Editor's Choice - High Heritability of Liability to Abdominal Aortic Aneurysms: A Population Based Twin Study.

OBJECTIVE: First degree relatives of patients with abdominal aortic aneurysm (AAA) have an increased risk of developing AAA; however, despite intensive investigation, the specific genetic factors involved in the development of the disease are still largely unknown. In twin studies the influence of genetic and environmental factors can be assessed by comparing concordance rates between monozygotic (MZ) and dizygotic (DZ) twins. Higher phenotypic similarity between MZ than DZ twins indicates a genetic attribution to the etiology. The objective of this study was to investigate the heritability of AAA among Danish twins using concordance rates and heritability estimates. METHODS: The Danish Twin Registry was used to identify all Danish twin pairs (born 1880-1971) where both twins were alive on January 1, 1977. AAA cases were then identified using the National Patient Registry and the Registry of Cause of Death. Probandwise concordance rates were calculated and heritability estimated using structural equation modeling. RESULTS: The study identified 414 twins with AAA; 69.8% (289/414) were men and 30.2% (125/414) women. The probandwise concordance rate in MZ twins was 30% (95% CI 20.3-43.3%) compared with 12% (95% CI 7.0-20.1%) in DZ twins. In the heritability analysis 77% (95% CI 67-85%) of the total variance was explained by additive genetic components and 23% (95% CI 15-33%) was explained by non-shared environmental factors. CONCLUSIONS: The probandwise concordance rate was found to be 2.5 times higher in MZ compared with DZ twins. An overall heritability of 77% was determined.

Abdominal aortic diameter is increased in males with a family history of abdominal aortic aneurysms: results from the Danish VIVA-trial.

OBJECTIVE: To investigate, at a population level, whether a family history of abdominal aortic aneurysm (AAA) is independently related to increased aortic diameter and prevalence of AAA in men, and to elucidate whether the mean aortic diameter and the prevalence of AAA are different between participants with male and female relatives with AAA. DESIGN: Observational population-based cross-sectional study. MATERIALS: 18,614 male participants screened for AAA in the VIVA-trial 2008-2011 with information on both family history of AAA and maximal aortic diameter. METHODS: Standardized ultrasound scan measurement of maximum antero-posterior aortic diameter. Family history obtained by questionnaire. Multivariate regression analysis was used to test for confounders: age, sex, smoking, comorbidity and medication. RESULTS: From the screened cohort, 569 participants had at least one first degree relative diagnosed with AAA, and 38 had AAA. Participants with a family history of AAA (+FH) had a significantly larger mean maximum aortic diameter (20.50 mm) compared with participants without family history of AAA (-FH) (19.07 mm, p < .0001), and +FH with female relatives with AAA had significantly larger mean maximum aortic diameter (21.8 mm) than +FH with male relatives (19.9 mm, p = .007). Furthermore the prevalence of AAA was significantly higher among +FH (6.7%) compared with -FH (3.0%) with an odds ratio (OR) of 2.2 (95% CI: 1.6 to 3.2, p < .001) and +FH with female relatives with AAA had a more than two and a half times increased prevalence of AAA compared with +FH with male relatives with AAA with an OR of 2.65. CONCLUSIONS: First-degree male relatives of AAA patients have wider aortas and a twofold higher prevalence of AAA compared with the age adjusted background population. The prevalence of AAA was markedly higher in participants related to female, rather than male, patients with AAA.

Optical coherence tomography for imaging of skin and skin diseases.

Optical coherence tomography (OCT) is an emerging imaging technology based on light reflection. It provides real-time images with up to 2-mm penetration into the skin and a resolution of approximately 10 microm. It is routinely used in ophthalmology. The normal skin and its appendages have been studied, as have many diseases. The method can provide accurate measures of epidermal and nail changes in normal tissue. Skin cancer and other tumors, as well as inflammatory diseases, have been studied and good agreement found between OCT images and histopathological architecture. OCT also allows noninvasive monitoring of morphologic changes in skin diseases and may have a particular role in the monitoring of medical treatment of nonmelanoma skin cancer. The technology is however still evolving and continued technological development will necessitate an ongoing evaluation of its diagnostic accuracy. Several technical solutions are being pursued to further improve the quality of the images and the data provided, and OCT is being integrated in multimodal imaging devices that would potentially be able to provide a quantum leap to the imaging of skin in vivo.

Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs.

Transduced deoxyribonucleoside kinases (dNK) can be used to kill recipient cells in combination with nucleoside prodrugs. The Drosophila melanogaster multisubstrate dNK (Dm-dNK) displays a superior turnover rate and has a great plasticity regarding its substrates. We used directed evolution to create Dm-dNK mutants with increased specificity for several nucleoside analogs (NAs) used as anticancer or antiviral drugs. Four mutants were characterized for the ability to sensitize Escherichia coli toward analogs and for their substrate specificity and kinetic parameters. The mutants had a reduced ability to phosphorylate pyrimidines, while the ability to phosphorylate purine analogs was relatively similar to the wild-type enzyme. We selected two mutants, for expression in the osteosarcoma 143B, the glioblastoma U-87M-G and the breast cancer MCF7 cell lines. The sensitivities of the transduced cell lines in the presence of the NAs fludarabine (F-AraA), cladribine (CdA), vidarabine and cytarabine were compared to the parental cell lines. The sensitivity of 143B cells was increased by 470-fold in the presence of CdA and of U-87M-G cells by 435-fold in the presence of F-AraA. We also show that a choice of the selection and screening system plays a crucial role when optimizing suicide genes by directed evolution.

[Study of dimerization of polysynthetic derivatives of the antibiotic eremomycin by ESI MS and its role in elucidating antibacterial activity]. / Izuchenie dimerizatsii polusinteticheskikh proizvodnykh antibiotika éremomitsina metodom ESU MS i ee rol' v proiavlenii antibakterial'noi aktivnosti.

The dimerization constants for glycopeptide antibiotics vancomycin, ristocetin, and eremomycin and nine semisynthetic eremomycin derivatives were determined by the electrospray ionization mass spectrometry; the constants for natural antibiotics turned out to be close to those previously determined by NMR. No correlation between these dimerization constants and antibacterial activities of all the compounds toward the clinical strains of Gram-positive bacteria was found.