Thougaard A.V.,TopoTarget A S |
Langer S.W.,Rigshospitalet |
Hainau B.,Roskilde Sygehus |
Grauslund M.,Rigshospitalet |
And 5 more authors.
Toxicology | Year: 2010
The bisdioxopiperazine topoisomerase II catalytic inhibitor dexrazoxane has successfully been introduced into the clinic as an antidote to accidental anthracycline extravasation based on our preclinical mouse studies. The histology of this mouse extravasation model was investigated and found to be similar to findings in humans: massive necrosis in the subcutis, dermis and epidermis followed by sequestration and healing with granulation tissue, and a graft-versus-host-like reaction with hyperkeratotic and acanthotic keratinocytes, occasional apoptoses, epidermal invasion by lymphocytes and healing with dense dermal connective tissue. The extension of this fibrosis was quantified, and dexrazoxane intervention resulted in a statistically significant decrease in fibrosis extension, as also observed in the clinic. Several mechanisms have been proposed in anthracycline extravasation cytotoxicity, and we tested two major hypotheses: (1) interaction with topoisomerase II alpha and (2) the formation of tissue damaging reactive oxygen species following redox cycling of an anthracycline Fe2+ complex. Dexrazoxane could minimise skin damage via both mechanisms, as it stops the catalytic activity of topoisomerase II alpha and thereby prevents access of anthracycline to the enzyme and thus cytotoxicity, and also acts as a strong iron chelator following opening of its two bisdioxopiperazine rings. Using the model of extravasation in a dexrazoxane-resistant transgenic mouse with a heterozygous mutation in the topoisomerase II alpha gene (Top2aY165S/+), we found that dexrazoxane provided a protection against anthracycline-induced skin wounds that was indistinguishable from that found in wildtype mice. Thus, interaction with topoisomerase II alpha is not central in the pathogenesis of anthracycline-induced skin damage. In contrast to dexrazoxane, the iron-chelating bisdioxopiperazine ICRF-161 do not inhibit the catalytic cycle of topoisomerase II alpha. This compound was used to isolate and test the importance of iron in the wound pathogenesis. ICRF-161 was found ineffective in the treatment of anthracycline-induced skin damage, suggesting that iron does not play a dominant role in the genesis of wounds. © 2010 Elsevier Ireland Ltd.
PubMed | Nordsjaellands Hospital, Rigshospitalet, Roskilde Sygehus, University of Southern Denmark and 2 more.
Type: | Journal: International journal of cardiology | Year: 2016
Multislice computed tomography (MSCT) is a non-invasive, less expensive, low-radiation alternative to coronary angiography (CAG) prior to valvular heart surgery. MSCT has a high negative predictive value for coronary artery disease (CAD) but previous studies of patients with valvular disease have shown that MSCT, as the primary evaluation technique, lead to re-evaluation with CAG in about a third of cases and it is therefore not recommended. If a subgroup of patients with low- to intermediate risk of CAD could be identified and examined with MSCT, it could be cost-effective, reduce radiation and the risk of complications associated with CAG.The study cohort was derived from a national registry of patients undergoing CAG prior to valvular heart surgery. Using logistic regression, we identified significant risk factors for CAD and developed a risk score (CT-valve score). The score was validated on a similar cohort of patients from another registry.The study cohort consisted of 2221 patients, 521 (23.5%) had CAD. The validation cohort consisted of 2575 patients, 771 (29.9%) had CAD. The identified risk factors were male sex, age, smoking, hyperlipidemia, hypertension, aortic valve disease, extracardiac arteriopathy, ejection fraction <30% and diabetes mellitus. CT-valve score could identify a third of the population with a risk about 10%.A score based on risk factors of CAD can identify patients that might benefit from using MSCT as a gatekeeper to CAG prior to heart valve surgery.
PubMed | Hvidovre Hospital, Danish Cancer Society, Herlev Hospital, Copenhagen University and Roskilde Sygehus
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016
Human papillomavirus (HPV) is a critical element in the rising incidence of oropharyngeal squamous cell carcinoma (OPSCC), although whether this trend will continue, and the types of HPV responsible, are currently unknown. We previously demonstrated an increased incidence of HPV-related OPSCC in the high HPV prevalence area of Eastern Denmark from 2000 to 2010. Therefore, we investigated if the incidence for OPSCC continued to rise, the association to HPV and putative HPV-types in Eastern Denmark from 2011 to 14. We then projected the expected incidence of OPSCC versus cervical cancer through to 2020.Patients with OPSCC (tonsillar squamous cell carcinoma [TSCC] and base of tongue squamous cell carcinoma [BSCC]) were identified via the Danish Head and Neck Cancer Group and the Danish Pathology Databank (n=700). Tumours were re-reviewed and assessed using p16 immunohistochemistry, HPV DNA polymerase chain reaction (PCR), with genotyping by next generation sequencing.Sixty-two percent (432/700) of tumours were HPV-positive (HPV+). The total incidence rate (per 100.000) for OPSCC increased from 4.0 in 2011 to 4.5 in 2014, primarily due to a rise in HPV+ TSCCsand HPV+ BSCCs, although numbers of HPV-negative (HPV-) OPSCC also increased during the study period. The majority of HPV+ tumours were HPV16 DNA positive (86%), but we also identified HPV33 DNA (6%), HPV35 DNA (4%)and others (3%), including HPV18, 26, 31, 45, 56, 58, 59and HPV67.An increasing incidence of OPSCC is driven primarily by HPV+ OPSCC. Sixty-two percent of tumours were HPV+, which is a high-prevalence, although the lower number of HPV- cases has yet to stabilise. HPV16 was the predominant genotype, although a significant proportion (14%) was of another genotype. Our projections suggest that the number of HPV+ OPSCC will exceed that of cervical cancer in 2016 in Eastern Denmark.
Ekelund C.K.,Rigshospitalet |
Petersen O.B.,Aarhus University Hospital |
Skibsted L.,Roskilde Sygehus |
Skibsted L.,Copenhagen University |
And 4 more authors.
Ultrasound in Obstetrics and Gynecology | Year: 2011
Objectives In Denmark a new national guideline for prenatal screening and diagnosis was issued in 2004 according to which all pregnant women should be offered a first-trimester combined risk assessment for trisomy 21 (T21). The aim of this study was to investigate whether the new screening strategy for T21 has changed the gestational age at which trisomy 18 (T18) and trisomy 13 (T13) are diagnosed prenatally, and the number of infants born with T18 or T13. Methods We collected from the Danish Cytogenetic Central Register information on all prenatal and postnatal chromosome analyses for T18 or T13, registered from 1997 to 2007. Information on first-trimester screening results was collected from each department of obstetrics and gynecology performing the nuchal translucency scans. The cut-off used for referral to invasive diagnostic testing for T21 and for T18/T13 was 1: 300 and 1: 150 at screening, respectively. Results In total, there were 435 cases with T18 and 168 cases with T13 between 1997 and 2007 in Denmark. The estimated incidence of T18 and T13 at the time of delivery was calculated as 2.5 and 1.6 per 10 000 deliveries, respectively. The number (proportion) of cases diagnosed before week 18 increased significantly, from 63 (59.4%) in 1997 and 1998 to 90 (80.4%) in 2006 and 2007 (P < 0.001). In addition, the number of T18 and T13 cases diagnosed prenatally after week 22 or postnatally decreased significantly, from 34 (32.1%) in 1997 and 1998 to seven (6.3%) in 2006 and 2007 (P < 0.0001). For women participating in first-trimester risk assessment in 2006 and 2007, the detection rate of T18 and T13 was 78.8% (95% CI, 71.0-86.7%). Conclusion The number of T18 and T13 fetuses diagnosed before week 18 increased significantly after the introduction of a combined first-trimester screening strategy for T21 in Denmark. In addition, the total number of fetuses diagnosed late in pregnancy and infants born with T18 or T13 decreased significantly. The national detection rate for T18 and T13 in the first trimester is comparable with detection rates found in modeled datasets and other prospective studies. © 2011 ISUOG. Published by John Wiley & Sons, Ltd.
Koningstein M.,Statens Serum Institute |
Simonsen J.,Statens Serum Institute |
Helms M.,Roskilde Sygehus |
Molbak K.,Statens Serum Institute
Journal of Antimicrobial Chemotherapy | Year: 2010
Objectives: The use of antimicrobial drugs for food animals selects for resistant non-typhoid Salmonella strains, but human consumption of antimicrobial drugs may also increase the risk of subsequent infection. The aim of this study was to determine the risk of salmonellosis attributable to human consumption of antimicrobial drugs in a case-control study of 22602 laboratory-confirmed Salmonella infections, diagnosed in Denmark between 1997 and 2005. Methods: A population registry-based case-control study, using several Danish databases: the National Prescription Database; the National Registry for Enteric Pathogens; the Civil Registry System; and the Integrated Database on Labour Market Research. Results: Exposure to trimethoprim, sulphonamides, broad-spectrum penicillins, tetracyclines and fluoroquinolones, during the year prior to diagnosis, was associated with an increased risk of non-typhoid Salmonella infection. Overall, the highest risk was associated with the prior use of fluoroquinolones. This risk increased as the time window of exposure approached the infection date. Previous use of fluoroquinolones was associated with an odds ratio (OR) of 4.55 [95% confidence interval (CI): 3.78-5.47] for Salmonella serotypes other than Salmonella Typhimurium or Salmonella Enteritidis, an OR of 2.21 (95% CI: 1.70-2.86) for Salmonella Typhimurium and an OR of 2.07 (95% CI: 1.76-2.42) for Salmonella Enteritidis. In particular for fluoroquinolones, there was an interaction between the pathogen resistance pattern and a history of antibiotic drug use. Conclusions: The increasing use of antibiotics, particularly fluoroquinolones, is likely to result in increased incidence of foodborne infections with drug-resistant Salmonella. © The Author 2010.
Litrup E.,Statens Serum Institute |
Torpdahl M.,Statens Serum Institute |
Malorny B.,German Federal Institute for Risk Assessment |
Huehn S.,German Federal Institute for Risk Assessment |
And 3 more authors.
BMC Microbiology | Year: 2010
Background. Salmonella enterica subsp. enterica is one of the leading food-borne pathogens in the USA and European countries. Outcome of human Salmonella serotype Typhimurium infections ranges from mild self-limiting diarrhoea to severe diarrhoea that requires hospitalization. Increased knowledge of the mechanisms that are responsible for causing infection and especially the severity of infection is of high interest. Results. Strains were selected from patients with mild infections (n = 9) and patients with severe infections (n = 9) and clinical data allowed us to correct for known underlying diseases. Additionally, outbreak isolates (n = 3) were selected. Strains were analyzed on a DNA-DNA microarray for presence or absence of 281 genes covering marker groups of genes related to pathogenicity, phages, antimicrobial resistance, fimbriae, mobility, serotype and metabolism. Strains showed highly similar profiles when comparing virulence associated genes, but differences between strains were detected in the prophage marker group. The Salmonella virulence plasmid was present in 72% of the strains, but presence or absence of the virulence plasmid did not correspond to disease symptoms. A dendrogram clustered strains into four groups. Clustering confirmed DT104 as being a clonal phagetype. Clustering of the remaining strains was mainly correlated to presence or absence of the virulence plasmid and mobile elements such as transposons. Each of the four clusters in the tree represented an almost equal amount of strains causing severe or mild symptoms of infection. Conclusions. We investigated clinical significance of known virulence factors of Salmonella serotype Typhimurium strains causing different disease symptoms, and conclude that the few detected differences in Salmonella serotype Typhimurium do not affect outcome of human disease. © 2010 Litrup et al; licensee BioMed Central Ltd.
PubMed | Copenhagen University and Roskilde Sygehus
Type: | Journal: Data in brief | Year: 2016
We assessed the CT attenuation density of the pulmonary tissue adjacent to the heart in patients with acute non-ST segment elevation myocardial infarction (J.T. Kuhl, T.S. Kristensen, A.F. Thomsen et al., 2016) . This data was related to the level of ground-glass opacification evaluated by a radiologist, and data on the interobserver variability of semi-automated assessment of pulmonary attenuation density was provided.
PubMed | Copenhagen University and Roskilde Sygehus
Type: Journal Article | Journal: Scandinavian cardiovascular journal : SCJ | Year: 2016
To test if cardiac computed tomography angiography (CCTA) can be used in the triage of patients at high risk of coronary artery disease.The diagnostic value of 64-detector CCTA was evaluated in 400 patients presenting with non-ST segment elevation myocardial infarction using invasive coronary angiography (ICA) as the reference method. The relation between the severity of disease by CCTA and a combined endpoint of death, re-hospitalization due to new myocardial infarction, or symptom-driven coronary revascularization was assessed.CCTA detects significant (>50%) coronary artery diameter stenosis with a sensitivity, specificity, and positive and negative predictive value of 99%, 81%, 96% and 95%, respectively. CCTA was used to triage patients into guideline defined treatment groups of no or medical treatment, referral to percutaneous coronary intervention or to coronary artery bypass graft surgery and was compared to the index ICA. CCTA correctly triaged patients in 86% of cases. During a median follow-up of 50 months, the presence of an occluded artery by CCTA was associated with adverse outcome.CCTA has high diagnostic and prognostic value in patients with high likelihood of coronary artery disease and could, in theory, be used to triage high risk patients. As many obstacles remain, including logistical and safety issues, our study does not support the use of CCTA as an additional diagnostic test before ICA in an all-comer NSTEMI population.
PubMed | Copenhagen University and Roskilde Sygehus
Type: Journal Article | Journal: Journal of cardiovascular computed tomography | Year: 2016
Signs of pulmonary congestion obtained from cardiac computed tomography angiographic (coronary CTA) images have not previously been related to clinical congestion or outcome and the clinical value is, therefore, unknown. Our objective was to test the hypothesis that signs of pulmonary congestion predict clinical heart failure and adverse outcome in patients with myocardial infarction.Coronary CTA was performed before invasive treatment in 400 prospectively included patients with non ST segment elevation myocardial infarction in an observational study. Using a previously described chest computed tomography evaluation algorithm, patients were classified as having no congestion, mild to moderate congestion or severe congestion.Using multivariate analyses, presence of pulmonary congestion on coronary CTA images was associated with age, female gender, left ventricular ejection fraction (LVEF) and left atrial size. The diagnostic accuracy for predicting clinical heart failure, defined as Killip class >1, was: sensitivity: 83%, specificity: 69%, positive predictive value: 25%, and negative predictive value: 97%. The median follow-up time was 50 months and the study end-point of death or hospitalization due to heart failure was reached in 68 (16%) patients. In a Cox proportional hazards model with adjustments for known risk factors and Killip class, the presence of mild to moderate congestion and severe congestion was independently associated with adverse outcome (Hazard ratio: 2.6 (95% CI:1.3-5.0) and 3.2 (1.3-7.5)).Signs of pulmonary congestion on coronary CTA images are closely correlated to cardiac dysfunction, predict clinical heart failure, and provide prognostic value independent of LVEF and Killip class.
PubMed | Copenhagen University and Roskilde Sygehus
Type: | Journal: The international journal of cardiovascular imaging | Year: 2016
The prognostic implications of myocardial computed tomography perfusion (CTP) analyses are unknown. In this sub-study to the CATCH-trial we evaluate the ability of adenosine stress CTP findings to predict mid-term major adverse cardiac events (MACE). In 240 patients with acute-onset chest pain, yet normal electrocardiograms and troponins, a clinically blinded adenosine stress CTP scan was performed in addition to conventional diagnostic evaluation. A reversible perfusion defect (PD) was found in 38 patients (16%) and during a median follow-up of 19 months (range 12-22 months) 25 patients (10%) suffered a MACE (cardiac death, non-fatal myocardial infarction and revascularizations). Accuracy for the prediction of MACE expressed as the area under curve (AUC) on receiver-operating characteristic curves was 0.88 (0.83-0.92) for visual assessment of a PD and 0.80 (0.73-0.85) for stress TPR (transmural perfusion ratio). After adjustment for the pretest probability of obstructive coronary artery disease, both detection of a PD and stress TPR were significantly associated with MACE with an adjusted hazard ratio of 39 (95% confidence interval 11-134), p<0.0001, for visual interpretation and 0.99 (0.98-0.99) for stress TPR, p<0.0001. Patients with a PD volume covering >10% of the LV myocardium had a worse prognosis compared to patients with a PD covering <10% of the LV myocardium, p=0.0002. The optimal cut-off value of the myocardial PD extent to predict MACE was 5.3% of the left ventricle [sensitivity 84% (64-96), specificity 95% (91-97)]. Myocardial CT perfusion parameters predict mid-term clinical outcome in patients with recent acute-onset chest pain.