| 1. |
- Brante, Thomas, et al.
(författare)
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Profession och vetenskap : idéer och strategier för ett professionslärosäte
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Förord av Björn Brorström, Prorektor Högskolan i Borås Ett professionslärosäte bedriver utbildning och forskning på vetenskaplig grund. Vetenskapliga metoder tillämpas och framkomna resultat prövas för att säkra tillförlitlighet och relevans. Förmågan att problematisera, formulera frågor och välja lämpliga metoder för att besvara frågor är egenskaper för god forskning och utmärkande för en stark utbildnings- och forskningsmiljö. Vid ett professionslärosäte finns samtidigt en stark strävan efter att i utbildning och forskning ta till vara den kunskap och de erfarenheter som professioner besitter och därigenom säkra en hög grad av praktisk relevans. Växelverkan mellan teori och praktik och erfarenhetsutbyte mellan forskare och praktiker är ständigt pågående. Det finns ingen avslutning på processen utan den pågår utan avbrott. En nödvändig förutsättning för ett fruktbart samarbete är en ömsesidig respekt och vilja att stödja och ifrågasätta varandra. Forskaren måste vara beredd på kritik för bristen på praktisk relevans och professionsföreträdaren måste vara beredd på att förtrogenhetskunskapens lämplighet ifrågasätts. Det är en fråga om med- och mothåll från båda håll i syfte att långsiktigt utveckla teori och praktik. Det är en utmaning att utveckla, etablera och därefter kontinuerligt försvara och förbättra professionslärosätet. Ett led i utvecklingen är att inom ramen för Högskolan i Borås föra en debatt om innebörden av ett professionslärosäte och vad vi behöver göra för att förbättra verksamheten. På uppdrag av rektor Lena Nordholm har medarbetare vid Bibliotekshögskolan utvecklat och ansvarat för en seminarieserie benämnd Profession och vetenskap. Seminarierna spände över ett brett fält. En av många viktiga frågor som diskuterades flitigt var huruvida vi ska forska om professioner, i för eller med, eller kanske alltihop samtidigt. Bidragen publiceras nu i denna antologi som ges ut inom ramen för Högskolan i Borås rapportserie Vetenskap för profession. Rapporten Profession och vetenskap – idéer och strategier för ett professionslärosäte, som redigerats av universitetsadjunkt Maria Lindh, kommer att få stor betydelse inom lärosätet och i vårt samarbete med företrädare för näringsliv, kulturliv och offentlig verksamhet. Jag ser det som en intressant fortsättning att anordna ett antal seminarier med inbjudna representanter för professioner där artiklarna i denna rapport kan ligga till grund för erfarenhetsutbyte och diskussioner.
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| 2. |
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| 3. |
- Hagström, Emil, et al.
(författare)
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Plasma parathyroid hormone and the risk of cardiovascular mortality in the community
- 2009
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Ingår i: Circulation. - : American Heart Association. - 0009-7322 .- 1524-4539. ; 119:21, s. 2765-2771
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Diseases with elevated levels of parathyroid hormone (PTH) such as primary and secondary hyperparathyroidism are associated with increased incidence of cardiovascular disease and death. However, data on the prospective association between circulating PTH levels and cardiovascular mortality in the community are lacking. METHODS AND RESULTS: The Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (mean age, 71 years; n=958), was used to investigate the association between plasma PTH and cardiovascular mortality. During follow-up (median, 9.7 years), 117 participants died of cardiovascular causes. In Cox proportional-hazards models adjusted for established cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease), higher plasma PTH was associated with higher risk for cardiovascular mortality (hazard ratio for 1-SD increase in PTH, 1.38; 95% confidence interval, 1.18 to 1.60; P<0.001). This association remained essentially unaltered in participants without previous cardiovascular disease and in participants with normal PTH (<6.8 pmol/L) with no other signs of a disturbed mineral metabolism (normal serum calcium, 2.2 to 2.6 mmol/L; normal glomerular filtration rate, >50 mL . min(-1) . 1.73 m(-2) and without vitamin D deficiency, plasma 25-OH vitamin D >37.5 nmol/L). Interestingly, elevated plasma PTH (>5.27 pmol/L) accounted for 20% (95% confidence interval, 10 to 26) of the population-attributable risk proportion for cardiovascular mortality. CONCLUSIONS: Plasma PTH levels predict cardiovascular mortality in the community, even in individuals with PTH within the normal range. Further studies are warranted to evaluate the clinical implications of measuring PTH in cardiovascular risk prediction and to elucidate whether PTH is a modifiable risk factor.
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| 4. |
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| 5. |
- Hermes, Andreas, et al.
(författare)
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Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: a randomized phase III trial.
- 2008
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 26:26, s. 4261-7
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: A Japanese randomized trial showed superior survival for patients with extensive-disease (ED) small-cell lung cancer (SCLC) receiving irinotecan plus cisplatin compared with etoposide plus cisplatin. The present trial evaluated the efficacy of irinotecan plus carboplatin (IC) compared with oral etoposide plus carboplatin (EC). PATIENTS AND METHODS: Patients with ED SCLC were randomly assigned to receive either IC, which consisted of carboplatin (area under the curve = 4; Chatelut formula) and irinotecan (175 mg/m2) intravenously both on day 1, or EC, which consisted of carboplatin as in IC and etoposide (120 mg/m(2)/d) orally on days 1 through 5. Courses were repeated every 3 weeks with four cycles planned. Doses were reduced by one third in patients with a WHO performance status (PS) of 3 to 4 and/or age older than 70 years. Primary end point was overall survival (OS). Secondary end points were quality of life (QOL) and complete response (CR) rate. RESULTS: Of 220 randomly assigned patients, 209 were eligible for analysis (IC, n = 105; EC, n = 104). Thirty-five percent were older than 70 years, and 47% had a PS of 2 to 4. The groups were well balanced with respect to prognostic factors. OS was inferior in the EC group (hazard ratio = 1.41; 95% CI, 1.06 to 1.87; P = .02). Median survival time was 8.5 months for IC compared with 7.1 months for EC. One-year survival rate was 34% for IC and 24% for EC. CR was seen in 18 IC patients compared with seven EC patients (P = .02). There were no statistically significant differences in hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea was more common in the IC group. QOL differences were small, with a trend toward prolonged palliation with the IC regimen. CONCLUSION: IC prolongs survival in ED SCLC with slightly better scores for QOL.
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| 6. |
- Johansson, Carolina, et al.
(författare)
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Mutagenesis and homology modelling of the Tn21 integron integrase IntI1
- 2009
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 48:8, s. 1743-1753
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Tidskriftsartikel (refereegranskat)abstract
- Horizontal DNA transfer between bacteria is widespread and a major cause of antibiotic resistance. For logistic reasons, single or combined genes are shuttled between vectors such as plasmids and bacterial chromosomes. Special elements termed integrons operate in such shuttling and are therefore vital for horizontal gene transfer. Shorter elements carrying genes, cassettes, are integrated in the integrons, or excised from them, by virtue of a recombination site, attC, positioned in the 3' end of each unit. It is a remarkable and possibly restricting elementary feature of attC that it must be single-stranded while the partner target site, attI, may be double-stranded. The integron integrases belong to the tyrosine recombinase family, and this work reports mutations of the integrase IntI1 from transposon Tn21, chosen within a well-conserved region characteristic of the integron integrases. The mutated proteins were tested for binding to a bottom strand of an attC substrate, by using an electrophoresis mobility shift assay. To aid in interpreting the results, a homology model was constructed on the basis of the crystal structure of integron integrase VchIntIA from Vibrio cholerae bound to its cognate attC substrate VCRbs. The local stability and hydrogen bonding network of key domains of the modeled structure were further examined using molecular dynamics simulations. The homology model allowed us to interpret the roles of several amino acid residues, four of which were clearly binding assay responsive upon mutagenesis. Notably, we also observed features indicating that IntI1 may be more prone to base-specific contacts with VCRbs than VchIntIA.
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| 7. |
- Soveri, Inga, et al.
(författare)
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Kidney function and discrimination of cardiovascular risk in middle-aged men
- 2009
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 266:4, s. 406-413
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo define the optimal glomerular filtration rate (GFR) cut off for discriminating the risk of myocardial infarction or cardiovascular death.DesignProspective longitudinal observational study.SettingA community-based cohort.ParticipantsA total of 2176 nondiabetic 50-year-old men without cardiovascular disease.MethodsThe men were followed until age 70. GFR was estimated at baseline using the Cockcroft–Gault formula. The optimal GFR cut-off points for discriminating risk of a fatal or nonfatal myocardial infarction and cardiovascular death were defined as the GFR levels maximizing integrated discrimination improvement (IDI).Main outcome measuresFatal or nonfatal myocardial infarction, cardiovascular death.ResultsDuring follow-up, 264 men experienced a fatal or nonfatal myocardial infarction, and 218 died of cardiovascular disease. The IDI-defined optimal GFR cut offs in this study were 98 mL min−1 for discriminating myocardial infarction risk and 92 mL min−1 for discriminating risk of cardiovascular death. In Cox proportional hazard models adjusting for established risk factors, the myocardial infarction risk was substantially higher in men with GFR below versus above 98 mL min−1 [hazard ratio (HR) 1.7, 95% confidence interval (CI) 1.3–2.3, P < 0.001], and the risk of cardiovascular death was doubled in men with GFR below versus above 92 mL min−1 (HR 2.1, 95% CI 1.5–3.0, P < 0.001).ConclusionThe GFR cut-off point for optimal discrimination of cardiovascular risk in the general population may be higher than previously suggested.
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| 8. |
- Sundström, Anna, 1969-, et al.
(författare)
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Fatigue before and after mild traumatic brain injury: Pre- and post-comparisons in relation to ApolipoproteinE
- 2007
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Ingår i: Brain Injury. - London : Informa UK Limited. - 0269-9052 .- 1362-301X. ; 21:10, s. 1049-1054
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Tidskriftsartikel (refereegranskat)abstract
- Primary objective: To assess the incidence of fatigue for persons following a mild traumatic brain injury (MTBI) and to evaluate the relationship between fatigue and APOE genotype. As fatigue is often found to be influenced by anxiety, depression and sleep disturbance, these factors were also measured. Methods and procedures: Thirty-one persons who sustained a MTBI were drawn from a population-based longitudinal study. Each person who sustained a MTBI was matched by age, gender, education and APOE genotype with two non-head injury controls. Self-reported pre- and post-injury incidence of fatigue, anxiety, depression and sleep disturbance was compared within-group and between groups. Results: For the MTBI group, incidence of fatigue was almost twice as common post- than pre-injury, whereas there was no corresponding change in a non-injured control group. Within the MTBI-group, post-injury fatigue was particularly common for carriers of the APOE ε4 allele. Conclusions: Fatigue is common sequela after a MTBI and especially pronounced for carriers of the APOE ε4 allele.
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| 9. |
- Sundström, Anna, et al.
(författare)
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Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE ε4 allele.
- 2007
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Ingår i: International Psychgeriatrics. ; 19
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Background: The є4-allele of Apolipoprotein-E (APOE) and head injury are risk factors for dementia diseases, and these factors may act synergistically to further increase the risk. The aim of the present study was to examine the association between mild head injury, APOE, and dementia.Methods: Data were obtained from the Betula prospective population-based study of aging, memory, and health. The study included 543 participants in the age range 40-85 years, free of dementia at baseline, who were followed-up within a 5-year interval. Dementia was classified using the Diagnostic and Statistical Manual of Mental Disorders Criteria. Information of previous head injury was done through screening of the participants’ answers to health questionnaires both at baseline and at following test occasions.Results: We found that subjects with head injury but without APOE є4 had no increased risk of dementia. Subjects with APOE є4 had elevated risk and those with both APOE є4 and head injury had the highest risk (OR = 5.2).Conclusions: This study confirms that APOE ε4 constitutes a risk factor of dementia, that mild injury in isolation does not increase the risk, but that head injury in combination with the APOE ε4 lead to increased risk of dementia.
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| 10. |
- Sundström, Anna, 1969-, et al.
(författare)
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Increased risk of dementia following mild head injury for carriers but not for non-carriers of the APOE ε4 allele
- 2007
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Ingår i: International psychogeriatrics. - New York : Springer. - 1041-6102 .- 1741-203X. ; 19:1, s. 159-165
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Tidskriftsartikel (refereegranskat)abstract
- Background: The ε4 allele of apolipoprotein E (APOE) and head injury are risk factors for dementia diseases, and may act synergistically to further increase the risk. The aim of this study was to examine the association between mild head injury, APOE and dementia.Methods: Data were obtained from the Betula prospective population-based study of aging, memory, and health. The study included 543 participants in the age range 40–85 years, free of dementia at baseline, who were followed up within a 5-year interval. Dementia was classified using DSM-IV criteria. Information on previous head injury was obtained through screening of the participants' answers to health questionnaires at baseline and at follow-up.Results: Subjects with head injury but without APOE ε4 had no increased risk of dementia. Subjects with APOE ε4 had an increased risk and those with both APOE ε4 and head injury had the highest risk of dementia (odds ratio = 5.2).Conclusions: APOE ε4 constitutes a risk factor for dementia, mild injury in isolation does not increase the risk, but head injury in combination with the APOE ε4 leads to increased risk of dementia.
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| 11. |
- Sundström, Johan, et al.
(författare)
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Cardiac troponin-I and risk of heart failure : a community-based cohort study
- 2009
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 30:7, s. 773-781
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: We examined if circulating levels of cardiac troponin-I (cTnI) predict subsequent heart failure in the community. METHODS AND RESULTS: Using Cox proportional hazards models, we examined the risk of a first hospitalization for heart failure during a maximum of 11.4 years in a community-based sample of 1089 70-year-old men without heart failure, valvular disease, or electrocardiographic left ventricular hypertrophy. Adjusting for smoking, systolic blood pressure, antihypertensive medication use, diabetes, body mass index, serum cholesterol, and myocardial infarction before baseline or during follow-up, 0.01 microg/L higher cTnI conferred a hazard ratio (HR) of 1.26 (95% confidence interval 1.15-1.38) for subsequent heart failure. Persons with cTnI > or =0.03 microg/L had an HR of 5.25 (2.00-13.77) compared with persons with cTnI <0.01 microg/L. Adjusting additionally for serum NTproBNP attenuated the estimates somewhat [HR 1.22 (1.11-1.34) per 0.01 microg/L of cTnI]. Excluding persons with myocardial infarction before baseline and censoring at time of myocardial infarction during follow-up, 0.01 microg/L higher cTnI was associated with a multivariable-adjusted HR of 1.31 (1.16-1.47) for heart failure. CONCLUSION: In a community-based sample, a direct measure of cardiomyocyte damage, cTnI, indicated a substantially increased risk of heart failure, accounting for other risk factors. Studies investigating the clinical utility of measuring cTnI in asymptomatic individuals are warranted.
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| 12. |
- Wohlin, Martin, et al.
(författare)
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Apolipoprotein E epsilon 4 genotype is independently associated with increased intima-media thickness in a recessive pattern
- 2007
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Ingår i: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 42:5, s. 451-456
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Tidskriftsartikel (refereegranskat)abstract
- Polymorphisms in the apolipoprotein E (Apo E) gene have been associated with lipid levels, carotid intima media thickness (CCA-IMT), inflammation and cardiovascular disease (CVD). Earlier findings suggested an association of the Apo E alleles with increased CCA-IMT following a recessive pattern. Whether associations might be independent of C-reactive protein (CRP), lipid levels and other CVD risk factors is not known. We investigated the relationships between Apo E (epsilon2, epsilon3 and epsilon4 alleles) and CCA-IMT, measured by B-mode ultrasound, in dominant and recessive models in a community-based sample of 437 men 75 years of age. In men homozygous for the epsilon4 allele CCA-IMT was significantly increased by 0.13 mm to 0.86 +/- 0.16 mm compared to 0.73 +/- 0.19 mm in non- epsilon4-carriers (P = 0.0012) and 0.73 +/- 0.21 mm in epsilon4 heterozygous (P = 0.0044) in unadjusted recessive models. The association between Apo E epsilon4 genotype and CCA-IMT was independent of Apo E epsilon2 and Apo E epsilon3 alleles, CRP, lipid variables (TG, LDL, HDL) and other CVD risk factors (smoking, hypertension, body mass index, diabetes) (P = 0.018). No relations between Apo E genotype and CCA-IMT were observed in dominant models. No significant associations between the Apo E epsilon2 and epsilon3 alleles and CCA-IMT were found. In this study, men homozygous with the ApoE epsilon4 allele had thicker CCA-IMT, independently of Apo E epsilon2 and epsilon3 alleles, CRP, lipid variables (TG, LDL, HDL) and other CVD risk factors (smoking, hypertension, body mass index, diabetes), suggesting CCA-IMT to be modified by the ApoE epsilon4 genotype in a recessive pattern.
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| 13. |
- Anderson, Martin, et al.
(författare)
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A 312-MHz CT Delta Sigma modulator using a SC feedback DAC with reduced peak current
- 2007
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Ingår i: ESSCIRC 2007: Proceedings of the33rd EuropeanSolid State Circuits Conference. - 1930-8833. - 9781424411252 ; , s. 240-243
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Konferensbidrag (refereegranskat)abstract
- This paper presents a second order continuous-time delta-sigma ADC based on a new feedback DAC technique with the low clock jitter sensitivity of the SC (switched-capacitor) technique and the low peak currents of the SI (switched current) technique. The delta-sigma ADC has been implemented in a 90 nm (1.2 V) RF-CMOS process. It measures 66.4 dB maximum SNR over 1.92 MHz bandwidth with a 312 MHz clock while consuming 5 mW. Simulations show a high level of clock pulse width suppression and the measured circuit performance is in good agreement with simulations.
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| 14. |
- Andersson, J., et al.
(författare)
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Echogenecity of the carotid intima-media complex is related to cardiovascular risk factors, dyslipidemia, oxidative stress and inflammation The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study
- 2009
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 204:2, s. 612-618
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increased carotid artery intima-media thickness (IMT), measured by ultrasound, is related to an increased risk of cardiovascular disease. Since presence of echolucent plaques increases the risk further, we investigated if echogenecity of the carotid intima-media complex is related to markers of cardiovascular risk. Our aim was therefore to investigate if intima-media echogenecity is related to cardiovascular risk factors, or to markers of inflammation and oxidation in an exploratory investigation. Methods: The PIVUS cohort study is an observational study of 1016 (509 women and 507 men) randomly chosen individuals aged 70 living in Uppsala, Sweden. Carotid artery ultrasound measurements were performed. IMT and the grey scale median (GSM) value were calculated in the intima-media complex (IM-GSM) in the far wall of the common carotid artery. Traditional risk factors were evaluated together with indices of oxidative stress and inflammation. Results: In the multiple regression analysis, HDL-cholesterol, body mass index, conjugated diens, glutathione, e-selectin and TNF alfa were significantly related to IM-GSM. IMT was independently related to blood pressure, smoking and body mass index. Conclusion: The echolucency of the carotid intima-media was related to several cardiovascular risk factors not related to IMT, such as dyslipidemia, oxidative stress and inflammation. Since the echogenecity of the carotid intima-media complex was related to different risk factors compared to carotid IMT, it is worthwhile to further explore the usefulness of this new marker of the vascular wall. (C) 2009 Published by Elsevier Ireland Ltd.
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| 15. |
- Andersson, Jessika, et al.
(författare)
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The carotid artery plaque size and echogenicity are related to different cardiovascular risk factors in the elderly : the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study
- 2009
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Ingår i: Lipids. - : Springer. - 0024-4201 .- 1558-9307. ; 44:5, s. 397-403
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Tidskriftsartikel (refereegranskat)abstract
- Carotid plaques can be characterised by ultrasound by size and echogenicity. Both size and echogenicity are predictors of cardiovascular events. The aim of this study was to examine whether traditional risk factors and markers of inflammation and oxidation were associated with plaque size and echogenicity. Computerised analysis of carotid plaque size and echogenicity (grey scale median, GSM) were performed by ultrasound in a population-based health survey in 1,016 subjects aged 70 years (PIVUS study). Information on cardiovascular risk factors was collected, together with markers of inflammation and oxidation. Increased Framingham risk score, systolic blood pressure, higher BMI and decreased HDL, lower glutathione levels were related to echolucent plaques. Previous or present smoking was common with significantly more pack-years related to the echorich plaques. Plaque size was associated with increased Framingham risk score, systolic blood pressure, blood glucose levels, smoking, ApoB/A1 ratio, OxLDL, TNF alpha, HOMA insulin resistance, leucocyte count, decreased BCD-LDL and low levels of l-selectin. Low HDL, increased BMI and decreased glutathione levels were associated with the echolucency of carotid plaques, implying metabolic factors to play a role for plaque composition. Markers of inflammation were related to plaque size alone, implying inflammation to be predominantly associated with the amount of atherosclerosis. These results suggest that plaque size and echogenicity are influenced by different risk factors.
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| 16. |
- Andersson, Martin, et al.
(författare)
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Design and measurement of a CT delta-sigma ADC with switched-capacitor switched-resistor feedback
- 2009
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Ingår i: IEEE Journal of Solid-State Circuits. - 0018-9200. ; 44:2, s. 473-483
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Tidskriftsartikel (refereegranskat)abstract
- The performance of traditional continuous-time (CT) delta-sigma analog-to-digital converters (ADCs) is limited by their large sensitivity to feedback pulse-width variations caused by clock jitter in their feedback digital-to-analog converters (DACs). To mitigate that effect, we propose a modified switched-capacitor (SC) feedback DAC technique, with a variable switched series resistor (SR). The architecture has the additional benefit of reducing the typically high SC DAC output peak currents, resulting in reduced slew-rate requirements for the loop-filter integrators. A theoretical investigation is carried out which provides new insight into the synthesis of switched-capacitor with switched series resistor (SCSR) DACs with a specified reduction of the pulse-width jitter sensitivity and minimal power consumption and complexity. To demonstrate the concept and to verify the reduced pulse-width jitter sensitivity a 5 mW, 312 MHz, second order, low-pass, 1-bit, CT delta-sigma modulator with SCSR feedback was implemented in a 1.2 V, 90 nm, RF-CMOS process. An SNR of 66.4 dB and an SNDR of 62.4 dB were measured in a 1.92 MHz bandwidth. The sensitivity to wideband clock phase noise was reduced by 30 dB compared to a traditional switched-current (SI) return-to-zero (RZ) DAC.
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| 17. |
- Andersson, Martin, et al.
(författare)
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DT Modeling of Clock Phase Noise Effects in LP CT Delta-Sigma ADCs with RZ Feedback
- 2009
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Ingår i: IEEE Transactions on Circuits and Systems II: Express Briefs. - 1549-7747. ; 56:7, s. 530-534
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Tidskriftsartikel (refereegranskat)abstract
- The performance of continuous-time (CT) Delta Sigma modulators is limited by their sensitivity to clock phase noise (PN). The clock PN-induced in-band noise (IBN) is dependent on the magnitude and frequency of both the desired in-band signals and the out-of-band signals, as well as the shape of the clock PN spectrum. This brief presents a discrete-time (DT) model of the dominant clock PN-induced errors. It enables fast and accurate simulations of the clock PN effects with arbitrary input signals, PN spectra, and noise-transfer functions. The model has been verified by CT simulations and measurements on a second-order low-pass CT Delta Sigma modulator with return-to-zero feedback. The flexibility and usefulness of the DT model are demonstrated, and the two dominant clock PN effects are compared by means of simulations with orthogonal frequency-division multiplexing input signals and various PN specifications.
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| 18. |
- Askling, J, et al.
(författare)
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Haematopoietic malignancies in rheumatoid arthritis : lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists
- 2005
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 64:10, s. 1414-1420
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear.OBJECTIVE:To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA.METHODS:A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed.RESULTS:Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas.CONCLUSION:Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.
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| 19. |
- Baecklund, Eva, et al.
(författare)
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Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:3, s. 692-701
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.METHODS:We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.RESULTS:The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.CONCLUSION:Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.
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| 20. |
- Baecklund, Eva, et al.
(författare)
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Characteristics of diffuse large B cell lymphomas in rheumatoid arthritis
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:12, s. 3774-3781
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes.METHODS:We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters.RESULTS:We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores.CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.
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| 21. |
- Baecklund, Eva, et al.
(författare)
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Expression of the human germinal-centre-associated lymphoma protein in diffuse large B-cell lymphomas in patients with rheumatoid arthritis
- 2008
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 141:1, s. 69-72
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B-cell lymphomas (DLBCL) can be subdivided into germinal centre (GC)-like and non-GC-like subtypes by CD10, BCL6 and MUM1/IRF4 status. We previously reported that patients with severe rheumatoid arthritis (RA) are at increased risk of non-GC DLBCL. This study examined a new GC-marker, human germinal-centre-associated lymphoma (HGAL) protein, in RA-DLBCL. Of 111, 38 (34%) DLBCL were HGAL-positive and showed less disseminated disease and a tendency toward improved overall survival compared to HGAL-negative cases. This supports that a majority of RA-DLBCL are of non-GC origin, indicating a specific role for activated peripheral B cells in the pathogenesis of RA-DLBCL.
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| 22. |
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| 23. |
- Byberg, Liisa, et al.
(författare)
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Total mortality after changes in leisure time physical activity in 50 year old men : 35 year follow-up of population based cohort
- 2009
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 338, s. b688-
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation.Design: Population based cohort study with follow-up over 35 years.Setting: Municipality of Uppsala, Sweden.Participants: 2205 men aged 50 in 1970-3 who were reexamined at ages 60, 70, 77, and 82 years.Main Outcome Measure: Total (all cause) mortality.Results: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking).Conclusions: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation
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| 24. |
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| 25. |
- Frumerie, Clara, 1974-
(författare)
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Functional characterization of a phage integrase and its possible use in gene therapy
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacteriophage P2 infecting Escherichia coli can integrate into the bacterial chromosome by site-specific recombination, which is catalyzed by the P2 Int recombinase. The recombination event takes place between the phage attachment site, attP, and the bacterial attachment site, attB. Once integrated into the host chromosome the P2 prophage is very stable since an additional phage protein, Cox, is required for excision. For both integration and excision, the host-encoded protein IHF is also required. In this thesis, I have made a functional characterization of the P2 integrase and investigated its future potential as a tool for gene therapy. The P2 integrase was found to have cooperative interactions upon DNA binding with its accessory proteins, IHF and Cox. An N-terminal truncated Int protein retained these cooperative interactions, although it was disrupted in arm-binding. Moreover, the Int protein was found to form stable dimers in the absence of DNA, and the C-terminus and amino acid E197 was found to be important for dimerization. Dimerization was found to be essential for recombination, but dimerization deficient mutant proteins were able to bind as well as the wt protein to attP. The P2 Int was found to mediate recombination with a human sequence at a low frequency. It was also found that the insertion of HMG-recognition boxes can substitute for the requirement of IHF for recombination in an eukaryotic cell extract and that the integrase protein is localized in the cell nucleus. Taken together, these results indicate that the P2 integrase could be of potential use in gene therapy.
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| 26. |
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| 27. |
- Grape, M., et al.
(författare)
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Two new dfr genes in trimethoprim-resistant integron-negative Escherichia coli isolates
- 2007
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 51:5, s. 1863-1864
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Tidskriftsartikel (refereegranskat)abstract
- Two Escherichia coli isolates resistant to trimethoprim but negative for integrons carried two new resistance genes, dfrA24 and dfrA26, remotely similar to one another and to the cassette-independent genes dfrA8 and dfrA9. The dfrA24 gene was not associated with known mobile elements, while dfrA26 was associated with the CR1 common region.
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| 28. |
- Guerriera, Gea, et al.
(författare)
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The RY/Sph element mediates transcriptional repression of MAT genes from late maturation to early seedling growth
- 2009
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 184:3, s. 552-565
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Tidskriftsartikel (refereegranskat)abstract
- P>In orthodox seeds, the transcriptional activator ABI3 regulates two major stages in embryo maturation: a mid-maturation (MAT) stage leading to accumulation of storage compounds, and a late maturation (LEA) stage leading to quiescence and desiccation tolerance. Our aim was to elucidate mechanisms for transcriptional shutdown of MAT genes during late maturation, to better understand phase transition between MAT and LEA stages. Using transgenic and transient approaches in Nicotiana, we examined activities of two ABI3-dependent reporter genes driven by multimeric RY and abscisic acid response elements (ABREs) from a Brassica napus napin gene, termed RY and ABRE, where the RY reporter requires ABI3 DNA binding. Expression of RY peaks during mid-maturation and drops during late maturation, mimicking the MAT gene program, and in Arabidopsis thaliana RY elements are over-represented in MAT, but not in LEA, genes. The ABI3 transactivation of RY is inhibited by staurosporine, by a PP2C phosphatase, and by a repressor of maturation genes, VAL1/HSI2. The RY element mediates repression of MAT genes, and we propose that transcriptional shutdown of the MAT program during late maturation involves inhibition of ABI3 DNA binding by dephosphorylation. Later, during seedling growth, VAL1/HSI2 family repressors silence MAT genes by binding RY elements.
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| 29. |
- Guerriero, Gea, et al.
(författare)
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The RY/Sph element mediates transcriptional repression of maturation genes from late maturation to early seedling growth
- 2009
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 184:3, s. 552-565
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Tidskriftsartikel (refereegranskat)abstract
- P>In orthodox seeds, the transcriptional activator ABI3 regulates two major stages in embryo maturation: a mid-maturation (MAT) stage leading to accumulation of storage compounds, and a late maturation (LEA) stage leading to quiescence and desiccation tolerance. Our aim was to elucidate mechanisms for transcriptional shutdown of MAT genes during late maturation, to better understand phase transition between MAT and LEA stages. Using transgenic and transient approaches in Nicotiana, we examined activities of two ABI3-dependent reporter genes driven by multimeric RY and abscisic acid response elements (ABREs) from a Brassica napus napin gene, termed RY and ABRE, where the RY reporter requires ABI3 DNA binding. Expression of RY peaks during mid-maturation and drops during late maturation, mimicking the MAT gene program, and in Arabidopsis thaliana RY elements are over-represented in MAT, but not in LEA, genes. The ABI3 transactivation of RY is inhibited by staurosporine, by a PP2C phosphatase, and by a repressor of maturation genes, VAL1/HSI2. The RY element mediates repression of MAT genes, and we propose that transcriptional shutdown of the MAT program during late maturation involves inhibition of ABI3 DNA binding by dephosphorylation. Later, during seedling growth, VAL1/HSI2 family repressors silence MAT genes by binding RY elements. New Phytologist (2009)doi: 10.1111/j.1469-8137.2009.02977.x.
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| 30. |
- Hammar, Lars-Åke, et al.
(författare)
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The effect of process conditions on pulp quality development at low consistency refining of mechanical pulp - TMP
- 2009
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Ingår i: 2009 International Mechanical Pulping Conference : proceedings. ; , s. 182-185
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Konferensbidrag (refereegranskat)abstract
- Low consistency refining (LC) as a second refining stage, after a HC-defibration is an energy-efficient process solution. This HC-LC concept has for some time been explored in pilot scale and shown promising results. However it is clear that in order to obtain an optimal development of pulp properties the LC-refining has to be optimized with regard to process conditions. In this study the effects of temperature, pH, and specific edge load in the LC-refining on the pulp quality were investigated. For this purpose a mobile LC refiner rig placed after a primary stage HC mill refiner in the Braviken Paper mill, Holmen Paper was used. The trials show that energy savings are possible with preserved properties in the production of mechanical pulp. High temperature, high pH and low specific edge load were indicated to be preferable for both the tensile index development and for preserving the fibre length of the pulp. An increased degree of refining developed as expected the tensile index but too high specific energy resulted in some fibre shortening.
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| 31. |
- Hansson, Jonas, et al.
(författare)
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Relations of serum MMP-9 and TIMP-1 levels to left ventricular measures and cardiovascular risk factors : a population-based study
- 2009
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Ingår i: European Journal of Cardiovascular Prevention & Rehabilitation. - 1741-8267 .- 1741-8275. ; 16:3, s. 297-303
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extracellular matrix remodeling is a hallmark of pathological left ventricular (LV) hypertrophy and heart failure. This process is tightly controlled by the degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). We hypothesized that circulating MMP-9 and TIMP-1 levels are altered already in persons with the signs of LV remodeling that forego clinical heart failure. DESIGN: Cross-sectional study in the Prospective Investigation of the Vasculature in Uppsala Seniors , a community-based cohort of 891 70-year-old men and women free from valvular disease, heart failure, and myocardial infarction. METHODS: We examined relations of serum MMP-9 and TIMP-1 to echocardiographic LV geometry and function. All models were adjusted for sex, height, intra-arterial systolic and diastolic blood pressures, antihypertensive medication use, and serum freezer time. RESULTS: Serum TIMP-1 was positively related to LV mass and wall thickness (r=0.15, P<0.0001 and r=0.16, P<0.0001, respectively), with a 32 g higher LV mass and 2.2 mm thicker walls in the fourth compared with the first quartile of serum TIMP-1. Serum TIMP-1 was also inversely related to LV ejection fraction (r=-0.10, P=0.009), but not to LV dimension or diastolic function indices. Serum MMP-9 was only weakly related to LV wall thickness and isovolumic relaxation time (r=0.08, P=0.04 and r=-0.08, P=0.04). CONCLUSION: In this large population-based sample, serum TIMP-1 levels were related to LV mass, wall thickness, and inversely to systolic function. This may imply that extracellular matrix remodeling is involved already in the earliest stages of the process leading to heart failure.
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| 32. |
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| 33. |
- Holm, Patrik, 1975-
(författare)
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Functional mapping and in vivo metabolism of the monoclonal antibody TS1 and its single-chain fragment : Its interaction with the antigen and the anti-idiotype
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibodies are proteins capable of specific interactions to a wide range of molecules. These interactions are facilitated by the complementary determining regions (CDR).Carcinomas are the most common of human cancers and they release significant amount of cytokeratins (CK) in the necrotic areas of the tumors. The CKs stay in the tumor, since they have low solubility. The antibody studied in this thesis, the anti-CK 8 antibody TS1, has shown to be effective in tumor targeting and is proposed to be useful in therapy.Single-chain antibodies (scFv) are recombinant antibodies which are much smaller than the intact IgG. This is an advantage when used in tumor therapy, since they can penetrate the tumors more easily than the larger IgG. Moreover, they are expressed by one single gene which make them easy to modify, for example by site-directed mutagenesis.The anti-idiotypic antibody αTS1 can be used to clear the TS1 form the circulation and thereby clear the body from non-tumor bound TS1 in therapy. To be able to modify the binding of an antibody to its antigen and or anti-idiotype, these interactions must be studied. In this study this is accomplished by chemical modifications of the IgGs TS1 and αTS1 and the antigen CK 8. Guided by these results, amino acid residues were mutated by using site-directed mutagenesis in the TS1-218 scFv and the effects were studied. From mutational study results, the functional epitope could be mapped and it was found that there are mainly tyrosines, but also charged residues, serine and a tryptophan that are important for both interactions. The binding of TS1-218 to both αTS1 and CK 8 could be improved by changing the negatively charged side-chains by mutations to their corresponding amide or alanine.Both the IgG and scFv versions of TS1 were administered in vivo. The IgG αTS1 was used to clear the TS1 from the circulation by forming immune complexes. The immune complexes, consisting of four or more antibodies, were mainly metabolized by the liver. The scFv TS1-218 could localize to the tumor in a tumor xenograft mouse model, although a higher uptake would be desired in a therapeutic strategy. The scFv was cleared rapidly by the kidneys, but the clearance could be slowed by pre-formed immune complexes with anti-TS1 scFv in vitro, prior to administration in vivo.
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| 34. |
- Ingelsson, Erik, et al.
(författare)
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Associations of serum adiponectin with skeletal muscle morphology and insulin sensitivity
- 2009
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:3, s. 953-957
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Skeletal muscle morphology and function are strongly associated with insulin sensitivity. OBJECTIVE: The objective of the study was to test the hypothesis that circulating adiponectin is associated with skeletal muscle morphology and that adiponectin mediates the relation of muscle morphology to insulin sensitivity. DESIGN, SETTINGS, AND PARTICIPANTS: This was a cross-sectional investigation of 461 men aged 71 yr, participants of the community-based Uppsala Longitudinal Study of Adult Men study. MAIN OUTCOME MEASURES: Measures included serum adiponectin, insulin sensitivity measured with euglycemic insulin clamp technique, and capillary density and muscle fiber composition determined from vastus lateralis muscle biopsies. RESULTS: In multivariable linear regression models (adjusting for age, physical activity, fasting glucose, and pharmacological treatment for diabetes), serum adiponectin levels rose with increasing capillary density (beta, 0.30 per 50 capillaries per square millimeter increase; P = 0.041) and higher proportion of type I muscle fibers (beta, 0.27 per 10% increase; P = 0.036) but declined with a higher proportion of type IIb fibers (beta, -0.39 per 10% increase; P = 0.014). Using bootstrap methods to examine the potential role of adiponectin in associations between muscle morphology and insulin sensitivity and the associations of capillary density (beta difference, 0.041; 95% confidence interval 0.001, 0.085) and proportion of type IIb muscle fibers (beta difference, -0.053; 95% confidence interval -0.107, -0.002) with insulin sensitivity were significantly attenuated when adiponectin was included in the models. CONCLUSIONS: Circulating adiponectin concentrations were higher with increasing skeletal muscle capillary density and in individuals with higher proportion of slow oxidative muscle fibers. Furthermore, our results indicate that adiponectin could be a partial mediator of the relations between skeletal muscle morphology and insulin sensitivity.
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| 35. |
- Ingelsson, Erik, et al.
(författare)
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Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly
- 2009
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 206:1, s. 239-244
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our aim was to examine relations of serum retinol-binding protein 4 (RBP4) to cardiovascular risk factors, and prevalent metabolic syndrome (MetS) and cardiovascular disease (CVD) in a large community-based sample of elderly. METHODS: We evaluated cross-sectional relations of serum RBP4 to cardiovascular risk factors including anthropometrical measures, blood pressure, lipid measures, fasting glucose and insulin, body fat distribution including truncal fat by dual-energy x-ray absorptiometry (DXA), homeostasis model assessment insulin resistance (HOMA-IR) and prevalent MetS in one thousand eight 70-year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in five hundred seven 82-year old men from Uppsala Longitudinal Study of Adult Men (ULSAM). In ULSAM, we also examined associations with prevalent CVD. RESULTS: RBP4 concentrations were positively correlated with serum triglycerides (r=0.30; P<0.0001 in both samples), whereas correlations with body mass index (BMI), waist circumference, sagittal abdominal diameter, total and truncal fat mass, total cholesterol, fasting glucose and HOMA-IR were weak. In multivariable-adjusted models, RBP-4 was associated with MetS (odds ratio (OR), 1.16 and 1.33; 95% confidence interval (CI), 0.99-1.37 and 1.05-1.67 per 1-standard deviation (SD) increase in PIVUS and ULSAM, respectively), and prior cerebrovascular disease (OR, 1.37; 95% CI, 1.00-1.88 per 1-SD increase in ULSAM), but not with prior myocardial infarction. CONCLUSION: In elderly, RBP4 concentrations were associated with MetS and its components in both sexes, and prior cerebrovascular disease in men. These findings are consistent with the hypothesis that circulating RBP4 could be a marker of metabolic complications and possibly also atherosclerosis and overt CVD.
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| 36. |
- Ingelsson, Erik, et al.
(författare)
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Diurnal blood pressure pattern and risk of congestive heart failure
- 2006
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Ingår i: Journal of the American Medical Association (JAMA). - 0098-7484 .- 1538-3598. ; 295:24, s. 2859-2866
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: High blood pressure is the most important risk factor for congestive heart failure (CHF) at a population level, but the relationship of an altered diurnal blood pressure pattern to risk of subsequent CHF is unknown. OBJECTIVES: To explore 24-hour ambulatory blood pressure characteristics as predictors of CHF incidence and to investigate whether altered diurnal blood pressure patterns confer any additional risk information beyond that provided by conventional office blood pressure measurements. DESIGN, SETTING, AND PARTICIPANTS: Prospective, community-based, observational cohort in Uppsala, Sweden, including 951 elderly men free of CHF, valvular disease, and left ventricular hypertrophy at baseline between 1990 and 1995, followed up until the end of 2002. Twenty-four-hour ambulatory blood pressure monitoring was performed at baseline, and the blood pressure variables were analyzed as predictors of subsequent CHF. MAIN OUTCOME MEASURE: First hospitalization for CHF. RESULTS: Seventy men developed heart failure during follow-up, with an incidence rate of 8.6 per 1000 person-years at risk. In multivariable Cox proportional hazards models adjusted for antihypertensive treatment and established risk factors for CHF (myocardial infarction, diabetes, smoking, body mass index, and serum cholesterol level), a 1-SD (9-mm Hg) increase in nighttime ambulatory diastolic blood pressure (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.02-1.55) and the presence of "nondipping" blood pressure (night-day ambulatory blood pressure ratio > or =1; HR, 2.29; 95% CI, 1.16-4.52) were associated with an increased risk of CHF. After adjusting for office-measured systolic and diastolic blood pressures, nondipping blood pressure remained a significant predictor of CHF (HR, 2.21; 95% CI, 1.12-4.36 vs normal night-day pattern). Nighttime ambulatory diastolic blood pressure and nondipping blood pressure were also significant predictors of CHF after exclusion of all participants who had an acute myocardial infarction before baseline or during follow-up. CONCLUSIONS: Nighttime blood pressure appears to convey additional risk information about CHF beyond office-measured blood pressure and other established risk factors for CHF. The clinical value of this association remains to be established in future studies.
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| 37. |
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| 38. |
- Ingelsson, Erik, et al.
(författare)
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Inflammation, as measured by the erythrocyte sedimentation rate, is an independent predictor for the development of heart failure
- 2005
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 45:11, s. 1802-1806
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Our objective was to explore inflammation, measured as erythrocyte sedimentation rate (ESR), as a predictor for the development of heart failure (HF). BACKGROUND: In recent years, evidence of the importance of inflammation in the pathophysiology of HF has emerged, and various inflammatory markers have been found to predict future HF. Erythrocyte sedimentation rate is an inexpensive and easily accessible marker of systemic inflammation, but to this date it is unknown whether ESR predicts subsequent HF. METHODS: In a community-based prospective study of 2,314 middle-aged men free from HF, myocardial infarction, and valvular disease at baseline, ESR was analyzed in multivariable models together with established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, obesity, and serum cholesterol) and hematocrit. RESULTS: A total of 282 men developed HF during a median follow-up time of 30 years. In Cox proportional hazards analyses, ESR was an independent predictor of HF (hazard ratio 1.46 for highest quartile vs. the lowest, 95% confidence interval 1.04 to 2.06). This observation remained significant when also adjusting for interim myocardial infarction during follow-up. CONCLUSIONS: Erythrocyte sedimentation rate was a significant predictor of HF, independent of established risk factors for HF, and interim myocardial infarction after three decades of follow-up in a population-based sample of middle-aged men. Our findings indicate that inflammation occurs early in the process leading to HF and that ESR could be used to evaluate this process.
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| 39. |
- Ingelsson, Erik, 1975-
(författare)
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Insulin Resistance and Inflammation as Risk Factors for Congestive Heart Failure
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congestive heart failure (CHF) is a major cause of morbidity and mortality and the identification of modifiable risk factors is crucial in order to diminish suffering of this common disease. The primary aim of this thesis was to investigate novel metabolic risk factors for CHF, with a focus on insulin resistance and inflammation. The secondary aim was to examine the validity of the CHF diagnosis in the Swedish hospital discharge register.This thesis was based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, a community-based prospective study started in 1970. The participants were examined at age 50 and 70 and the data was completed with annual updates on mortality and in-hospital morbidity using national registers. We showed that insulin resistance predicts CHF incidence independently of established risk factors in both middle-aged and elderly men. The previously described association between obesity and subsequent CHF may be mediated partly by insulin resistance. Moreover, it was established that inflammation, measured as erythrocyte sedimentation rate is a significant predictor of CHF, independent of established risk factors including an interim myocardial infarction. Furthermore, a low beta-carotene level, as well as an increased apolipoprotein B/A-I-ratio was found to predict CHF independently of established risk factors.We also showed that the validity of the CHF diagnosis in the Swedish hospital discharge register appears less precise than for other recently investigated cardiovascular diagnoses. However, when including only cases from selected clinics or cases with a primary diagnosis of CHF, the validity is comparable to the above diagnoses. In conclusion, insulin resistance and inflammation are strong independent risk factors for the development of CHF, and seem to be involved in the early process leading to CHF. If confirmed, our observations could have large clinical implications as they may offer new approaches in the prevention of CHF.
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| 40. |
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| 41. |
- Ingelsson, Erik, et al.
(författare)
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Insulin resistance and risk of congestive heart failure
- 2005
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Ingår i: Journal of the American Medical Association (JAMA). - 0098-7484 .- 1538-3598. ; 294:3, s. 334-41
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Diabetes and obesity are established risk factors for congestive heart failure (CHF) and are both associated with insulin resistance. OBJECTIVE: To explore if insulin resistance may predict CHF and may provide the link between obesity and CHF. DESIGN, SETTING, AND PARTICIPANTS: The Uppsala Longitudinal Study of Adult Men, a prospective, community-based, observational cohort in Uppsala, Sweden. We investigated 1187 elderly (>or=70 years) men free from CHF and valvular disease at baseline between 1990 and 1995, with follow-up until the end of 2002. Variables reflecting insulin sensitivity (including euglycemic insulin clamp glucose disposal rate) and obesity were analyzed together with established risk factors (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, and serum cholesterol level) as predictors of subsequent incidence of CHF, using Cox proportional hazards analyses. MAIN OUTCOME MEASURE: First hospitalization for heart failure. RESULTS: One hundred four men developed CHF during a median follow-up of 8.9 (range, 0.01-11.4) years. In multivariable Cox proportional hazards models adjusted for established risk factors for CHF, increased risk of CHF was associated with a 1-SD increase in the 2-hour glucose value of an oral glucose tolerance test (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.08-1.93), fasting serum proinsulin level (HR, 1.29; 95% CI, 1.02-1.64), body mass index (HR, 1.35; 95% CI, 1.11-1.65), and waist circumference (HR, 1.36; 95% CI, 1.10-1.69), whereas a 1-SD increase in clamp glucose disposal rate decreased the risk (HR, 0.66; 95% CI, 0.51-0.86). When adding clamp glucose disposal rate to these models as a covariate, the obesity variables were no longer significant predictors of subsequent CHF. CONCLUSIONS: Insulin resistance predicted CHF incidence independently of established risk factors including diabetes in our large community-based sample of elderly men. The previously described association between obesity and subsequent CHF may be mediated largely by insulin resistance.
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| 42. |
- Ingelsson, Erik, et al.
(författare)
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Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men
- 2007
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 28:14, s. 1739-1745
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Tidskriftsartikel (refereegranskat)abstract
- Aims To investigate associations of urinary albumin excretion rate (UAER) and heart failure (HF) incidence in a community-based sample. Methods and results In a prospective study of 70-year-old men free from HF at baseline (n = 1106), UAER (from timed overnight samples) was analysed with established risk factors for HF [acute MI before baseline, acute MI during follow-up (modelled as a time-dependent covariate), hypertension, diabetes, left ventricular hypertrophy, smoking, body mass index, and glomerular filtration rate] and more recently described risk factors [high-sensitive C-reactive protein and insulin sensitivity (clamp glucose disposal rate)] as predictors of HF incidence. Ninety-eight participants developed HF during a median follow-up of 9.0 years. In Cox proportional hazards models adjusted for established and novel risk factors for HF, a 1 SD increase in log UAER increased the risk of HF in individuals without anti-hypertensive treatment (hazard ratio 1.49; 95% CI 1.13–1.98; P = 0.005). Furthermore, UAER remained an independent predictor of HF, also in participants without diabetes at baseline or myocardial infarction at baseline or during follow-up. There were no significant associations between UAER and HF incidence in individuals with anti-hypertensive treatment. Conclusion Our observations support the notion that low-grade albuminuria is a marker for subclinical cardiovascular damage that predisposes to future HF in the community.
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| 43. |
- Ingelsson, Erik, et al.
(författare)
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Metabolic syndrome and risk for heart failure in middle-aged men
- 2006
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 92:10, s. 1409-1413
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To explore metabolic syndrome as a possible risk factor for development of heart failure (HF). Design: Community-based cohort study. Setting: Uppsala, Sweden. Participants: 2314 50-year-old men free from HF, myocardial infarction and valvular disease at baseline were enrolled between 1970 and 1974 and were followed up until the age of 70. A modified National Cholesterol Education Program definition of metabolic syndrome was used with body mass index in the place of waist circumference. Main outcome measure: First hospitalisation for HF. Results: In multivariable Cox proportional hazards models adjusted for established risk factors for HF (hypertension, diabetes, ECG left ventricular hypertrophy, smoking and body mass index), the presence at baseline of metabolic syndrome (hazard ratio 1.66, 95% confidence interval (CI) 1.02 to 2.70) was a predictor of subsequent HF. This relation was even stronger after adjustment for the presence of an acute myocardial infarction during follow up in addition to the other established risk factors for HF (hazard ratio 1.80, 95% CI 1.11 to 2.91). Conclusion: Metabolic syndrome was a significant predictor of HF, independent of established risk factors for HF including an interim myocardial infarction, during two decades of follow up in a community-based sample of middle-aged men. This implies that metabolic syndrome provides important risk information beyond that of established risk factors for HF.
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| 44. |
- Ingelsson, Erik, et al.
(författare)
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Novel metabolic risk factors for heart failure
- 2005
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 46:11, s. 2054-2060
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Our objectives were to explore novel metabolic risk factors for development of heart failure (HF).BACKGROUND: In the past decade, considerable knowledge has been gained from limited samples regarding novel risk factors for HF, but the importance of these in the general population is largely unexplored.METHODS: In a community-based prospective study of 2,321 middle-aged men free from HF and valvular disease at baseline, variables reflecting glucose and lipid metabolism and variables involved in oxidative processes were compared with established risk factors for HF (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, obesity, and serum cholesterol) using Cox proportional hazards analyses.RESULTS: During a median follow-up time of 29 years, 259 subjects developed HF. In a multivariable Cox proportional hazards backward stepwise model, a 1-SD increase of fasting proinsulin (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.15 to 1.66) and apolipoprotein B/A-I-ratio (HR 1.27, 95% CI 1.09 to 1.48) increased the risk, whereas a 1-SD increase in serum beta-carotene (HR 0.79, 95% CI 0.66 to 0.94) decreased the risk of HF. These variables also remained significant when adjusting for acute myocardial infarction during follow-up.CONCLUSIONS: Novel variables reflecting insulin resistance and dyslipidemia, together with a low beta-carotene level, were found to predict HF independently of established risk factors. If confirmed, our observations could have large clinical implications, as they may offer new approaches in the prevention of HF.
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| 45. |
- Ingelsson, Erik, et al.
(författare)
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Sleep disturbances independently predict heart failure in overweight middle-aged men
- 2007
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 9:2, s. 184-190
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sleep disturbances are associated with manifest heart failure (HF). However, the relationship between sleep disturbances and incident HF has been less studied. AIMS: To investigate self-reported sleep disturbances as predictors of HF in a longitudinal, community-based cohort of 2314 middle-aged men. METHODS AND RESULTS: Data on self-reported sleep disturbances, as well as established risk factors for HF were collected and analyzed using Cox proportional hazards analyses. In multivariable Cox proportional hazards models adjusted for established risk factors for HF, the presence at baseline of sleep disturbances (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.16-1.99; p=0.002) was an independent risk factor for HF. There was evidence of effect modification between BMI and sleep disturbances. In multivariable-adjusted models, sleep disturbance (HR, 1.58; 95% CI, 1.13-2.21; p=0.008) was an independent risk factor for HF in overweight participants (BMI>25), but not in normal-weight participants (BMI< or =25). All results remained similar in a sub-sample excluding all participants suffering from a myocardial infarction during follow-up. CONCLUSIONS: Self-reported sleep disturbances imply an increased risk of subsequent HF in overweight middle-aged men, via mechanisms largely independent of established risk factors for HF, including an interim myocardial infarction.
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| 46. |
- Ingelsson, Erik, et al.
(författare)
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Socioeconomic factors as predictors of incident heart failure
- 2006
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Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 12:7, s. 540-545
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Studies of socioeconomic factors as predictors of heart failure (HF) are few and have given opposing results. Further, it is unknown if these factors predict incident HF independently of myocardial infarction and other established risk factors for HF. METHODS AND RESULTS: In a community-based cohort of 2314 middle-age men free from HF, valvular disease, and previous myocardial infarction at baseline, socioeconomic factors were examined as predictors for HF using Cox proportional hazards analyses. In multivariable Cox proportional hazards models adjusted for established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, serum cholesterol, and interim myocardial infarction), low occupational classification (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.03-2.35 for low vs. high occupational classification), low education level (HR 1.98, 95% CI 1.07-3.68 for elementary school vs. college exam) and being unmarried (HR 1.44, 95% CI 0.99-2.10 for being unmarried vs. being married) increased the risk of HF. CONCLUSION: High occupational classification and high education level decreased, and being unmarried increased, the risk of subsequent HF in middle-age men, via mechanisms largely independent of established risk factors for HF, including an interim myocardial infarction. Further studies are needed to understand the mechanisms behind these associations.
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| 47. |
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| 48. |
- Ingelsson, Erik, et al.
(författare)
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The validity of a diagnosis of heart failure in a hospital discharge register
- 2005
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 7:5, s. 787-791
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: The accuracy of a diagnosis of heart failure (HF) in hospital discharge registers is largely unknown. We aimed to determine the validity of such a diagnosis in the Swedish hospital discharge register. METHODS AND RESULTS: In a population-based study of 2322 middle-aged men (the ULSAM study), 321 participants were diagnosed with HF according to the Swedish hospital discharge register, during a median follow-up time of 29 years. A review board examined the validity of the diagnosis according to the European Society of Cardiology definition of HF. Eighty-two percent of the possible cases were classified as having definite HF. An echocardiographic examination increased the validity to 88%. For patients treated at an internal medicine or cardiology clinic the validity was 86% and 91%, respectively. If HF was the primary diagnosis, the validity was 95%, irrespective of clinic type. CONCLUSION: The HF diagnosis in the Swedish hospital discharge register appears slightly less precise than for acute myocardial infarction and stroke. For population-based research, only those with a primary diagnosis of HF in the hospital discharge register should be regarded as definite HF cases, or alternatively the cases should be validated individually.
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| 49. |
- Jobs, Elisabeth, et al.
(författare)
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Cathepsin S is independently associated with cytokine mediated inflammation in elderly men
- 2009
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Ingår i: European Society of Cardiology Congress. - Uppsala.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Cathepsin S is independently associated with cytokine mediated inflammation in elderly men Conclusion: Higher serum levels of Cathepsin S were independently associated with higher CRP and IL-6 in a community– based sample of elderly men. Our data provides support for the notion that Cathepsin S is involved in inflammatory processes, possibly leading to atherosclerosis and cardiovascular disease. Background: Cathepsin S is a lysosomal protease that has been suggested to play a key role in the development of atherosclerosis and cardiovascular disease by degradation of vascular extracellular matrix. Previous studies have suggested that cathepsin S provides a molecular link between obesity and atherosclerosis, possibly via increased inflammatory activity. Yet, the association between circulating cathepsin S and inflammation markers has not previously been reported in the community. Aim: To investigate the association between plasma levels of cathepsin- S, C-reactive protein (CRP) and Interleukin 6 (IL-6), in the community. Methods: Serum levels of cathepsin S, CRP, IL-6 were measured in frozen samples from the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based cohort of elderly men (n=999, mean age 71 years). Results: Cross-sectional association between Cathepsin S, CRP and IL-6 at age 70 showed that one standard deviation (SD) higher serum Cathepsin S was significantly associated with 0.14 SD higher serum CRP and 0.07-0.08 SD higher serum IL-6 when adjusting for age, life style factors (body mass index, physic activity and smoking), cardiovascular risk factors (hypertension, dyslipidemia, previous cardiovascular disease and diabetes and smoking), and the combination of all covariates
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| 50. |
- Johansson, Carolina, et al.
(författare)
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Differential expression analysis of Escherichia coli proteins using a novel software for relative quantitation of LC-MS/MS data
- 2006
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Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 6:16, s. 4475-4485
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Tidskriftsartikel (refereegranskat)abstract
- The study of changes in protein levels between samples derived from cells representing different biological conditions is a key to the understanding of cellular function. There are two main methods available that allow both for global scanning for significantly varying proteins and targeted profiling of proteins of interest. One method is based on 2-D gel electrophoresis and image analysis of labelled proteins. The other method is based on LC-MS/MS analysis of either unlabelled peptides or peptides derived from isotopically labelled proteins or peptides. In this study, the non-labelling approach was used involving a new software, DeCydei (TM) S Differential Analysis Software (DeCyder MS) intended for automated detection and relative quantitation of unlabelled peptides in LC-MS/MS data. Total protein extracts of E. coli strains expressing varying levels of dihydrofolate reductase and integron integrase were digested with trypsin and analyzed using a nanoscale liquid chromatography system, Ettan (TM) MDLC, online connected to an LTQ (TM) linear ion-trap mass spectrometer fitted with a nanospray interface. Acquired NIS data were subjected to DeCyder NIS analysis where 2-D representations of the peptide patterns from individual LC-MS/MS analyses were matched and compared. This approach to unlabelled quantitative analysis of the E. coli proteome resulted in relative protein abundances that were in good agreement with results obtained from traditional methods for measuring protein levels.
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