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Tan S.Y.-Y.,Nanyang Technological University | Chua S.L.,National University of Singapore | Liu Y.,Nanyang Technological University | Hoiby N.,Rigshopitalet | And 6 more authors.
Genome Biology and Evolution | Year: 2013

The emergence of extreme-drug-resistant (EDR) bacterial strains in hospital and nonhospital clinical settings is a big and growing public health threat. Understanding the antibiotic resistance mechanisms at the genomic levels can facilitate the development of next-generation agents. Here, comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU within a 1-month interval. Multilocus sequence typing indicates that these two isolates belonged to ST208. The A. baumannii 53264 strain gained colistin resistance compared with the 48055 strain and became an EDR strain. Genome sequencing indicates that A. baumannii 53264 and 48055 have almost identical genomes-61 single-nucleotide polymorphisms (SNPs) were found between them. The A. baumannii 53264 strain was assembled into 130 contigs, with a total length of 3,976,592 bp with 38.93% GC content. The A. baumannii 48055 strain was assembled into 135 contigs, with a total length of 4,049,562 bp with 39.00% GC content. Genome comparisons showed that this A. baumannii clone is classified as an International clone II strain and has 94% synteny with the A. baumannii ACICU strain. The ResFinder server identified a total of 14 antibiotic resistance genes in the A. baumannii clone. Proteomic analyses revealed that a putative porin protein was down-regulated when A. baumannii 53264 was exposed to antimicrobials, which may reduce the entry of antibiotics into the bacterial cell. © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Warlick E.,University of Minnesota | Ahn K.W.,Center for International Blood and Marrow Transplant Research | Pedersen T.L.,Center for International Blood and Marrow Transplant Research | Artz A.,University of Chicago | And 25 more authors.
Blood | Year: 2012

Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/non-myeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to the Center for International Blood and Marrow Transplant Research aged 40 years and older undergoing RIC/NMAHCT from 2001 to 2007: 117 (38%) aged 40 to 49 years, 119 (39%) 50 to 59 years, and 70 (23%) 60 years or older. The majority (74%) had treatment with imatinib before HCT. At HCT, most patients aged 40 to 49 years were in chronic phase (CP) 1 (74%), compared with 31% aged 60 years or older. Siblings were donors for 56% aged 40 to 49 years; older cohorts had more unrelated donors. The majority received peripheral blood grafts and RIC across all age groups. 3 year overall survival (54%, 52%, and 41%), day +100 grade II-IV acute GVHD (26%, 32%, and 32%), chronic GVHD (58%, 51%, and 43%), and 1-year treatment-related mortality (18%, 20%, and 13%) were similar across ages. The 3-year relapse incidence (36%, 43%, and 66%) and disease-free survival (35%, 32%, and 16%) were inferior in the oldest cohort. Importantly, for CP1 patients, relapse and disease-free survival were similar across age cohorts. Allogeneic RIC HCT for older patients with CML can control relapse with acceptable toxicity and survival in TKI-exposed CML, especially if still in CP1. © 2012 by The American Society of Hematology.

Pedersen S.J.,Post University | Pedersen S.J.,Copenhagen University | Sorensen I.J.,Copenhagen University | Garnero P.,French Institute of Health and Medical Research | And 18 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objectives: To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. Methods: ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Results: Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/ high differences in responsiveness for major versus no/ clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Conclusion: Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. identifier NCT00133315.

Pijls N.H.J.,Catharina Hospital | Fearon W.F.,Stanford University | Tonino P.A.L.,Catharina Hospital | Siebert U.,University of Medical Sciences and Technology | And 11 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives: The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD). Background: In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up. Methods: At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was ≤0.80. Results: The number of indicated lesions was 2.7 ± 0.9 in the angiography-guided group and 2.8 ± 1.0 in the FFR-guided group (p = 0.34). The number of stents used was 2.7 ± 1.2 and 1.9 ± 1.3, respectively (p < 0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p = 0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p = 0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p = 0.08). For lesions deferred on the basis of FFR >0.80, the rate of myocardial infarction was 0.2 % and the rate of revascularization was 3.2 % after 2 years. Conclusions: Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774) © 2010 American College of Cardiology Foundation.

Anderson W.F.,U.S. National Cancer Institute | Rosenberg P.S.,U.S. National Cancer Institute | Petito L.,U.S. National Cancer Institute | Katki H.A.,U.S. National Cancer Institute | And 5 more authors.
International Journal of Cancer | Year: 2013

Long-term breast cancer trends in incidence in the United States (US) show rising estrogen receptor (ER)-positive rates and falling ER-negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries with similar risk factor profiles. Therefore, we analyzed invasive female breast cancers in Denmark, a country with similar risk factors as the US. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic (1993-2010) and used age-period-cohort models to estimate age-specific EAPCs, cohort rate ratios and projections for future time periods (2011-2018). In Denmark, the overall rate of ER-positive cancers rose between 1993 and 2010 by 3.0% per year (95% CI: 2.8-3.3% per year), whereas the overall rate of ER-negative cancers fell by 2.1% per year (95% CI: -2.5 to -1.6% per year). The ER-positive rate increased fastest among postmenopausal women and the ER-negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER-positive tumors and lower risk of ER-negative tumors. If current trends continue, ER-positive cancers will increase at least 13% by 2018 in Denmark, ER-negative cancers will fall 15% by 2018, and breast cancer overall will increase at least 7% by 2018. Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors are responsible, the Danish and US experience may foreshadow a common pattern worldwide. What's new? Estrogen receptor- (ER-)negative breast cancer incidence rates are declining nationwide in Denmark and the United States, whereas rates for ER-positive breast cancers are rising. This report suggests that the divergent trends in ER breast cancers in both countries can be explained by parallel trends in environmental and lifestyle factors that are known to either increase or decrease risk for ER-positive or ER-negative malignancies. The patterns observed in Denmark and the United States may foreshadow a common pattern for many countries worldwide. Copyright © 2013 UICC.

Bartholdy K.,Glostrup Hospital Rigshospitalet | Biering-SOrensen T.,Glostrup Hospital Rigshospitalet | Biering-SOrensen T.,Copenhagen University | Malmqvist L.,Glostrup Hospital Rigshospitalet | And 10 more authors.
Journal of Spinal Cord Medicine | Year: 2014

Objective: Cardiovascular complications including cardiac arrest and arrhythmias remain a clinical challenge in the management of acute traumatic spinal cord injury (SCI). Still, there is a lack of knowledge regarding the characteristics of arrhythmias in patients with acute traumatic SCI. The aim of this prospective observational study was to investigate the occurrence of cardiac arrhythmias and cardiac arrests in patients with acute traumatic SCI. Methods: As early as possible after SCI 24-hour Holter monitoring was performed. Additional Holter recordings were performed 1, 2, 3, and 4 weeks after SCI. Furthermore, 12-lead electrocardiograms (ECGs) were obtained shortly after SCI and at 4 weeks. Results: Thirty patients were included. Bradycardia (heart rate (HR) <50 b.p.m.) was present in 17-35% of the patients with cervical (C1-C8) SCI (n= 24) within the first 14 days. In the following 14 days, the occurrence was 22-32%. Bradycardia in the thoracic (Th1-Th12) SCI group (n= 6) was present in 17-33% during the observation period. The differences between the two groups were not statistically significant. The mean minimum HR was significantly lower in the cervical group compared with the thoracic group both on 12-lead ECGs obtained shortly after SCI (P = 0.030) and at 4 weeks (P = 0.041). Conclusion: Many patients with cervical SCI experience arrhythmias such as bradycardia, sinus node arrest, supraventricular tachycardia, and more rarely cardiac arrest the first month after SCI. Apart from sinus node arrests and limited bradycardia, no arrhythmias were seen in patients with thoracic SCI. Standard 12-lead ECGs will often miss the high prevalence these arrhythmias have. © The Academy of Spinal Cord Injury Professionals, Inc. 2014.

PubMed | Rigshopitalet, Statens Serum Institute, Danish Breast Cancer Group DBCG and U.S. National Cancer Institute
Type: | Journal: International journal of epidemiology | Year: 2016

Associations of reproductive history with breast cancer risk differ by oestrogen receptor (ER) status and possibly by the joint expression of ER and the human epidermal growth factor receptor-2 (ER/HER2). However, large sample sizes are needed to establish ER-specific risks by HER2 expression.We linked a cancer registry covering nearly 95% of the primary breast cancer diagnoses in Denmark with a research parity database to assess associations for parity, number of live births and age at first live birth (AFLB) with receptor-specific risk. Relative risks (RRs) for associations were estimated with Poisson regression models.With nearly 31 million women-years of follow-up, 45786 Danish women aged 20-84 years developed invasive breast cancer during 1992-2011. ER expression was available for the entire study period and HER2 after 2006. Of the breast cancers with known ER expression, 79% were ER+. Most breast cancers with known ER and HER2 were HER2- (90% of ER+ cancers and 65% of ER- cancers). RRs differed by ER expression for all reproductive variables (p-homogeneity < 0.001). Associations were stronger for ER+ than ER- cancers and for those diagnosed before age 50. Parity and later AFLB showed a protective association with ER+/HER2- and risk association with ER-/HER2- cancers.Associations of reproductive history with breast cancer risk varied among Danish women by ER and ER/HER2 expression and age-at-diagnosis, consistent with receptor-specific and age-related etiological heterogeneity. Further stratification by HER2 status demonstrated dual (or opposite) effects for ER+/HER2- and ER-/HER2- cancers.

PubMed | Copenhagen University, Rigshospitalet 7641, Rigshospitalet, Rigshopitalet. and 2 more.
Type: | Journal: Journal of applied physiology (Bethesda, Md. : 1985) | Year: 2016

Physical activity and alternate-day fasting/caloric restriction may both ameliorate aspects of the metabolic syndrome, such as insulin resistance, visceral fat mass accumulation, and cognitive impairment, by overlapping mechanisms.To test the hypothesis that alternate-day caloric restriction (ADCR) with overall energy balance would reduce insulin resistance and accumulation of visceral fat, in addition to improving cognitive functions, after eight consecutive days in bed.Healthy, lean men (n = 20) were randomized to 1) 8 days bed rest with 3 daily iso-energetic meals (control group, n = 10); and 2) 8 days bed rest with 25% of total energy requirements every other day and 175% of total energy requirements every other day (ADCR group). Oral glucose tolerance testing, DXA scans, magnetic resonance imaging of the abdomen and brain, VOBed rest induced insulin resistance, visceral fat accumulation, and worsening of mood. No positive effects emerged from ADCR on these negative health outcomes. Compared to the control group, ADCR was associated with improved and steadier glycemic control on fasting days, and higher glycemic fluctuation and indices of insulin resistance on overeating days.In contrast to our hypothesis, the metabolic impairment induced by eight days of bed rest was not counteracted by ADCR with overall energy balance.

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