Stellar Feedback and Resolved Stellar IFU Spectroscopy in the nearby Spiral Galaxy NGC 300

We present MUSE Integral Field Unit (IFU) observations of five individual HII regions in two giant (> 100 pc in radius) star-forming complexes in the low-metallicity (Z~0.33 Z) nearby (D ~ 2 Mpc) dwarf spiral galaxy NGC 300. We combine the IFU data with high spatial resolution HST photometry to demonstrate the extraction of stellar spectra and the classification of individual stars from ground-based data at the distance of 2 Mpc. For the two star-forming complexes, in which no O-type stars had previously been identified, we find a total of 13 newly identified O-type stars in the mass range 15-50 M, as well as 4 Wolf-Rayet stars. We use the derived massive stellar content to analyze the impact of stellar feedback on the HII regions. As already found for HII regions in the Magellanic Clouds, the dynamics of the analyzed NGC 300 HII regions are dominated by a combination of the pressure of the ionized gas and stellar winds. By comparing the derived ionized gas mass loading factors to the total gas mass loading factor across the NGC 300 disk, we find that the latter is an order of magnitude higher, either indicating very early evolutionary stages for these HII regions, or being a direct result of the multi-phase nature of feedback-driven bubbles. Moreover, we analyze the relation between the star formation rate and the pressure of the ionized gas as derived from small (<100 pc) scales, as both quantities are systematically overestimated when derived on galactic scales. With the wealth of ongoing and upcoming IFU instruments and programs, this study serves as a pathfinder for the systematic investigation of resolved stellar feedback in nearby galaxies, and it delivers the necessary analysis tools to enable massive stellar content and feedback studies sampling an unprecedented range of HII region properties across entire galaxies in the nearby Universe

Cancer pharmacogenetics

The large number of active combination chemotherapy regimens for most cancers has led to the need for better information to guide the \u27standard\u27 treatment for each patient. In an attempt to individualise therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies) encompass the search for answers to the hereditary basis for interindividual differences in drug response. This review will focus on the results of studies assessing the effects of polymorphisms in drug-metabolising enzymes and drug targets on the toxicity and response to commonly used chemotherapy drugs. In addition, the need for polygenic pharmacogenomic strategies to identify patients at risk for adverse drug reactions will be highlighted

CYP3A4 and CYP3A5 genotyping by Pyrosequencing

BACKGROUND: Human cytochrome P450 3A enzymes, particularly CYP3A4 and CYP3A5, play an important role in drug metabolism. CYP3A expression exhibits substantial interindividual variation, much of which may result from genetic variation. This study describes Pyrosequencing assays for key SNPs in CYP3A4 (CYP3A4*1B, CYP3A4*2, and CYP3A4*3) and CYP3A5 (CYP3A5*3C and CYP3A5*6). METHODS: Genotyping of 95 healthy European and 95 healthy African volunteers was performed using Pyrosequencing. Linkage disequilibrium, haplotype inference, Hardy-Weinberg equilibrium, and tag SNPs were also determined for these samples. RESULTS: CYP3A4*1B allele frequencies were 4% in Europeans and 82% in Africans. The CYP3A4*2 allele was found in neither population sample. CYP3A4*3 had an allele frequency of 2% in Europeans and 0% in Africans. The frequency of CYP3A5*3C was 94% in Europeans and 12% in Africans. No CYP3A5*6 variants were found in the European samples, but this allele had a frequency of 16% in the African samples. Allele frequencies and haplotypes show interethnic variation, highlighting the need to analyze clinically relevant SNPs and haplotypes in a variety of ethnic groups. CONCLUSION: Pyrosequencing is a versatile technique that could improve the efficiency of SNP analysis for pharmacogenomic research with the ultimate goal of pre-screening patients for individual therapy selection

A concept for trial institutions focussing on randomised controlled trials in surgery

<p>Abstract</p> <p>Background</p> <p>Although considered the reference standard for generating valid scientific evidence of a treatment's benefits and harms, the number of Randomised Controlled Trials (RCT) comparing surgical techniques remains low. Much effort has been made in order to overcome methodological issues and improve quality of RCTs in surgery. To the present there has been, however, only little emphasis on development and maintenance of institutions for implementation of adequately designed and conducted surgical RCTs.</p> <p>Mehods/Design</p> <p>Description of the developments in surgical RCT infrastructure in Germany between 2001 and 2006. Cross sectional evaluation of completed and ongoing surgical RCTs within the German Surgical Society and the Clinical Study Centre, Department of Surgery, University of Heidelberg.</p> <p>Results</p> <p>Foundation of a national Clinical Trial Centre (CTC) for the organisation of multi-centre RCTs in the surgical setting (Study Center of the German Surgical Society, SDGC). Establishment of a network of CTCs with affiliated Clinical Sites (CSs) to enhance patient recruitment and shorten the duration of RCTs. Since its foundation four surgical RCTs with a total sample size of 1650 patients (1006 of these randomised) have been supervised by the SDGC with 35 CSs involved in patient recruitment. Five further CTCs were set up in 2006. Together with their affiliated CSs a network has been organised providing improved conditions for the conduction of surgical RCTs.</p> <p>Conclusion</p> <p>Improvement of infrastructure substantially facilitates integration of RCTs into routine surgical practice. A network of collaborating CTCs and CSs can provide an adequate infrastructure for the conduction of multi-centre RCTs.</p

Sudden cardiac death in childhood RASopathy-associated hypertrophic cardiomyopathy: Validation of the HCM risk-kids model and predictors of events

Background: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated. Aim: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. Methods: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters. Results: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7–28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43–1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49–169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58–19.03, p < 0.007) were predictors of SCD on univariate analysis. Conclusion: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further

Diagnostic Accuracy of Fine Needle Biopsy for Metastatic Melanoma and Its Implications for Patient Management

The use of fine needle biopsy (FNB) for the diagnosis of metastatic melanoma can lead to the early removal and treatment of metastases, reduce the frequency of unnecessary surgery, and facilitate the staging of patients enrolled in clinical trials of adjuvant therapies. In this study, the accuracy of FNB for the diagnosis of metastatic melanoma was investigated. A retrospective cohort study was performed with 2204 consecutive FNBs performed on 1416 patients known or suspected to have metastatic melanoma. Almost three-quarters (1582) of these FNBs were verified by either histopathologic diagnosis following surgical resection or clinical follow-up. FNB for metastatic melanoma was found to have an overall sensitivity of 92.1% and a specificity of 99.2%, with 69 false-negative and 5 false-positive findings identified. The sensitivity of the procedure was found to be influenced by six factors. The use of immunostains, reporting of the specimen by a cytopathologist who had reported >500 cases, lesions located in the skin and subcutis, and patients with ulcerated primary melanomas were factors associated with a significant improvement in the sensitivity of the test. However, FNBs performed in masses located in lymph nodes of the axilla and FNBs that required more than one needle pass to obtain a sample were far more likely to result in false-negative results. FNB is a rapid, accurate, and clinically useful technique for the assessment of disease status in patients with suspected metastatic melanoma

Patterns of Retinal Damage Facilitate Differential Diagnosis between Susac Syndrome and MS

Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS