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Aims: Using Scandinavian population-based registries, we assessed risk of stroke/systemic embolism (SE) and bleeding with non-vitamin K antagonist oral anticoagulants compared with warfarin in anticoagulation-naïve patients with atrial fibrillation (AF)., Methods and Results: This historical cohort study included 219 545 AF patients [median age 74 years; 43% women; mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, age 65-74 years, sex category) score 3.3] initiating apixaban, dabigatran, rivaroxaban, or warfarin in Denmark, Norway, and Sweden (1 January 2013 to 31 December 2016). The primary endpoints were stroke/SE and major bleeding. The median follow-up times were 9.7 (3.9-21.5) months for stroke/SE and 9.6 (3.8-21.3) months for bleeding. Apixaban and warfarin initiators were older and had higher CHA2DS2-VASc scores compared with dabigatran and rivaroxaban initiators. After 1:1 propensity score matching, three cohorts were created: apixaban-warfarin (n = 111 162), dabigatran-warfarin (n = 56 856), and rivaroxaban-warfarin (n = 61 198). Adjusted hazard ratios (HRs) were estimated using a Cox regression. For stroke/SE, adjusted HRs against warfarin were 0.96 [95% confidence interval (CI): 0.87-1.06] for apixaban, 0.89 (95% CI: 0.80-1.00) for dabigatran, and 1.03 (95% CI: 0.92-1.14) for rivaroxaban. For major bleeding, the HRs against warfarin were 0.73 (95% CI: 0.67-0.78) for apixaban, 0.89 (95% CI: 0.82-0.97) for dabigatran, and 1.15 (95% CI: 1.07-1.25) for rivaroxaban. The results in the dabigatran cohort did not hold in all dose-defined subgroups., Conclusion: In this large Scandinavian study among AF patients initiating oral anticoagulation, those initiating dabigatran, apixaban, and rivaroxaban had similar rates of stroke/SE to patients initiating warfarin. Rates of major bleeding were lower with apixaban and dabigatran and higher with rivaroxaban, each compared with warfarin., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: The long-term somatic and psychiatric consequences of Cushing's syndrome are well-described, but the socioeconomic consequences are largely unknown., Objective: We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing's syndrome in the years before diagnosis and after surgery., Design: Nationwide register-based cohort study., Methods: We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing's syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year -10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression., Results: Compared to the reference population, the patients' employment was permanently reduced from year -6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression., Conclusion: Cushing's syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing's syndrome and, not least, the pervasive health threats of glucocorticoid excess., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover., Aim: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control., Methods: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR)., Results: Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000)., Conclusion: 1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover., Clinical Trials Registration: NCT00647179., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While the field of computational protein design has witnessed amazing progression in recent years, folding properties still constitute a significant barrier towards designing new and larger proteins. In order to assess and improve folding properties of designed proteins, we have developed a genetics-based folding assay and selection system based on the essential enzyme, orotate phosphoribosyl transferase from Escherichia coli. This system allows for both screening of candidate designs with good folding properties and genetic selection of improved designs. Thus, we identified single amino acid substitutions in two failed designs that rescued poorly folding and unstable proteins. Furthermore, when these substitutions were transferred into a well-structured design featuring a complex folding profile, the resulting protein exhibited native-like cooperative folding with significantly improved stability. In protein design, a single amino acid can make the difference between folding and misfolding, and this approach provides a useful new platform to identify and improve candidate designs., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Aims: The current guidelines from the European Society of Cardiology and European Society of Anaesthesiology on non-cardiac surgery (ESC/ESA-NCS) divide surgical procedures into those associated with low risk (<1%), intermediate risk (1-5%), and high risk (>5%) of major adverse cardiac events (MACE). Evaluating surgical risk might be particularly appropriate in patients with recent stent implantation, and thus we validated the ESC/ESA-NCS classification in patients undergoing NCS within 1 year after coronary drug-eluting stent (DES) implantation., Methods and Results: By record-linking the Western Denmark Heart Registry and the Danish National Patient Registry, we identified 4046 patients, who underwent NCS between 1 and 12 months after DES implantation. Primary outcomes were MACE [cardiac death and myocardial infarction (MI)] and a combined endpoint of mortality and MI within 30 days after surgery. Both MACE (low risk 0.6%, intermediate risk 1.2%, and high risk 3.4%) and the combined endpoint of mortality and MI (1.5%, 4.6%, and 14.9%) were associated with the ESC/ESA-NCS classification. As compared with low-risk surgery, the odds ratios (OR) for MACE were 1.9 [95% confidence interval (CI) 0.9-4.1] for intermediate-risk surgery and 5.8 (95% CI 1.7-20.1) for high-risk surgery. For the combined endpoint of mortality and MI, the OR's were 3.1 (95% CI 2.1-4.7) for intermediate-risk surgery and 11.3 (95% CI 5.9-21.9) for high-risk surgery., Conclusion: The ESC/ESA-NCS classification is a valid tool to predict the risk of both MACE and the combined endpoint of mortality and MI for patients undergoing NCS.

Aims: To show non-inferiority of the 67- or 87 µm thick, sirolimus-eluting Orsiro drug eluting stent (DES) to the 122 µm thick, biolimus-eluting Nobori DES regarding size of vessel lumen outside the stent at 13-month follow-up., Methods and Results: This study was a substudy to the SORT-OUT VII trial, a prospective, 1:1-randomized, comparison of the two stents in patients with stable coronary artery disease or acute coronary syndrome. Optical coherence tomography was acquired after percutaneous coronary intervention and at 13-month follow-up. The substudy was powered to access non-inferiority (Δ = 0.60 mm2) of the Orsiro DES to the Nobori DES for the primary endpoint of mean extra stent lumen (ESL) i.e. vessel lumen outside the stent at 13-month follow-up. We randomized 124 patients to Orsiro (n = 60) or Nobori (n = 64). Due to a difference in the one-sided 95%-confidence interval of 0.26 mm2, but increased to 0.82 mm2 after appropriate log-transformation, it could not be rejected that Orsiro exceeded the non-inferiority limit. Testing for superiority, Orsiro had a significantly larger mean ESL at follow-up (Orsiro: 0.11 mm2 [0.02;0.30] mm2, Nobori: 0.03 mm2 [0.00;0.17] mm2, P = 0.04). Stent strut coverage was, Orsiro: 97.6 % [93.8;99.4]%, and Nobori: 96.3 % [90.5;98,6]% (P = 0.13)., Conclusion: Orsiro DES had a significantly larger mean ESL at follow-up and it could not be excluded that Orsiro exceeded the limit for non-inferiority. Nobori DES had a more heterogeneous distribution of neointima but stent strut coverage did not differ significantly between the two stents., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Objective: Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original 'feast and famine hypothesis' by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression., Design and Methods: Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion ('feast') and ii) after a 36 h fast ('famine'). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise., Results: GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days., Conclusions: This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the 'feast and famine hypothesis'; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization., (© 2015 European Society of Endocrinology.)

Aims: To examine trends in the use of diagnostic coronary angiography according to distance from home to the nearest invasive heart centre following implementation of fast-track protocols and extensive pre-hospital triaging of acute coronary syndrome patients., Methods and Results: We performed a register-based cohort study of all patients admitted to Danish hospitals with incident acute coronary syndrome in 2005-2011. Diagnostic coronary angiography within 60 days of admission was investigated according to distance tertiles (DTs) calculated as range from each patient's home to the nearest invasive heart centre (short DT: <22 km, medium DT: 22-65 km, long DT: >65 km). Cox proportional hazards models were applied.Among the 52,409 patients included, diagnostic coronary angiography was increasingly used during 2005-2011 (short DT: 76% to 81%; medium DT: 74% to 81%; long DT: 69% to 78%; all p-values for trend <0.001). Using the short DT as reference the adjusted hazard ratios for medium DT were 0.87 (0.84-0.89) for 2005-2007, 0.94 (0.90-0.98) for 2008-2009 and 0.94 (0.90-0.98) for 2010-2011. Corresponding figures for long DT were 0.74 (0.72-0.76) for 2005-2007, 0.87 (0.83-0.90) for 2008-2009 and 0.94 (0.90-0.98) for 2010-2011. Length of hospital stay, time to coronary angiography, and 60-day mortality decreased in all DT., Conclusions: This nationwide study found significant increases in diagnostic coronary angiography use over time in incident acute coronary syndrome patients with a relatively larger increase in patients residing farthest from an invasive heart centre. Additionally, selected quality of care measures improved in the entire cohort, suggesting a benefit of national clinical protocols., (© The European Society of Cardiology 2014.)

Aims: The aim of this Danish nationwide study was to evaluate the treatment of myocardial infarction (MI) in patients with non-end-stage chronic kidney disease (CKD) and in patients requiring renal replacement therapy (RRT). Upgraded guidelines for the management of MI were implemented around 2004; hence, the treatment of MI in the time periods before and after 2004 was compared in order to evaluate the impact for patients with CKD., Methods and Results: By linking nationwide registries by the personal registration number, we identified patients admitted to Danish hospitals with first time MI in the period 2000-09 (79 585 with no renal disease, 3144 with non-end-stage CKD, and 725 requiring RRT). Cox proportional hazards model was used to estimate the chance of invasive treatment within 60 days after MI and the chance of filling prescriptions on recommended post-MI drugs within 90 days before and after 2004. Significantly less use of relevant MI treatment in patients with non-end-stage CKD and patients requiring RRT compared with patients with no renal disease were seen; however, the absolute frequencies of invasive procedures and filled prescriptions on post-MI drugs increased after 2004 in all patients., Conclusions: After 2004, invasive and pharmacological treatment of first-time MI improved in patients with non-end-stage CKD and patients requiring RRT; however, all CKD patients were less treated with standard MI care compared with patients with no renal disease.

The mechanisms behind social differences in mortality rates have been debated. The authors examined the extent to which shared family background and health in early life could explain the association between educational status and all-cause mortality rates using a sibling design. The study was register-based and included all individuals born in Denmark between 1950 and 1979 who had at least 1 full sibling born in the same time period (n = 1,381,436). All individuals were followed from 28 years of age until death, emigration, or December 2009. The authors used Cox regression analyses to estimate hazard ratios for mortality according to educational level. Conventional cohort and intersibling analyses were carried out and conducted separately for deaths occurring before and after the age of 45 years, respectively. The cohort analyses showed an inverse association between educational status and all-cause mortality that was strongest for males, increased with younger birth cohorts, and tended to be strongest in the analyses of death before 45 years of age. The associations were attenuated slightly in the intersibling analyses and after adjustment for serious health conditions in early life. Hence, health selection and confounding by factors shared by siblings explained only a minor part of the association between educational level and all-cause mortality.

Background: Reperfusion delay in ST-segment elevation myocardial infarction (STEMI) predicts adverse outcome. We evaluated time from alarm call (system delay) and time from first medical contact (PCI-related delay), where fibrinolysis could be initiated, to balloon inflation in a pre-hospital organization with tele-transmitted electrocardiograms, field triage and direct transfer to a 24/7 primary percutaneous coronary intervention (PPCI) center., Methods and Results: This was a single center cohort study with long-term follow-up in 472 patients. The PPCI center registry was linked by person identification number to emergency medical services (EMS) and National Board of Health databases in the period of 2005-2008. Patients were stratified according to transfer distances to PPCI into zone 1 (0-25 km), zone 2 (65-100 km) and zone 3 (101-185 km) and according to referral by pre-hospital triage. System delay was 86 minutes (interquartile range (IQR) 72-113) in zone 1, 133 (116-180) in zone 2 and 173 (145-215) in zone 3 (p<0.001). PCI-related delay in directly referred patients was 109 (92-121) minutes in zone 2, but exceeded recommendations in zone 3 (139 (121-160)) and for patients admitted via the local hospital (219 (171-250)). System delay was an independent predictor of mortality (p<0.001)., Conclusions: Pre-hospital triage is feasible in 73% of patients. PCI-related delay exceeded European Society of Cardiology (ESC) guidelines for patients living >100 km away and for non-directly referred patients. Sorting the PPCI centers catchment area into geographical zones identifies patients with long reperfusion delays. Possible solutions are pharmaco-invasive regiments, research in early ischemia detection, airborne transfer and EMS personnel education that ensures pre-hospital triage.

Objective: To investigate possible gender differences in patients with acute myocardial infarction (AMI) and without significant stenoses on coronary angiography (CAG) regarding prognosis and use of secondary preventive medication., Design: Nationwide register-based cohort study., Patients: By compiling data from Danish registries, we identified 20,800 patients hospitalized with AMI during 2005-2007. We included the 834 women and 761 men without significant stenoses on CAG who were discharged and alive after 60 days., Main Outcome Measures: All-cause mortality, recurrent AMI, and redeeming a prescription for a lipid-lowering drug, beta-blocker, clopidogrel, or aspirin within 60 days of discharge., Results: During follow-up, 97 women and 60 men died, resulting in a crude female/male hazard ratio (HR) of 1.51 (95% CI 1.09-2.08). After adjustment for age, time-period, and comorbidity, the gender difference was attenuated (HR 1.22, 95% CI 0.86-1.72). AMI recurrence was experienced by 28 women and 29 men with a female/male HR 0.88 (95% CI 0.52-1.48). After multivariable adjustment results were similar (HR 0.84, 95% CI 0.50-1.43). More women than men redeemed a prescription for lipid-lowering drugs with no differences in other medication. In the adjusted models lipid-lowering drugs, beta-blockers, clopidogrel, and aspirin were all redeemed equally with odds ratio (OR) 1.25 (95% CI 0.99-1.59), OR 1.10 (95% CI 0.88-1.37), OR 1.09 (95% CI 0.88-1.34), and OR 1.13 (95% CI 0.90-1.42), respectively., Conclusion: Our study shows that in a population of patients with a first admission for AMI and no significant stenoses on CAG, women share the same prospects as men regarding long-term prognosis and the extent of secondary preventive medical treatment.

Context: Pegvisomant is a GH antagonist, which is used for the treatment of acromegalic patients. It effectively blocks the hepatic and peripheral effects of GH, but transient elevations in circulating liver enzymes of unknown pathogenesis may occur, which seems to be more prevalent when the treatment is combined with a somatostatin analog (SA). Accumulation of intrahepatic lipid is a known cause of elevated liver enzymes, and there is evidence to suggest that GH impacts lipid content in liver and skeletal muscle., Objective: Our objective was to measure lipid content in liver and skeletal muscle in acromegalic patients before and after cotreatment with pegvisomant and SA as compared with SA monotherapy., Design: Eighteen acromegalic patients well controlled on SA monotherapy were randomized in a parallel study over 24 wk to 1) unchanged SA monotherapy, or 2) cotreatment with pegvisomant (15-30 mg twice a week) and SA (half the usual dosage)., Setting: This was an investigator-initiated study in a single tertiary referral center., Main Outcome Measures: Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) was assessed by ¹H magnetic resonance spectroscopy., Results: IHL increased in the cotreatment group compared with SA only (P = 0.002). The increase was positively correlated to weekly pegvisomant dose (r² = 0.52; P = 0.01). By contrast, IMCL decreased in the cotreatment group compared with SA only (P = 0.01). These changes related neither to insulin sensitivity nor inflammatory markers., Conclusion: Cotreatment with pegvisomant and a reduced SA dose increase IHL and decrease IMCL compared with SA monotherapy. The clinical implications remain unclear, but increased IHL may be causally linked to the transient elevations in liver enzymes observed during pegvisomant treatment.

Aims: The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study., Methods and Results: All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint., Conclusion: Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.

Context: Cotreatment of acromegaly with pegvisomant and a somatostatin analog (SA) has proven feasible. Previous studies in the field have focused on patients with an insufficient response to SA monotherapy in whom pegvisomant was added without changing the SA dose., Objective: The objective of the study was to study whether patients sufficiently controlled on SA monotherapy can be transferred to combination therapy with low-dose pegvisomant and a reduced SA dose., Design: Eighteen acromegalic patients well controlled on SA monotherapy, mean ± se aged 54 ± 3 yr, were randomized in a parallel study over 24 wk to unchanged SA monotherapy or cotreatment with pegvisomant (15-30 mg twice a week) and SA (half the usual dosage)., Setting: This was an investigator-initiated study in a single tertiary referral center., Main Outcome Measures: Glucose tolerance, substrate metabolism, insulin sensitivity, body composition, and quality of life were measured., Results: Median pegvisomant dose was 52.5 mg/wk (range 30-60). IGF-I (micrograms per liter) was comparable both at baseline (P = 0.88) and after 24 wk of treatment (P = 0.48). The change in IGF-I between baseline and wk 24 also did not differ between groups (P = 0.15). Apart from increased peak insulin levels during the oral glucose tolerance test in the cotreatment group, no substantial differences between the two groups were detected. Moderately elevated liver enzymes were found in 17% of the patients on pegvisomant therapy., Conclusion: Acromegalic patients well controlled on SA monotherapy can maintain safe IGF-I levels during 24 wk of cotreatment with low-dose pegvisomant and a 50% reduced SA dose. This treatment modality, however, does not seem to provide significant benefits for the patients.

Context: Ghrelin is the endogenous agonist for the growth hormone secretagogue receptor (GHS-R). Intravenous administration of ghrelin induces insulin resistance and hyperglycemia and increases the levels of free fatty acids (FFA)., Objective: To investigate whether these effects are mediated directly by ghrelin in skeletal muscle tissue., Design: This study was single blinded, randomized, and placebo controlled. Eight healthy men (25.5 ± 3.1 years) received 240 min of intraarterial ghrelin infusion (4.2 ng × kg(-1) × min(-1)) into one femoral artery and intraarterial placebo infusion into the contralateral artery. Simultaneous blood samples were drawn from both femoral veins and muscle biopsies were obtained from both legs during both a basal period and during a hyperinsulinemic and euglycemic clamp period., Results: Ghrelin significantly elevated venous FFA levels and venous dilution of palmitate, suggestive of increased lipolysis. Glucose metabolism was unchanged, and there were no direct effects on pertinent enzymes in the insulin signaling cascade. The metabolic clearance rate of acyl ghrelin was 12.5 ± 3.3 ml × kg(-1) × min(-1). Acyl and desacyl ghrelin levels both increased., Conclusions: The results of this study suggest that ghrelin may stimulate lipolysis directly in skeletal muscle.

Context: Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial., Objective: To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA)., Design and Methods: Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ))., Results: Total and bioactive IGF1 (μg/l) levels were similar (total: 185 ± 10 (SA) versus 171 ± 8 (surgery) (P=0.28); bioactive: 1.9 ± 0.2 vs 1.9 ± 0.1 (P=0.70)). Suppression of total and free GH (μg/l) during OGTT was blunted in the SA group (total GH(nadir): 0.59 ± 0.08 (SA) versus 0.34 ± 0.06 (surgery) (P=0.01); free GH(nadir): 0.43 ± 0.06 vs 0.19 ± 0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02)., Conclusions: i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

Background: The incidence of chronic renal replacement therapy (RRT) varies markedly between Danish nephrology centres. The aim of the present study was to establish if there is regional and social variation in the incidence of chronic RRT in Denmark when analysed according to patient residence. The importance of diabetic nephropathy and patients aged 70 years or older was also studied., Methods: Incident patients on chronic RRT in the period 1995-2006 were identified in the Danish National Registry on Regular Dialysis and Transplantation. Information on residence, income, educational status and ethnic origin was obtained from Statistics Denmark. Rates of incident RRT patients were standardized for regional differences of sex and age as well as income, educational status and ethnic origin. Poisson regression was used when comparing rates., Results: Age- and sex-standardized incident chronic RRT rates among individuals with low income or short educational level were higher (P < 0.0001) compared to other groups. Also, standardized rates of patients in total and patients aged 70 years or older were higher in the catchment areas of the nephrology centres located in the two largest cities than for patients with residence in other areas of the country (P < 0.0001). Standardizing for regional differences of ethnic origin did not change the rates. The incident chronic RRT rate caused by diabetic nephropathy was higher for patients with residence in the catchment area of the nephrology centre in the largest city [49 per million people (p.m.p.) (95% CI = 40-57 p.m.p.)] compared to the catchment area of the nephrology centre located in the second largest city [31 (95% CI = 26-37 p.m.p.)] and other areas [29 p.m.p. (95% CI = 26-31 p.m.p.)] in 2001-06. When standardizing for differences in income among the 30-69-year-old persons, the rate of patients with residence in the catchment area of the nephrology centre located in the largest city decreased but was still higher than in other regions (P = 0.0003)., Conclusions: There are marked socio-economic and regional differences in rates of incident RRT patients. The rates of incident RRT patients are highest in the catchment areas of the two largest nephrology centres and this may be partly explained by a higher frequency of end-stage diabetic nephropathy and a new treatment programme targeting frail, mainly elderly, patients.

To disentangle an independent effect of educational status on mortality risk from direct and indirect selection mechanisms, the authors used a discordant twin pair design, which allowed them to isolate the effect of education by means of adjustment for genetic and environmental confounding per design. The study is based on data from the Danish Twin Registry and Statistics Denmark. Using Cox regression, they estimated hazard ratios for mortality according to the highest attained education among 5,260 monozygotic and 11,088 dizygotic same-sex twin pairs born during 1921-1950 and followed during 1980-2008. Both standard cohort and intrapair analyses were conducted separately for zygosity, gender, and birth cohort. Educational differences in mortality were demonstrated in the standard cohort analyses but attenuated in the intrapair analyses in all subgroups but men born during 1921-1935, and no effect modification by zygosity was observed. Hence, the results are most compatible with an effect of early family environment in explaining the educational inequality in mortality. However, large educational differences were still reflected in mortality risk differences within twin pairs, thus supporting some degree of independent effect of education. In addition, the effect of education may be more pronounced in older cohorts of Danish men.

Aims: To investigate if gender bias is present in today's setting of an early invasive strategy for patients with acute coronary syndrome in Denmark (population 5 million)., Methods and Results: We identified all patients admitted to Danish hospitals with acute coronary syndrome in 2005-07 (9561 women and 16 406 men). Cox proportional hazard models were used to estimate the gender differences in coronary angiography (CAG) rate and subsequent revascularization rate within 60 days of admission. Significantly less women received CAG (cumulative incidence 64% for women vs. 78% for men, P < 0.05), with a hazard ratio (HR) of 0.68 (95% CI 0.65-0.70, P < 0.0001) compared with men. The difference was narrowed after adjustment for age and comorbidity, but still highly significant (HR 0.82, 95% CI 0.80-0.85, P < 0.0001). Revascularization after CAG was less likely in women with an HR of 0.68 (95% CI 0.66-0.71, P < 0.0001) compared with men. More women (22%) than men (10%) (P < 0.0001) had no significant stenosis on their coronary angiogram. However, after adjustment for the number of significant stenoses, age, and comorbidity women were still less likely to be revascularized (HR 0.91, 95% CI 0.87-0.95, P < 0.0001)., Conclusion: Women with ACS are approached in a much less aggressively invasive way and receive less interventional treatment than men even after adjusting for differences in comorbidity and number of significant stenoses.

Background: The Danish National Registry on Regular Dialysis and Transplantation (NRDT) provides systematic information on the epidemiology and treatment of end-stage chronic kidney disease in Denmark. It is therefore of major importance that the registry is valid and complete. The aim of the present study was to evaluate the registration of incident patients on chronic renal replacement therapy (RRT)., Methods: Incident patients on chronic RRT in the period 2001-2004 were identified in NRDT and in the National Patient Registry, which contains information on hospital admissions and treatments. In the National Patient Registry, identification of patients was as follows: patients receiving the procedure of dialysis during a minimum of 90 days and for a minimum of 12 times or the procedure of renal transplantation. Only patients with at least 2 years of dialysis-free interval before and never being transplanted were included. The completeness of NRDT was calculated as the percentage of new patients on chronic RRT registered in the National Patient Registry also found in NRDT. Validity of data in NRDT was assessed by information from medical records and analysed using kappa statistics., Results: Completeness of NRDT: Of 3020 patients registered in the National Patient Registry as incident chronic RRT patients, 97.2% were found in NRDT but 22.5% with another year of entry. There were no differences in completeness between hospitals or regions. Validity of NRDT: Validity of common renal diagnoses and RRT modality was high: diabetic nephropathy (kappa = 0.98), adult polycystic kidney disease (kappa = 0.95), chronic glomerulonephritis (kappa = 0.78) and RRT modality (kappa = 0.94). The diagnosis CKD of unknown aetiology and type of diabetes were less valid (kappa = 0.62, 0.60 and 0.73, respectively). The date of RRT start had also high validity., Conclusions: Completeness of incident patient registration in NRDT was highly acceptable. Validity of incident patient data was also good, except for type of diabetes.

Aims: To examine the risk of death associated with antiarrhythmic drug (AAD) therapy in a nationwide unselected cohort of patients with atrial fibrillation (AF)., Methods and Results: All patients admitted with AF in Denmark from 1995 to 2004 and their subsequent use of AADs were identified by individual-level linkage of nationwide registries. Multivariable Cox proportional-hazard models with time-dependent covariates were used to analyse the risk of death associated with AAD therapy. A total of 141,500 patients were included in the study; of these 3356 (2.4%) patients received treatment with flecainide, 3745 (2.6%) propafenone, 23,346 (16.5%) sotalol, and 10,376 (7.3%) amiodarone. Annualized mortality rates were 2.54, 4.25, 5.29, and 7.42 per year per 100 person years for flecainide, propafenone, sotalol, and amiodarone, respectively. Multivariable Cox proportional-hazard models did not show increased risk of death associated with any of the AADs. Hazard ratio (95% confidence interval) for flecainide 0.38 (0.32-0.44), propafenone 0.65 (0.58-0.71), sotalol 0.65 (0.63-0.67), and amiodarone 0.94 (0.89-1.00)., Conclusion: In an unselected cohort of patients with AF, antiarrhythmic treatment with flecainide, propafenone, sotalol, or amiodarone was not associated with increased risk of death. From a safety perspective, this indicates appropriate selection of patients for AAD therapy.

Aims: To study evolvement in pharmacotherapy of atrial fibrillation from 1995 to 2004., Methods and Results: All Danish patients were discharged following first-time atrial fibrillation and their pharmacotherapy was identified by individual-level-linkage of nationwide registers of hospitalization and drug dispensing from pharmacies. A total of 108 791 patients survived 30 days after discharge and were included. In 1995-1996, 7.4% of the patients received beta-blockers, increasing to 44.3% in 2003-2004. The corresponding figures for amiodarone were 2.9 and 5.4%. In contrast, use of nondihydropyridine calcium-channel blockers, digoxin, sotalol, and class 1C antiarrhythmics decreased from 20.6, 63.9, 21.3, and 4.0% in 1995-1996 to 12.6, 43.8, 4.2, and 1.3% in 2003-2004, respectively. Notably, patients receiving anticoagulants increased from 29.8 to 43.5%. Multivariate logistic regression analysis revealed females to be associated with more use of digoxin, but less use of amiodarone and oral anticoagulants than males. Patients above 80 years received less pharmacotherapy, apart from digoxin treatment that was more commonly used in elderly., Conclusion: Pharmacotherapy of atrial fibrillation has changed towards increased beta-blocker use with a coincident decrease in the use of other rate-limiting drugs and sotalol. Treatment with amiodarone or class 1C antiarrhythmics remained very low. Oral anticoagulant therapy increased considerably, but women and elderly were apparently undertreated.

According to many national recommendations, women should be physically active during pregnancy, but empirical evidence to support this recommendation is sparse. The authors' aim in this study was to examine the relation between physical exercise during pregnancy and the risk of preterm birth. Self-reported data on physical exercise during pregnancy were collected prospectively for 87,232 singleton pregnancies included in the Danish National Birth Cohort between 1996 and 2002. Hazard ratios for preterm birth according to hours of exercise per week, type of exercise, and metabolic equivalent-hours per week, respectively, were calculated using Cox regression analysis. Results showed a reduced risk of preterm birth among the almost 40% of women who engaged in some kind of exercise during pregnancy in comparison with nonexercisers (hazard ratio = 0.82, 95% confidence interval: 0.76, 0.88), but no dose-response relation was seen. The association was not affected by the type of exercise, and the results were not altered when the degree of preterm birth was taken into account. These findings do not indicate any adverse effects of exercise on the risk of preterm birth and therefore do not contradict current recommendations.

Background: We have previously demonstrated renal enlargement in pigs treated with ciclosporin A (CsA) 10 mg/kg/day orally for 6 months. The aim of the study was to investigate the effect of oral CsA (10 mg/kg/day) for 12 months on kidney structure and function and the potential renoprotective role of angiotensin II (Ang II) receptor blocker telmisartan on chronic CsA nephrotoxicity in pigs., Methods: Fourteen Göttingen minipigs aged 12-14 months were included: pigs received either CsA 10 mg/kg/day (n = 7) or CsA 10 mg/kg/day + telmisartan 40 mg/day (n = 7) orally for 12 months. At week 0, 12, 31, 38, 47 and 54, we measured body weight, mean arterial blood pressure (MAP), serum creatinine, whole blood trough CsA, plasma Ang II, haemoglobin and liver function parameters. Magnetic resonance imaging was used to estimate kidney length, volume, relative glomerular filtration rate (rGFR) and renal blood flow (RBF). Kidney tissue biopsies were used for conventional histological examination., Results: Plasma Ang II levels were significantly higher during telmisartan treatment. Interstitial fibrosis and glomerulosclerosis occurred in both groups, but were attenuated in the telmisartan-treated pigs (P = 0.064). A significant increase in renal volume was seen in both groups, but tended to be lower in the CsA + telmisartan pigs at 54 weeks (P = 0.097). Telmisartan did not reduce MAP, RBF or rGFR., Conclusions: Long-term CsA treatment causes histopathological changes in the porcine kidney similar to those observed in humans and results in renal enlargement. Telmisartan attenuates the CsA-induced histopathological changes and enlargement in the pig kidney.

Aims: To study initiation, dosages, and compliance with beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors, and statins in patients after acute myocardial infarction (AMI) and to identify likely targets for improvement., Methods and Results: Patients admitted with first AMI between 1995 and 2002 were identified by linking nationwide administrative registers. A total of 55 315 patients survived 30 days after discharge and were included; 58.3% received beta-blockers, 29.1% ACE-inhibitors, and 33.5% statins. After 1, 3, and 5 years, 78, 64, and 58% of survivors who had started therapy were still receiving beta-blockers, 86, 78, and 74% were receiving ACE-inhibitors, and 85, 80, and 82% were receiving statins, respectively. Increased age and female sex were associated with improved compliance. The dosages prescribed were generally 50% or less of the dosages used in clinical trials, and dosages did not increase during the observation period. Patients who did not start treatment shortly after discharge had a low probability of starting treatment later., Conclusion: The main problem with underuse of recommended treatment after AMI is that treatment is not initiated at an appropriate dosage shortly after AMI. A focused effort in the immediate post-infarction period would appear to provide long-term benefit.

CD163 is the monocyte/macrophage-specific receptor for haptoglobin-hemoglobin (Hp-Hb) complexes. The cytoplasmic tail of human CD163 exists as a short tail variant and two long tail variants. Reverse transcriptase-polymerase chain reaction analysis indicated that all three CD163 variants are substantially expressed in blood, liver, and spleen, and the short tail variant is the predominant mRNA species. Using cell transfectants in which cDNA encoding the CD163 variants was inserted at the same site in the genome, we evaluated the expression and endocytic properties of the tail variants. Ligand uptake analysis showed that cells expressing the CD163 short tail variant exhibited a higher capacity for ligand endocytosis than cells expressing the CD163 long tail variants. The difference in endocytic activity was explained by confocal microscopic analysis, showing marked deviations in subcellular distribution. Surface expression was far most pronounced for the CD163 short tail variant, whereas the long tail variants were most abundant in the Golgi region/endosomes. Mutational change of a putative signal for endocytosis (Tyr-Arg-Glu-Met), present in a common part of the cytoplasmic tail of the variants, almost completely inactivated the endocytic activity of the short tail variant. In conclusion, the three physiological tail variants of CD163 may contribute to Hp-Hb endocytosis by means of the common ligand-binding region and endocytic signal. However, the high mRNA expression level and relatively high endocytic capacity of the short tail variant suggest that it accounts for the majority of Hp-Hb uptake from the circulation, whereas the long tail variants may have yet-unknown intracellular roles.

Aims: To analyse the effect of the change in diagnostic criteria for acute myocardial infarction (AMI) and the use of troponin as a diagnostic marker on the hospitalization rate and mortality of hospitalized AMI patients from 1994 to 2001., Methods and Results: Patients (> or =30 years) admitted for their first AMI were identified using the National Patient Registry in Denmark. We registered when each hospital introduced troponin as a diagnostic marker. The reported hospitalization rate decreased until 1998 and then increased substantially from 1999 to 2001 from 3472 to 4163 per million inhabitants (19.9%) for men and from 1648 to 2020 per million inhabitants (22.6%) for women. Troponin use was associated with a significant 14% increase in hospitalization rate in this period [rate ratio 1.14, 95% confidence interval (CI) 1.11-1.18]. The effect of troponin was greatest among patients 70 years and older (rate ratio 1.19, 95% CI 1.14-1.23). The 28 day mortality decreased steadily from 25.9% in 1994 to 17.5% in 2002 (32.4%) and was not affected by troponin use., Conclusion: The reported hospitalization rate for AMI increased significantly after the new diagnostic criteria for AMI were introduced. The measurement of cardiac troponins further increased the hospitalization rate. The mortality among hospitalized patients with AMI declined steadily and was not affected by the use of troponins.

Aims: To apply and evaluate LG (LPS genes) genotyping, which is a genotyping method based on a cluster of genes involved in the synthesis of surface lipopolysaccharides (LPS) in Campylobacter species, for typing of Campylobacter jejuni isolates obtained from Danish broiler chickens. Furthermore, the LG genotyping method was used to study the genetic stability of four C. jejuni strains after gastrointestinal passage through experimentally infected chickens., Methods and Results: In the present study, the LG genotyping method was modified with respect to the restriction enzymes used. To validate the method, 63 Penner serotype reference strains and 107 C. jejuni chicken isolates, representing the most common Penner serotypes of C. jejuni in Danish poultry, were selected for typing. The method was successfully used for typing all isolates and the LG genotype profiles were reproducible. There were no changes in the LG genotype of the C. jejuni strains obtained after experimental passage through chickens., Conclusions: All C. jejuni strains obtained from broiler chickens were typeable by the LG genotyping method. Application of the RsaI restriction enzyme improved the method in terms of ease and consistency of analyses and increase of discriminatory power., Significance and Impact of the Study: The LG genotyping method is a valuable tool for typing C. jejuni isolates obtained from poultry. However, the association between Penner serotyping based on passive haemagglutination of heat-stable antigens and LG genotyping was low when applied to poultry isolates. This is in contrast to previous studies on isolates of human origin that reported a high correlation between results obtained by the two typing methods (Shi et al. 2002).

Aims: To study the prevalence of seven virulence and toxin genes, and cytolethal distending toxin (CDT) production of Campylobacter jejuni and C. coli isolates from Danish pigs and cattle., Methods and Results: The presence of the cadF, ceuE, virB11, flaA, cdtA, cdtB, cdtC and the cdt gene cluster among 40 C. jejuni and C. coli isolates was detected by polymerase chain reaction. The CDT production of the isolates was determined on Vero, colon 205 and chicken embryo cells. The cadF, flaA, ceuE and cdtB genes were detected from 100% of the isolates. The cdtA and cdtC genes were found in 95.0 and 90.0% of the isolates, respectively. The cdt gene cluster was detected in 82.5% isolates. Only 7.5% of the isolates were positive for virB11. Ninety-five per cent of the isolates produced CDT in Vero and colon 205 cell assays, and 90% of the isolates produced CDT in chicken embryo cell assays., Conclusions: High prevalence of the cadF, ceuE, flaA and cdtB genes was found. Data of the prevalence of cdt genes was consistent with the CDT titres produced by the isolates. Campylobacter coli from pigs produced high CDT titres., Significance and Impact of the Study: The high prevalence of seven virulence and toxin genes demonstrated that these putative pathogenic determinants are widespread among Campylobacter isolates from pigs and cattle. Campylobacter coli isolates from pigs produced much higher CDT titres compared with C. coli isolates from other sources suggesting that C. coli may be particularly adapted to or associated with this species.

Aims: To investigate contamination of surfaces on a poultry slaughter line from infected poultry and subsequent cross-contamination of non-infected poultry., Methods and Results: A broiler slaughterhouse was investigated for the presence of Salmonella on 17 defined points over two 1-week periods. Flocks supplied to slaughter and neck skin samples from processed chicken were likewise investigated. Salmonella was detected in 10 out of 18 flocks at ante-mortem inspection, while seven flocks tested positive in the finished products. Equipment at all but one control point at the slaughter line tested positive at least once during the study. The chicken receiving area was the most contaminated. By comparison of typing results from serotyping, plasmid profile typing and phage typing, direct evidence for cross-contamination with Salm. serotype Typhimurium, Salm. Serotype 4.12:b:- and Salm. serotype Virchow on the slaughter line was obtained for four of the flocks. The cleaning procedure in place did not remove all Salmonella from the contaminated areas., Conclusions: Evidence for contamination of equipment on a slaughter line and subsequent cross-contamination to non-infected chicken was provided by typing methods., Significance and Impact of the Study: This study has provided detailed information on cross-contamination on a slaughter line by the use of phage typing and plasmid profiling. The study stresses the importance of controlling Salmonella in the primary production, as contamination of the equipment on the slaughter line will act as a vehicle to contaminate finished products. Cleaning procedures on slaughter lines cannot be expected to control this problem with the current equipment.

Aims: To develop and evaluate a rapid and sensitive PCR method for detection of Campylobacter spp. directly from chicken faeces., Methods and Results: DNA was isolated from faecal swabs using magnetic beads followed by PCR using a prealiquoted PCR mixture, which had been stored in the freezer. The result could be obtained in <6 h. The method was evaluated on 1282 samples from the Danish surveillance programme for Campylobacter in broilers by comparing with conventional culture. The diagnostic specificity was calculated to be 0.99. The detection limits of the PCR method and of the conventional culture were compared using spiked control material. For both methods the detection limit was 36 CFU ml-1., Conclusions: It was concluded that the PCR proved useful for detection of Campylobacter in pooled cloacal swabs from broilers., Significance and Impact of the Study: By taking cloacal samples in the broiler flocks the technique can be used as an important tool for planning and directing the broiler slaughtering process. This will be a great help in minimizing the risk of contaminating Campylobacter-free flocks at the abattoir.

Aims: To validate a phenotypic Campylobacter species identification method employed to identify campylobacters in broilers by comparison with campylobacterial species identification using various species-specific PCR analyses., Methods and Results: From a collection of 2733 phenotypically identified campylobacterial cultures, 108 Campylobacter jejuni cultures and 351 campylobacterial cultures other than Camp. jejuni were subjected to various species-specific PCR assays. On the basis of the genotypic tests, it was demonstrated that Camp. jejuni and Camp. coli constituted approx. 99% of all cultures, while other species identified were Helicobacter pullorum, Camp. lari and Camp. upsaliensis. However, 29% of the 309 Camp. coli cultures identified by phenotypic tests were hippurate-variable or negative Camp. jejuni cultures, whereas some Camp. lari cultures and unspeciated campylobacter cultures belonged to H. pullorum. It was also notable that 2-6% of the cultures were, in fact, mixed cultures., Conclusions: The phenotypic identification scheme employed failed to appropriately differentiate Campylobacter species and particularly to identify the closely related species, H. pullorum., Significance and Impact of the Study: Future phenotypic test schemes should be designed to allow a more accurate differentiation of Campylobacter and related species. Preferably, the phenotypic tests should be supplemented with a genotypic strategy to disclose the true campylobacterial species diversity in broilers.

Background: Recently, 2-h samples (C2) have been found superior to trough levels for therapeutic monitoring of transplanted patients receiving cyclosporin. The present study was undertaken to see if the same was the case for tacrolimus., Methods: Blood tacrolimus levels were determined in 21 consecutive patients at 3 and 14 days after renal transplantation, and before and 1, 2, 3, 4, and 6 h after oral intake of 0.1 mg/kg tacrolimus. The area under the blood concentration/time curve (AUC) was determined by the trapezoidal method, association between blood concentration at each sampling time and AUC by Pearson's correlation coefficient, and pairs of correlation coefficients were compared by an asymptotic Wald-type test., Results: AUC varied five-fold despite near-equal dosing. Pearson's correlation coefficient for trough level, 1, 2, 3, 4, and 6 h were 0.84, 0.60, 0.81, 0.95, 0.95, and 0.94 on day 3 and 0.94, 0.69, 0.92, 0.96, 0.94, 0.92 on day 14. Three-, 4- and 6-h levels had significantly higher correlation coefficients compared to trough, 1- and 2-h levels. One-hour samples had significantly lower correlation coefficients compared to all other sampling times on day 14. The patient with the highest AUC developed nephrotoxicity despite trough levels in the desired range., Conclusions: Two-hour levels are not superior to trough levels in tacrolimus-treated renal transplant patients. Despite good correlation between trough level and AUC, some patients may still receive nephrotoxic doses despite trough levels in the desired range. Sampling 3-6 h after oral intake may be at least as good as trough levels.

Background: Young adults with a history of Epstein-Barr virus (EBV)-related infectious mononucleosis have an increased risk for Hodgkin's lymphoma. EBV is detected in Hodgkin's lymphoma Reed-Sternberg cells from some patients, but in young adult patients, it is detected at a relatively low frequency in these cells. Hodgkin's lymphoma and infectious mononucleosis are both associated with high social class, and unknown confounding factors that are also associated with socioeconomic status might explain or contribute to the apparent association between these diseases. To indirectly assess the importance of socioeconomic status on the association between these diseases, we determined the risk for hematopoietic and lymphatic cancers in first-degree relatives of patients with confirmed EBV-related infectious mononucleosis., Methods: We identified parents, siblings, and offspring of 17,045 persons with serologically confirmed EBV-related infectious mononucleosis. Subjects in these cohorts were linked with the population-based Danish Cancer Register to identify those developing hematopoietic/lymphatic cancers after the index patient was diagnosed with infectious mononucleosis. The relative risk for cancer in the infectious mononucleosis family members was expressed as standardized incidence ratios (SIRs; i.e., the ratio between the number of cancers observed and the number of cancers expected, obtained from age-specific, sex-specific, and period-specific incidence rates)., Results: We identified 8052 parents, 5264 siblings, and 28,605 offspring of patients with EBV-related infectious mononucleosis who were followed for a total of 892,213 person-years at risk. The risk for Hodgkin's lymphoma was unaltered in the combined group of first-degree relatives of these patients (SIR = 0.99; 95% confidence interval [95% CI] = 0.62 to 1.59; number of cases [n] = 17), in the group of parents (SIR = 0.83; 95% CI = 0.31 to 2.22; n = 4), in the group of siblings (SIR = 0.96; 95% CI = 0.31 to 2.97; n = 3), and in the group of offspring (SIR = 1.08; 95% CI = 0.58 to 2.02; n = 10)., Conclusion: The unremarkable risk for Hodgkin's lymphoma in family members of patients with EBV-related infectious mononucleosis indicates that socioeconomic confounding is an unlikely explanation for the association between EBV-related infectious mononucleosis and Hodgkin's lymphoma.

Background: The influence of dialysis modality on prognosis is controversial. In the absence of randomized trials, epidemiological investigations present the best method for studying the problem., Methods: 4568 haemodialysis (HD) and 2443 peritoneal dialysis (PD) records in 4921 dialysis patients treated between 1990 and 1999 were retrieved from the Danish Terminal Uremia register in order to determine the influence of dialysis form on prognosis. The register is national, comprehensive, and incident., Results: Factors reducing survival included age, cardiovascular disease, malignancy, lung disease, diabetes, alcoholism, haematological disease, but not sex or hypertension. Transplant non-candidacy was associated with an adjusted relative risk of 4.7 (CI 4.0-5.6). PD mortality relative to HD (after correction for comorbidity and transplant candidacy) was 0.65 (CI 0.59-0.72, P<0.001) on an "as treated" and "history" analysis and 0.86 (CI 0.78-0.95, P<0.01) on an intention-to-treat (ITT) analysis. The difference was confined to the first 2 years of dialysis. Change in dialysis modality was associated with increased mortality, and change from PD to HD with an accelerated mortality for the first 6 months. This was presumably due to the transfer of sick PD patients, but did not explain the difference. The relative advantage of PD was lower for diabetic patients, where it was not significant on ITT analysis. Dialysis prognosis improved by 14% during the period, with similar results for HD and PD patients. PD patients who were subsequently transplanted had a significantly shorter time to onset of graft function (3.5 vs 5.1 days, P<0.05)., Conclusions: These results show a survival advantage for PD during the first 2 years of dialysis treatment. This may be due to unregistered differences in comorbidity at the start of treatment, or may be causal, possibly due to better preservation of residual renal function. The study lends credence to the "integrative care" approach to uraemia, where patients are started on PD and transferred to HD when PD related mortality increases.

Aims: The objective of this study was to subtype Arcobacter butzleri isolates using RAPD-PCR., Methods and Results: Thirty-five A. butzleri isolates obtained from chicken carcasses were examined. PCR-mediated DNA fingerprinting technique with primers of the variable sequence motifs was used to detect polymorphism within the isolates. Eleven distinct DNA profiles were obtained as follows: Of the 35 strains, 10 as profile 4; seven as profile 1; five as profile 3; three as profiles 2 and 9; two as profile 10; one as profiles 5, 6, 7, 8 and 11., Conclusions: Chicken carcasses sold in markets were found to be contaminated with several different strains of A. butzleri. RAPD-PCR technique was found to be a useful technique for distinguishing A. butzleri isolates., Significance and Impact of the Study: The presence of several different A. butzleri strains on chicken carcasses may indicate multiple sources of contamination. The epidemiological role of A. butzleri in human and animal diseases should be investigated further.

Aims: To determine the flock prevalence and to estimate the within flock prevalence of Campylobacter in broiler flocks from different rearing systems, and to determine the antimicrobial susceptibility of Campylobacter isolates to selected antimicrobial substances., Methods and Results: One hundred and sixty broiler flocks originating from organic, conventional and extensive indoor production farms were investigated for the presence of Campylobacter at the time of slaughter. Campylobacter isolates from a subsample of positive flocks were subjected to susceptibility testing. Campylobacter spp. were isolated from 100% of organic broiler flocks, from 36.7% of conventional broiler flocks and from 49.2% of extensive indoor broiler flocks. Six of 62 Campylobacter isolates were resistant to one or more of the antimicrobials tested., Conclusion: These results indicate that the special characteristics of organic broiler production provide a high prevalence of Campylobacter-positive flocks. Antimicrobial resistance was scarce among Campylobacter isolates from all rearing systems., Significance and Impact of the Study: Organic broiler flocks constitute a strong potential for introduction of Campylobacter to the processing line upon arrival at slaughter.

Aims: The effect of batch depletion of broiler houses for campylobacter occurrence in broiler flocks was estimated in 10 flocks, each comprising a separate female and male batch., Methods and Results: The chicks were sampled first by cloacal swabs in the broiler houses before the start of the depopulation and secondly, on arrival at the abattoir. Females were slaughtered at 5 weeks of age, males at 6 weeks. The number of campylobacter-positive batches increased from five to seven female batches, and from five to 10 male batches, between the two sampling rounds., Conclusion: It is concluded that batch depletion of broiler houses increased the prevalence of Campylobacter spp.-infected broilers in the flocks, that the introduction occurred when catching the first batch, and that campylobacter spreads through the entire flock within a week., Significance and Impact of the Study: The results from this study emphasize the need to manage depopulation of broiler houses as quickly as possible and in one batch only.

Background: Infectious mononucleosis, which is caused by the Epstein-Barr virus, has been associated with an increased risk for Hodgkin's disease. Little is known, however, about how infectious mononucleosis affects long-term risk of Hodgkin's disease, how this risk varies with age at infectious mononucleosis diagnosis, or how the risk for Hodgkin's disease varies in different age groups. In addition, the general cancer profile among patients who have had infectious mononucleosis has been sparsely studied., Methods: Population-based cohorts of infectious mononucleosis patients in Denmark and Sweden were followed for cancer occurrence. The ratio of observed-to-expected numbers of cancers (standardized incidence ratio [SIR]) served as a measure of the relative risk for cancer. SIRs of Hodgkin's disease in different subsets of patients were compared with the use of Poisson regression analysis. All statistical tests including the trend tests were two-sided., Results: A total of 1381 cancers were observed during 689 619 person-years of follow-up among 38 562 infectious mononucleosis patients (SIR = 1. 03; 95% confidence interval [CI] = 0.98-1.09). Apart from Hodgkin's disease (SIR = 2.55; 95% CI = 1.87-3.40; n = 46), only skin cancers (SIR = 1.27; 95% CI = 1.13-1.43; n = 291) occurred in statistically significant excess. In contrast, the SIR for lung cancer was reduced (SIR = 0.71; 95% CI = 0.58-0.86; n = 102). The SIR for Hodgkin's disease remained elevated for up to two decades after the occurrence of infectious mononucleosis but decreased with time since diagnosis of infectious mononucleosis (P: for trend <.001). The SIR for Hodgkin's disease tended to increase with age at diagnosis of infectious mononucleosis (P: for trend =.05). Following infectious mononucleosis, the SIR for Hodgkin's disease at ages 15-34 years was 3.49 (95% CI = 2.46-4.81; n = 37), which was statistically significantly higher than the SIR for any other age group (P: for difference =.001)., Conclusion: The increased risk of Hodgkin's disease after the occurrence of infectious mononucleosis appears to be a specific phenomenon.

To understand how neutrophils are recruited to the lung in pneumococcal pneumonia, the ability of pneumococcal components to elicit the chemokine interleukin (IL)-8 from monolayers of cultured human type II cells was assessed. Heat-killed clinical and laboratory strains of Streptococcus pneumoniae and secreted proteins from exponentially growing pneumococci elicited significant quantities of IL-8 from A549 cells. All strains that elicited IL-8 production secreted a protein ( approximately 90 kDa) that comigrated on SDS-PAGE with a C3-binding protein previously identified in S. pneumoniae. As little as 7 pmol of the purified 90-kDa protein readily elicited levels of IL-8 production equivalent to those obtained with 1 U of IL-1alpha. Supernatant proteins and heat-killed cells of an isogenic mutant that failed to produce the C3-binding protein elicited significantly less IL-8 than did supernatant proteins or heat-killed cells of the parent strain. These results implicate the C3-binding protein of S. pneumoniae in a novel pathway of pulmonary inflammation.

Background: Cardiovascular mortality has been declining in Denmark over the past 20 years. Trends in incidence of myocardial infarction (MI) over the period 1982-1991 are described within the framework of the World Health Organization MONICA Project., Methods: The DAN-MONICA heart register included all cases of MI in 25-74-year-old men and women living in 11 municipalities around Glostrup County Hospital evolving over a period of 10 years. They were identified retrospectively based mainly on relevant ICD diagnoses in death certificates and hospital discharge reports. Cases meeting WHO-MONICA criteria for definite or possible MI, recurrent as well as first-ever MI, were registered. Subsequent tracing of cases through national registers on deaths and hospitalizations by means of the patient's civil registration number ensured the completeness of the registration., Results: A total of 6025 cases of MI occurred in the period, 4532 among men and 1493 among women. A total of 2923 men and 1047 women had a first-ever MI in the period. The age-standardized rates show a definite decline over the registration period for men and a less distinct decline for women., Conclusions: The DAN-MONICA heart register meets the requirements for completeness and uniformity throughout the registration period. Causes and magnitude of bias are well described. Even when possible sources of bias are taken into account, the incidence of MI decreased significantly over the 10-year-period 1982-1991 by an average of 5.0% per year for men and 3.5% per year for women.

The present study compares four different sampling methods potentially applicable to detection of Salmonella in broiler flocks, based on collection of faecal samples (i) by hand, 300 fresh faecal samples (ii) absorbed on five sheets of paper (iii) absorbed on five pairs of socks (elastic cotton tubes pulled over the boots and termed 'socks') and (iv) by using only one pair of socks. Twenty-three broiler flocks were included in the investigation and 18 of these were found to be positive by at least one method. Seven serotypes of Salmonella with different patterns of transmission (mainly horizontal or vertical) were found in the investigation. The results showed that the sock method (five pairs of socks) had a sensitivity comparable with the hand collection method (60 pools of five faecal samples); the paper collection method was inferior, as was the use of only one pair of socks. Estimation of the effective pool sizes for the different methods was also carried out.

In December 1994, Salmonella enterica serovar Infantis (S. Infantis) was accidentally introduced into a Danish broiler house by stocking an S. Infantis-infected broiler flock of 39,900 day-old chicks. At the time of the study, the infection had persisted through 6 broiler cycles. Typhaea stercorea (L.), the hairy fungus beetle, was found in large quantities inside and around the broiler house. Various attempts to control the beetle had failed; T. stercorea had been uncontrollable on the farm since Alphitobius diaperinus (Panzer), the lesser mealworm, was eradicated approximately 10 yr earlier. We investigated the ability of T. stercorea to act as a carrier of S. Infantis in the broiler house between 2 broiler cycles. We examined the empty, cleaned, and disinfected broiler house for S. Infantis 3 d before stocking the 7th broiler flock, and S. Infantis was isolated from the beetles only. Of 20 singly examined T. stercorea, 9 (45%) were S. Infantis positive. A rapid spread of the infection was seen in the 7th broiler flock; 100% of the culled chicks were S. Infantis positive 3 d after stocking. Under experimental conditions chicks were observed eating beetles, and when 5 d-old, specified pathogen-free chicks were fed with S. Infantis-positive T. stercorea collected from the broiler house, all 5 chicks became infected in 4 d. We conclude that T. stercorea may act as a potential carrier of S. Infantis between successive broiler cycles.

Background: In Denmark, as in many other Western countries, a decline in mortality from ischaemic heart disease (IHD) has been observed. The present study assesses whether the decline in IHD mortality is due to a decrease in incidence and/or case-fatality, and whether parallel changes occurred in the various manifestations of IHD requiring hospitalization., Methods: The National Patient Register of hospital discharges and the Causes-of-Death Register were linked and all cases of first admission for IHD including AMI and fatal first manifestations of IHD since 1977 in the entire Danish population were identified. Cases of AMI and IHD were considered as incident cases if no admission for these diagnoses had occurred during the preceding 5 years. Sex-specific, age-standardized annual mortality, incidence and case-fatality rates of AMI (ICD8 code 410), narrowly defined IHD (NIHD, ICD8 codes 410-4) and broadly defined IHD (BIHD, ICD8 codes 410-4, 427 and 795-6) were calculated for the period 1982-1992., Results: During the entire period the age-standardized mortality of AMI, NIHD and BIHD decreased in both men and women. The incidence of AMI and NIHD decreased, while the incidence of BIHD remained constant. Case fatality of AMI decreased in both men and women, while case fatality of NIHD and BIHD decreased in men and in women aged 0-64 years only., Conclusion: The declining mortality from IHD in Denmark may be partly due to declining incidence as well as declining case fatality, but changes in disease manifestation or diagnostic drift may also contribute because more broadly defined diagnostic groups showed less or no decline in incidence.

Of 1041 renal allograft transplantations performed in our centre, 142 (13.6%) were carried out with ABO-minor-incompatible kidneys. Anti-recipient ABO antibodies were found in two of 34 patients treated with cyclosporin. These two cases of severe but self-limited haemolysis due to anti-A1 and anti-B, respectively, are reported in detail. Among 108 azathioprine-treated patients no evidence of the disorder was found. The condition should be suspected in any recipient with an unexpected reduction in haematrocrit or other signs of haemolysis after ABO-minor-incompatible organ transplantation.

In 14 patients with pulmonary sarcoidosis and 14 matched controls we studied peripheral blood lymphocyte and monocyte counts, distribution of T and B lymphocytes, the functional helper:suppressor T cell balance, the antibody-dependent cell-mediated cytotoxicity of monocytes (monocyte ADCC), and the capacity of peripheral monocytes to generate angiotensin converting enzyme (ACE) in culture. Apart from lymphopenia in sarcoidosis patients we found a normal lymphocyte subset distribution and no evidence of increased suppressor T cell activity, using a PWM driven proliferative assay. The patients exhibited a normal monocyte count, but the proportion of monocytes was increased in sarcoidosis. Patients with active sarcoidosis had a significantly increased monocyte ADCC which was positively correlated with raised serum ACE. Peripheral monocytes had a measurable, but low ACE activity, which was modestly higher in active sarcoidosis than in controls. We could not reproduce earlier reported results on a glucocorticoid induced ACE synthesis from cultured human monocytes.