Rigid 5′-6-locked phenanthroline-derived nucleosides chelated to ruthenium and europium ions

We describe complexes of ruthenium and europium with rigid, 5′-6-locked 1,10-phenanthroline-containing nucleosides. Both nucleosides were synthesized from condensation of 5-amino-2′-deoxycytidine with the corresponding diketone. The ruthenium nucleoside displayed fluorescence characteristic of polypyridine ruthenium complexes with a maximum at 616 nm and a quantum yield of 0.011. Binding of europium to the 1,10-phenanthroline-2,9-diacid moiety of the lanthanide binding nucleoside showed formation of a 1:1 complex with emission at 570–630 nm, whose emission was enhanced by addition of two phenanthroline ligands. The lanthanide-binding nucleoside was incorporated into DNA oligonucleotides and shown to selectively bind one equivalent of europium ions.     

Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin—A Nationwide Cohort Study

Aim

Cardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy.

Methods and Results

Through the nationwide Danish registries we included 1,230 oral anticoagulation naïve patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42). Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08).

Conclusion

Anticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin.     

Sarcoidosis in Patients with Psoriasis: A Population-Based Cohort Study

Purpose

Psoriasis is a chronic inflammatory disease characterized by a systemic immunological response which is mainly driven by activated T helper (Th) 1 and Th17 lymphocytes. Like psoriasis, sarcoidosis is a chronic inflammatory disorder with Th1/Th17-driven inflammation. Therefore, we investigated the risk of sarcoidosis in patients with psoriasis compared to the background population in a nationwide cohort.

Methods

The study included the entire Danish population aged ≥10 years followed from 1^st January 1997 until diagnosis of sarcoidosis, death or 31^st December 2011. Patients with a history of psoriasis and/or sarcoidosis at baseline were excluded. Information on comorbidity and concomitant medication was identified by individual-level linkage of administrative registers. Incidence rates of sarcoidosis were calculated and adjusted hazard ratios (HRs) were estimated by multivariable Cox regression models adjusted for age, gender, comorbidity, medications and socioeconomic status.

Results

A total of 6,043,518 subjects were eligible for analysis. In the study period 70,125 patients with new-onset psoriasis, including 11,834 patients with severe psoriasis, were identified. The overall incidence rates of sarcoidosis were 1.18, 2.22, and 4.06 per 10,000 person-years for the reference population (9,717 cases), mild psoriasis (78 cases) and severe psoriasis (22 cases), respectively. Compared to the reference population, the age- and gender-adjusted HRs for sarcoidosis were increased in patients with psoriasis with HR 1.49 (95% confidence interval [CI] 1.18–1.87) and HR 2.51 (CI 1.64–3.85) for those with mild and severe disease, respectively.

Conclusion

In this nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of sarcoidosis.     

Interannual phenological variability in two North-East Atlantic populations of Calanus finmarchicus

Phenological variations of the marine copepod Calanus finmarchicus were studied in Svalbard and northern Iceland, where samples were collected in summer and spring, respectively, over two decades. Four phenological indices, developed for copepodite stage-structured data, were used: the proportion of CV to total abundance (CVT), the population development index (PDI), the average weighted stage (AWS), and the average age in days (AAD). The variation of these indices was compared within and between locations to evaluate their suitability for the analysis of phenological effects. For both populations, phenology was related to local temperature and spring bloom dynamics, influenced by Atlantic water inflow. Large-scale climate was related to phenological variation only in the Svalbard population. C. finmarchicus phenology advanced under warmer conditions in both locations. We conclude that vertical phenological indices, i.e. based on interannual changes in copepodite stage structure, are useful to investigate zooplankton phenology, especially when data series covering the whole life cycle are unavailable. We suggest that AWS and AAD can be applied irrespective of sampling time, while PDI and CVT should be applied for early and late sampling seasons, respectively. When multiple phenological indices are needed, AAD in combination with either CVT or PDI should be preferred.     

The Association of Gum Bleeding with Respiratory Health in a Population Based Study from Northern Europe

Background

There is little knowledge about how oral and respiratory health is interrelated even though the mucosa of the oral cavity and airways constitutes a continuum and the exposures to these are partly similar.

Aims

To investigate whether gum bleeding is related to asthma, respiratory symptoms and self-reported COPD.

Methods

A postal questionnaire including questions about respiratory and oral health was sent to general population samples in seven Northern European centres. In 13,409 responders, gum bleeding when brushing teeth was reported always/often by 4% and sometimes by 20%. Logistic regressions accounted for age, smoking, educational level, centre and gender. Effects of BMI, cardio-metabolic diseases, early life factors, gastro-oesophageal reflux, dental hygiene, nasal congestion, and asthma medication were addressed.

Results

Gum bleeding always/often was significantly associated with ≥3 asthma symptoms (OR 2.58, 95% CI 2.10–3.18), asthma (1.62 [1.23–2.14]) and self-reported COPD (2.02 [1.28–3.18]). There was a dose-response relationship between respiratory outcomes and gum bleeding frequency (≥3 symptoms: gum bleeding sometimes 1.42 [1.25–1.60], often/always 2.58 [2.10–3.18]), and there was no heterogeneity between centres (p_{heterogeneity} = 0.49). None of the investigated risk factors explained the associations. The observed associations were significantly stronger among current smokers (p_interaction = 0.004).

Conclusions

A consistent link between gum bleeding and obstructive airways disease was observed, not explained by common risk factors or metabolic factors. We speculate that oral pathogens might have unfavourable impact on the airways, and that the direct continuity of the mucosa of the oral cavity and the airways reflects a pathway that might provide novel opportunities for interventions.     

Establishment of three human breast epithelial cell lines derived from carriers of the 999del5 <Emphasis Type="Italic">BRCA2</Emphasis> icelandic founder mutation

Summary Germ line mutations in BRCA1 and BRCA2 account for a large proportion of inherited breast and ovarian cancer. Both genes are involved in DNA repair by homologous recombination and are thought to play a vital role in maintaining genomic stability. A major drawback for long-term functional studies of BRCA in general and BRCA2 in particular has been a lack of representative human breast epithelial cell lines. In the present study, we have established three cell lines from two patients harboring the 999del5 germ line founder mutation in the BRCA2 gene. Primary cultures were established from cellular outgrowth of explanted tissue and subsequently transfected with a retroviral construct containing the HPV-16 E6 and E7 oncogenes. Paired cancer-derived and normal-derived cell lines were established from one patient referred to as BRCA2-999del5-2T and BRCA2-999del5-2N, respectively. In addition, one cell line was derived from cancer-associated normal tissue from another patient referred to as BRCA2-999del5-1N. All three cell lines showed characteristics of breast epithelial cells as evidenced by expression of breast epithelial specific cytokeratins. Cytogenetic analysis showed marked chromosomal instability with tetraploidy and frequent telomeric association. In conclusion, we have established three breast cpithelial cell lines from two patients carrying the BRCA2 Icelandic 999del5 founder mutation. These cell lines from the basis for further studies on carcinogenesis and malignant progression of breast cancer on a defined genetic background. Agla J. Rubner Fridriksdottir and Thorarinn Gudjonsson contributed equally to this study.     

Human breast microvascular endothelial cells retain phenotypic traits in long-term finite life span culture

Summary Attempts to study endothelial-epithelial interactions in the human breast have been hampered by lack of protocols for long-term cultivation of breast endothelial cells (BRENCs). The aim of this study was to establish long-term cultures of BRENCs and to compare their phenotypic traits with the tissue of origin. Microvasculature was localized in situ by immunohistochemitry in breast samples. From this tissue, collagen-rich stroma and adipose tissue were dissected mechanically and further disaggregated to release microvessel organoids BRENCs were cultured from these organoids in endothelial specific medium and characterized by staining for endothelial markers. Microvessels were a prominent feature of intralobular tissue as evidenced by immunostaining against endothelial specific markers such as CD31, VE-cadherin, and von Willebrand factor (VWF). Double staining against VE-cadherin and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) showed that blood and lymphatic vessels could be distinguished. An antibody against CD31 was used to refine protocols for isolation of microvasculature from reduction mammoplasties. BRENCs retained critical traits even at high passage, including uptake of low-density lipoprotein, and had E-selectin induced upon treatment with tumor necrosis factor-α. The first signs of senescence in passage 14 were accompained by gain of trisomy 11. At passage 18 cells showed chromosomal aberrations and growth arrest as revealed by β-galactosidase staining. We demonstrate here that breast microvasculature may serve as a large-scale source for expansion of BRENCs with molecular and functional traits preserved. These cells will form the basis for studies on the role of endothelial cells in breast morphogenesis.     

Seasonal abundance and distribution of Caridea larvae in Isafjord-deep, north-west Iceland

The abundance and distribution of Candea larvae was studiedin Ísafjord-deep, north-west Iceland, at approximatelymonthly intervals from February 1987 to February 1988 Zooplanktonsampling was made at nine stations along the length of the fjord,while temperature and chlorophyll a measurements from one ofthe stations are also presented Larvae of six species occurredin the samples, Eualus pusiolus and Pandalus borealis were mostnumerous, constituting 62 8 and 25 9% of the larvae respectively.The other species were, in declining order of abundance, Pandalusmontagui, Spirontocaris spp. (S spinus and s lilljeborgii) andSabinea septemcarinata. Eualus pusiolus was of highest abundancein the outer and middle parts of the fjord, while P.borealiswas most common in the middle and inner parts The onset of hatchingof all species in April–May appeared closely linked tothe phytoplankton spring bloom, while the temperature in thefjord was by then near the annual low (2–3°C). Exceptfor E pusiolus, of which a small part of the population produceda second brood during the summer, most of the larvae had disappearedfrom the plankton by the middle of August The monthly carapacegrowth of P.borealis larvae during the summer months was estimatedto be 1.0 mm.