Anticoagulation for radiation-induced neurotoxicity revisited

No effective treatment for delayed radiation-induced neurotoxicity has been established. Its natural course is highly variable, but spontaneous recovery has been well documented. Here we report our experience with therapeutic anticoagulation in patients with cerebral lesions (n=3), cranial nerve lesions (n=1) or myelopathy (n=4) attributed to irradiation. Two of three patients with cerebral lesions and the patient with cranial nerve lesions showed a minor improvement of clinical symptoms. In contrast, none of the patients with radiation myelopathy improved. No patient suffered hemorrhage or other adverse effects of anticoagulation. Overall, anticoagulation therapy demonstrates only modest activity for delayed radiation-induced neurotoxicity in this small case serie

Integration of LCA in the planning phases of adaptive buildings

The high consumption of resources in the building industry requires a significant reduction of material in buildings and consequently a reduction of emissions over all phases of the life cycle. This is the aim of the Collaborative Research Centre 1244 Adaptive Skins and Structures for the Built Environment of Tomorrow, funded by the German Research Foundation (DFG), which addresses research on the development and integration of adaptive systems in building structures and skins. New approaches in building planning are required for the implementation of adaptive buildings. Therefore, a multidisciplinary team from various fields such as architecture, civil and mechanical engineering, and system dynamics is necessary. The environmental impacts of the whole life cycle have to be considered for an integral planning process for adaptive buildings right from the beginning. For the integration of the Life Cycle Assessment (LCA), four temporal and content-related interfaces were identified in the planning process. Inputs and outputs of the LCA were defined for the relevant planning stages in order to enable the greatest possible benefit for the planners and to minimize the environmental impacts as far as possible. The result of the research work is a methodology that can be used in the future to reduce life cycle-related environmental impacts in the planning process of adaptive buildings (ReAdapt)

Ty1 integrase overexpression leads to integration of non-Ty1 DNA fragments into the genome of Saccharomyces cerevisiae

The integrase of the Saccharomyces cerevisiae retrotransposon Ty1 integrates Ty1 cDNA into genomic DNA likely via a transesterification reaction. Little is known about the mechanisms ensuring that integrase does not integrate non-Ty DNA fragments. In an effort to elucidate the conditions under which Ty1 integrase accepts non-Ty DNA as substrate, PCR fragments encompassing a selectable marker gene were transformed into yeast strains overexpressing Ty1 integrase. These fragments do not exhibit similarity to Ty1 cDNA except for the presence of the conserved terminal dinucleotide 5′-TG-CA-3′. The frequency of fragment insertion events increased upon integrase overexpression. Characterization of insertion events by genomic sequencing revealed that most insertion events exhibited clear hallmarks of integrase-mediated reactions, such as 5 bp target site duplication and target site preferences. Alteration of the terminal dinucleotide abolished the suitability of the PCR fragments to serve as substrates. We hypothesize that substrate specificity under normal conditions is mainly due to compartmentalization of integrase and Ty cDNA, which meet in virus-like particles. In contrast, recombinant integrase, which is not confined to virus-like particles, is able to accept non-Ty DNA, provided that it terminates in the proper dinucleotide sequence

From insect to man: Photorhabdus sheds light on the emergence of human pathogenicity

Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The pericardial reflection and the tip of the central venous catheter - topographical analysis in stillborn babies

Central venous cannulation is widely used in neonatal critical care. Pericardial tamponade caused by vessel wall perforation can occur if the catheter tip induces extravasation at the level of the pericardium. To investigate the level of the superior pericardial reflection in stillborn babies. We dissected 20 bodies (11 female, mean gestational age 33 6/7 weeks, range 25-43 weeks), with careful opening of the thoracic area. After injecting contrast medium into the pericardial sac, we introduced a catheter through the right internal jugular vein. We then took radiographs to analyse the relationship between visual osseous landmarks and the pericardium. Mean distance between the pericardial reflection at its upper end and the first thoracic vertebra was 1.3 cm (standard deviation [SD]: 0.3 cm) and did not extend over the 3rd intercostal space. The mean distance from the entry of the superior vena cava into the pericardial sac and the 1st thoracic vertebra was 2.3 cm (SD: 0.5). The upper end of the pericardial reflection in neonates at autopsy lies below the middle of the 3rd thoracic vertebra. The tip of an upper inserted catheter should not extend below the level of the 3rd intercostal space

Expression of Prostacyclin-Synthase in Human Breast Cancer: Negative Prognostic Factor and Protection against Cell Death In Vitro

Endogenously formed prostacyclin (PGI2) and synthetic PGI2 analogues have recently been shown to regulate cell survival in various cell lines. To elucidate the significance of PGI2 in human breast cancer, we performed immunohistochemistry to analyze expression of prostacyclin-synthase (PGIS) in 248 human breast cancer specimens obtained from surgical pathology files. We examined patients’ 10-year survival retrospectively by sending a questionnaire to their general practitioners and performed univariate analysis to determine whether PGIS expression correlated with patient survival. Lastly, the effects of PGI2 and its analogues on cell death were examined in a human breast cancer cell line (MCF-7) and a human T-cell leukemia cell line (CCRF-CEM). PGIS expression was observed in tumor cells in 48.7% of samples and was associated with a statistically significant reduction in 10-year survival (P=0.038; n=193). Transient transfection of PGIS into MCF-7 cells exposed to sulindac increased cell viability by 50% and exposure to carbaprostacyclin protected against sulindac sulfone induced apoptosis in CCRF-CEM cells. Expression of PGIS is correlated with a reduced patient survival and protects against cell death in vitro, suggesting that PGIS is a potential therapeutic target in breast cancer

Towards a Laser-driven polarized 3He Ion-Beam Source

In order to investigate the polarization degree of laser-accelerated 3He ions from a pre-polarized 3He gas-jet target, several challenges have to be overcome beforehand. One of these includes the demonstration of the feasibility of laser-induced ion acceleration out of gas-jet targets. In particular, the ion-emission angles as well as the ion-energy spectra have to be determined for future polarization measurements. Such an experiment was performed at the PHELIX Petawatt Laser Facility, GSI Darmstadt. As laser target, both 4He, and in a second step, unpolarized 3He gas were applied