP). In a prospective study of CAP aetiology, an EDTA plasma sample was collected together with blood culture in 92 adult CAP patients and 91 adult controls. Among the 92 CAP patients, lytA PCR was positive in eight (9%), Spn9802 PCR was positive in 11 (12%) and ply PCR was positive in 19 (21%) cases. Of 91 controls, the ply PCR was positive in eight cases (9%), but no positive cases were noted by Spn9802 or lytA PCRs. Ten CAP patients had pneumococcal bacteraemia. Compared to blood culture, PCR for lytA, Spn9802 and ply had sensitivities of 70% (7/10), 60% (6/10) and 70% (7/10), and specificities of 96% (79/82), 94% (77/82) and 85% (70/82) respectively. With blood culture and/or culture of representative sputum, and/or urinary antigen detection, S. pneumoniae was identified in 31 CAP patients. Compared to these tests in combination, PCR for lytA, Spn9802 and ply showed sensitivities of 26% (8/31), 32% (10/31) and 42% (13/31), and specificities of 100% (61/61), 98% (60/61) and 90% (55/61) respectively. We conclude that Spn9802 and lytA PCRs may be useful for the rapid detection of bacteraemic pneumococcal pneumonia, whereas ply PCR is not specific enough for routine use and blood PCR with small plasma volumes is not useful for the detection of nonbacteraemic pneumococcal pneumonia.

  • 44.
    Abdeldaim, Guma M. K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    PCR detection of haemophilus influenzae from respiratory specimens2013Ingår i: PCR Detection of Microbial Pathogens / [ed] Mark Wilks, Humana Press, 2013, 2, s. 115-123Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The detection of Haemophilus influenzae by conventional methods like culture is time-consuming and may give false-negative results, especially during ongoing antibiotic treatment. Therefore, non-culture based methods that are sensitive, specific, and rapid are valuable for early diagnosis and effective therapy. Here we describe a quantitative real-time PCR assay based on the outer membrane P6 gene omp6, to detect H. influenzae and its application on respiratory tract specimens.

  • 45.
    Abdeldaim, Guma M. K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Stralin, Kristoffer
    Olcen, Per
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk virologi.
    Molling, Paula
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Quantitative fucK gene polymerase chain reaction on sputum and nasopharyngeal secretions to detect Haemophilus influenzae pneumonia2013Ingår i: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 76, nr 2, s. 141-146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A quantitative polymerase chain reaction (PCR) for the fucK gene was developed for specific detection of Haemophilus influenzae. The method was tested on sputum and nasopharyngeal aspirate (NPA) from 78 patients with community-acquired pneumonia (CAP). With a reference standard of sputum culture and/or serology against the patient's own nasopharyngeal isolate, H. influenzae etiology was detected in 20 patients. Compared with the reference standard, fucK PCR (using the detection limit 10(5) DNA copies/mL) on sputum and NPA showed a sensitivity of 95.0% (19/20) in both cases, and specificities of 87.9% (51/58) and 89.5% (52/58), respectively. In a receiver operating characteristic curve analysis, sputum fucK PCR was found to be significantly superior to sputum P6 PCR for detection of H. influenzae CAP. NPA fucK PCR was positive in 3 of 54 adult controls without respiratory symptoms. In conclusion, quantitative fucK real-time PCR provides a sensitive and specific identification of H. influenzae in respiratory secretions.

  • 46.
    Abdeldaim, Guma M. K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital.
    Kirsebom, Leif A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Olcén, Per
    Department of Clinical Microbiology, Örebro University Hospital.
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Detection of Haemophilus influenzae in respiratory secretions from pneumonia patients by quantitative real-time polymerase chain reaction2009Ingår i: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 64, nr 4, s. 366-373Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A quantitative real-time polymerase chain reaction (PCR) based on the omp P6 gene was developed to detect Haemophilus influenzae. Its specificity was determined by analysis of 29 strains of 11 different Haemophilus spp. and was compared with PCR assays having other target genes: rnpB, 16S rRNA, and bexA. The method was evaluated on nasopharyngeal aspirates from 166 adult patients with community-acquired pneumonia. When 104 DNA copies/mL was used as cutoff limit for the method, P6 PCR had a sensitivity of 97.5% and a specificity of 96.0% compared with the culture. Of 20 culture-negative but P6 PCR-positive cases, 18 were confirmed by fucK PCR as H. influenzae. Five (5.9%) of 84 nasopharyngeal aspirates from adult controls tested PCR positive. We conclude that the P6 real-time PCR is both sensitive and specific for identification of H. influenzae in respiratory secretions. Quantification facilitates discrimination between disease-causing H. influenzae strains and commensal colonization.

  • 47.
    Abdeldaim, Guma M. K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Strålin, Kristoffer
    Olcén, Per
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Toward a quantitative DNA-based definition of pneumococcal pneumonia: a comparison of Streptococcus pneumoniae target genes, with special reference to the Spn9802 fragment2008Ingår i: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 60, nr 2, s. 143-150Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The current shift from phenotypically toward genotypically based microbial diagnosis is not unproblematic. A novel quantitative real-time polymerase chain reaction (PCR) assay based on the Spn9802 DNA fragment was therefore developed for detection of Streptococcus pneumoniae. Out of 44 bacterial species, only S. pneumoniae and Streptococcus pseudopneumoniae were positive in Spn9802 PCR. In an evaluation on nasopharyngeal aspirates from 166 patients with community-acquired pneumonia, the assay was positive in 49 of 50 culture-positive cases. Of 19 culture-negative but Spn9802 PCR-positive cases, 12 were confirmed as S. pneumoniae by rnpB sequence analysis. With an expanded reference standard, including culture and rnpB sequencing, Spn9802 had a sensitivity of 94% and a specificity of 98%. A cutoff for clinically significant positivity was 10(4) DNA copies/mL, giving 71% sensitivity and 100% specificity. In conclusion, Spn9802 real-time PCR is highly sensitive and specific. The quantification it provides enables differentiation between pneumococcal pathogenicity and commensalism.

  • 48.
    Abdeldaim, Guma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Strålin, Kristoffer
    Department of Infectious Diseases, Örebro University Hospital, Örebro.
    Korsgaard, Jens
    Department of Chest Diseases, Aarhus University Hospital, Aalborg, Denmark.
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Multiplex quantitative PCR for detection of lower respiratory tract infection and meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis2010Ingår i: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 10, s. 310-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Streptococcus pneumoniae and Haemophilus influenzae cause pneumonia and as Neisseria meningitidis they are important agents of meningitis. Although several PCR methods have been described for these bacteria the specificity is an underestimated problem. Here we present a quantitative multiplex real-time PCR (qmPCR) for detection of S. pneumoniae (9802 gene fragment), H. influenzae (omp P6 gene) and N. meningitidis (ctrA gene). The method was evaluated on bronchoalveolar lavage (BAL) samples from 156 adults with lower respiratory tract infection (LRTI) and 31 controls, and on 87 cerebrospinal fluid (CSF) samples from meningitis patients.

    Results. The analytical sensitivity was not affected by using a combined mixture of reagents and a combined DNA standard (S. pneumoniae/H. influenzae/N. meningitidis) in single tubes. By blood- and BAL-culture and S. pneumoniae urinary antigen test, S. pneumoniae and H. influenzae were aetiological agents in 21 and 31 of the LTRI patients, respectively. These pathogens were identified by qmPCR in 52 and 72 of the cases, respectively, yielding sensitivities and specificities of 95% and 75% for S. pneumoniae, and 90% and 65% for H. influenzae, respectively. When using a cut-off of 105 genome copies/mL for clinical positivity the sensitivities and specificities were 90% and 80% for S. pneumoniae, and 81% and 85% for H. influenzae, respectively. Of 44 culture negative but qmPCR positive for H. influenzae, 41 were confirmed by fucK PCR as H. influenzae. Of the 103 patients who had taken antibiotics prior to sampling, S. pneumoniae and H. influenzae were identified by culture in 6% and 20% of the cases, respectively, and by the qmPCR in 36% and 53% of the cases, respectively. In 87 CSF samples S. pneumoniae and N. meningitidis were identified by culture and/or 16 S rRNA in 14 and 10 samples and by qmPCR in 14 and 10 samples, respectively, giving a sensitivity of 100% and a specificity of 100% for both bacteria.

    Conclusions. The PCR provides increased sensitivity and the multiplex format facilitates diagnosis of S. pneumoniae, H. influenzae and N. meningitidis and the assay enable detection after antibiotic treatment has been installed. Quantification increases the specificity of the etiology for pneumonia.

  • 49.
    Abdeldaim, Guma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi. Benghazi Univ, Fac Med, Dept Med Microbiol & Parasitol, Benghazi, Libya..
    Svensson, Erik
    Statens Serum Inst, Int Reference Lab Mycobacteriol, Copenhagen, Denmark..
    Blomberg, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk virologi.
    Herrmann, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Duplex detection of the Mycobacterium tuberculosis complex and medically important non-tuberculosis mycobacteria by real-time PCR based on the rnpB gene2016Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, nr 11, s. 991-995Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A duplex real-time PCR based on the rnpB gene was developed for Mycobacterium spp. The assay was specific for the Mycobacterium tuberculosis complex (MTB) and also detected all 19 tested species of non-tuberculous mycobacteria (NTM). The assay was evaluated on 404 clinical samples: 290 respiratory samples and 114 from tissue and other nonrespiratory body sites. M. tuberculosis was detected by culture in 40 samples and in 30 samples by the assay. The MTB assay showed a sensitivity similar to Roche Cobas Amplicor MTB-PCR (Roche Molecular Systems, Pleasanton, CA, USA). There were only nine samples with non-tuberculous mycobacteria detected by culture. Six of them were detected by the PCR assay.

  • 50. Abdelfatah Possnert, Heba
    Detection of Thymidine Kinase 1 Activity in Whole Blood Using an Oligonucleotide System2014Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [en]

    In today’s medical science studies, many tumor markers are being used to monitor cancer cell proliferation, but the number of assays for analysis of these markers are few. The aim of this study was to find an easier and more time-efficient way to measure the activity of a specific tumor marker called tymidine kinase 1 (TK1). This tumor marker is an important enzyme involved in cell proliferation and is a key enzyme in the salvage pathway. TK1 activity is related to the occurrence of hematological malignancies and cell activity and therefore have been used as a marker when monitoring this group of patients in treatment. Measurement of the enzyme activity in this study was performed by using an oligonucleotide assay. Detection of the enzyme activity in whole blood and in plasma has not previously been shown. The TK1 activity measured in whole blood and plasma correlated with TK1 activity measured in serum (R2=0,8651 and R2 =0,9845, respectively). It was found that it is possible to determine the TK1 activity in whole blood but only if the activity was measured on the same day as the blood samples were taken. The results shows that the activity measurement of TK1 in plasma and whole blood can be used as a marker to verify patients' therapy in cancer care. This study is only the beginning and further investigations should be made in the future to determine if the method that is subject to this study has the requested effects.

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