Chemical ultraviolet absorbers topically applied in a skin barrier mimetic formulation remain in the outer stratum corneum of porcine skin

The objective of the present study was to evaluate the fate of three chemical sunscreens, isoamyl p-methoxycinnamate (IPMC), diethylamino hydroxybenzoyl hexyl benzoate (DHHB), and bis-ethylhexylphenol methoxyphenyl triazine (BEMT), topically applied to mammalian skin from a skin barrier mimetic oil-in-water formulation. High Performance Liquid Chromatography (HPLC) methods were developed for the analysis of each molecule and validated. Franz cell permeation studies were conducted following application of finite doses of the formulations to excised porcine skin. A vehicle formulation containing no sunscreens was evaluated as a control. Permeation studies were conducted for 12 h after which full mass balance studies were carried out. Analysis of individual UV sunscreens was achieved with HPLC following application of the formulation to the skin with no interference from the vehicle components. No skin permeation of any of the chemical sunscreens was evident after 12 h. While sunscreens were detected in up to 12 tape strips taken from the SC, 87% or more of the applied doses recovered in the first 5 tape strips. When corrected for the amount of protein removed per tape strip this corresponded to a penetration depth in porcine stratum corneum of ∼1.7 μm. Mass balance studies indicated total recovery values were within accepted guidelines for cosmetic formulations. Overall, only superficial penetration into the SC was observed for each compound. These findings are consistent with the physicochemical properties of the selected UV absorbing molecules and their formulation into an ordered biomimetic barrier formulation thus support their intended use in topical consumer formulations designed to protect from UV exposure. To our knowledge this is the first report of depth profiling of chemical sunscreens in the SC that combines tape stripping and protein determination following in vitro Franz cell studies

In vitro permeation and disposition of niacinamide in silicone and porcine skin of skin barrier-mimetic formulations.

Niacinamide (NIA) is an amide form of vitamin B3 which is used in cosmetic formulations to improve various skin conditions and it has also been shown to increase stratum corneum thickness following repeated application. In this study, three doses (5, 20 and 50μl per cm(2)) of two NIA containing oil-in-water skin barrier-mimetic formulations were evaluated in silicone membrane and porcine ear skin and compared with a commercial control formulation. Permeation studies were conducted over 24h in Franz cells and at the end of the experiment membranes were washed and niacinamide was extracted. For the three doses, retention or deposition of NIA was generally higher in porcine skin compared with silicone membrane, consistent with the hydrophilic nature of the active. Despite the control containing a higher amount of active, comparable amounts of NIA were deposited in skin for all formulations for all doses; total skin absorption values (permeation and retention) of NIA were also comparable across all formulations. For infinite (50μL) and finite (5μL) doses the absolute permeation of NIA from the control formulation was significantly higher in porcine skin compared with both test formulations. This likely reflects differences in formulation components and/or presence of skin penetration enhancers in the formulations. Higher permeation for the 50 and 20μl dose was also evident in porcine skin compared with silicone membrane but the opposite is the case for the finite dose. The findings point to the critical importance of dose and occlusion when evaluating topical formulations in vitro and also the likelihood of exaggerated effects of excipients on permeation at infinite and pseudo-finite dose applications

A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes

Attachment of ubiquitin to lysine 119 of Histone 2A (H2AK119Ub) is an epigenetic mark characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here we report the crystal structure of the Drosophila PR-DUB, revealing that the deubiquitinase Calypso and its activating partner ASX form a 2:2 complex. The bidentate Calypso–ASX complex is generated by dimerisation of two activated Calypso proteins through their coiled-coil regions. Disrupting the Calypso dimer interface does not affect inherent catalytic activity, but inhibits removal of H2AK119Ub as a consequence of impaired recruitment to nucleosomes. Mutating the equivalent surface on the human counterpart, BAP1, also compromises activity on nucleosomes. Together, this suggests that high local concentrations drive assembly of bidentate PR-DUB complexes on chromatin—providing a mechanistic basis for enhanced PR-DUB activity at specific genomic foci, and the impact of distinct classes of PR-DUB mutations in tumorigenesis

Assessing methods for dealing with treatment switching in clinical trials: A follow-up simulation study

When patients randomised to the control group of a randomised controlled trial are allowed to switch onto the experimental treatment, intention-to-treat analyses of the treatment effect are confounded because the separation of randomised groups is lost. Previous research has investigated statistical methods that aim to estimate the treatment effect that would have been observed had this treatment switching not occurred and has demonstrated their performance in a limited set of scenarios. Here, we investigate these methods in a new range of realistic scenarios, allowing conclusions to be made based upon a broader evidence base. We simulated randomised controlled trials incorporating prognosis-related treatment switching and investigated the impact of sample size, reduced switching proportions, disease severity, and alternative data-generating models on the performance of adjustment methods, assessed through a comparison of bias, mean squared error, and coverage, related to the estimation of true restricted mean survival in the absence of switching in the control group. Rank preserving structural failure time models, inverse probability of censoring weights, and two-stage methods consistently produced less bias than the intentionto-treat analysis. The switching proportion was confirmed to be a key determinant of bias: sample size and censoring proportion were relatively less important. It is critical to determine the size of the treatment effect in terms of an acceleration factor (rather than a hazard ratio) to provide information on the likely bias associated with rank-preserving structural failure time model adjustments. In general, inverse probability of censoring weight methods are more volatile than other adjustment methods

Stellar winds from Massive Stars

We review the various techniques through which wind properties of massive stars - O stars, AB supergiants, Luminous Blue Variables (LBVs), Wolf-Rayet (WR) stars and cool supergiants - are derived. The wind momentum-luminosity relation (e.g. Kudritzki et al. 1999) provides a method of predicting mass-loss rates of O stars and blue supergiants which is superior to previous parameterizations. Assuming the theoretical sqrt(Z) metallicity dependence, Magellanic Cloud O star mass-loss rates are typically matched to within a factor of two for various calibrations. Stellar winds from LBVs are typically denser and slower than equivalent B supergiants, with exceptional mass-loss rates during giant eruptions Mdot=10^-3 .. 10^-1 Mo/yr (Drissen et al. 2001). Recent mass-loss rates for Galactic WR stars indicate a downward revision of 2-4 relative to previous calibrations due to clumping (e.g. Schmutz 1997), although evidence for a metallicity dependence remains inconclusive (Crowther 2000). Mass-loss properties of luminous (> 10^5 Lo) yellow and red supergiants from alternative techniques remain highly contradictory. Recent Galactic and LMC results for RSG reveal a large scatter such that typical mass-loss rates lie in the range 10^-6 .. 10^-4 Mo/yr, with a few cases exhibiting 10^-3 Mo/yr.Comment: 16 pages, 2 figures, Review paper to appear in Proc `The influence of binaries on stellar population studies', Brussels, Aug 2000 (D. Vanbeveren ed.), Kluwe

Conservative management versus open reduction and internal fixation for mid-shaft clavicle fractures in adults - The Clavicle Trial: Study protocol for a multicentre randomized controlled trial

Background: Clavicle fractures account for around 4% of all fractures and up to 44% of fractures of the shoulder girdle. Fractures of the middle third (or mid-shaft) account for approximately 80% of all clavicle fractures. Management of this group of fractures is often challenging and the outcome can be unsatisfactory. In particular it is not clear whether surgery produces better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform our decision.Methods/Design: We aim to undertake a multicentre randomised controlled trial evaluating the effectiveness and safety of conservative management versus open reduction and internal fixation for displaced mid-shaft clavicle fractures in adults. Surgical treatment will be performed using the Acumed clavicle fixation system. Conservative management will consist of immobilisation in a sling at the side in internal rotation for 6 weeks or until clinical or radiological union. We aim to recruit 300 patients. These patients will be followed-up for at least 9 months. The primary endpoint will be the rate of non-union at 3 months following treatment. Secondary endpoints will be limb function measured using the Constant-Murley Score and the Disabilities of the Arm, Shoulder and Hand (DASH) Score at 3 and 9 months post-operatively.Discussion: This article presents the protocol for a multicentre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity.Trial Registration: United Kingdom Clinical Research Network ID: 8665. The date of registration of the trial is 07/09/2006. The date the first patient was recruited is 18/12/2007. © 2011 Longo et al; licensee BioMed Central Ltd

Multi-slice ptychographic tomography

Ptychography is a form of Coherent Diffractive Imaging, where diffraction patterns are processed by iterative algorithms to recover an image of a specimen. Although mostly applied in two dimensions, ptychography can be extended to produce three dimensional images in two ways: via multi-slice ptychography or ptychographic tomography. Ptychographic tomography relies on 2D ptychography to supply projections to conventional tomographic algorithms, whilst multi-slice ptychography uses the redundancy in ptychographic data to split the reconstruction into a series of axial slices. Whilst multi-slice ptychography can handle multiple-scattering thick specimens and has a much smaller data requirement than ptychographic tomography, its depth resolution is relatively poor. Here we propose an imaging modality that combines the benefits of the two approaches, enabling isotropic 3D resolution imaging of thick specimens with a small number of angular measurements. Optical experiments validate our proposed method

Borderline gestational diabetes mellitus and pregnancy outcomes

Background: The impact of borderline gestational diabetes mellitus (BGDM), defined as a positive oral glucose challenge test (OGCT) and normal oral glucose tolerance test (OGTT), on maternal and infant health is unclear. We assessed maternal and infant health outcomes in women with BGDM and compared these to women who had a normal OGCT screen for gestational diabetes. Methods: We compared demographic, obstetric and neonatal outcomes between women participating in the Australian Collaborative Trial of Supplements with antioxidants Vitamin C and Vitamin E to pregnant women for the prevention of pre-eclampsia (ACTS) who had BGDM and who screened negative on OGCT. Results: Women who had BGDM were older (mean difference 1.3 years, [95% confidence interval (CI) 0.3, 2.2], p = 0.01) and more likely to be obese (27.1% vs 14.1%, relative risk (RR) 1.92, [95% CI 1.41, 2.62], p < 0.0001) than women who screened negative on OGCT. The risk of adverse maternal outcome overall was higher (12.9% vs 8.1%, RR 1.59, [95% CI 1.00, 2.52], p = 0.05) in women with BGDM compared with women with a normal OGCT. Women with BGDM were more likely to develop pregnancy induced hypertension (17.9% vs 11.8%, RR 1.51, [95% CI 1.03, 2.20], p = 0.03), have a caesarean for fetal distress (17.1% vs 10.5%, RR 1.63, [95% CI 1.10, 2.41], p = 0.01), and require a longer postnatal hospital stay (mean difference 0.4 day, [95% CI 0.1, 0.7], p = 0.01) than those with a normal glucose tolerance. Infants born to BGDM mothers were more likely to be born preterm (10.7% vs 6.4%, RR 1.68, [95% CI 1.00, 2.80], p = 0.05), have macrosomia (birthweight ≥4.5 kg) (4.3% vs 1.7%, RR 2.53, [95% CI 1.06, 6.03], p = 0.04), be admitted to the neonatal intensive care unit (NICU) (6.5% vs 3.0%, RR 2.18, [95% CI 1.09, 4.36], p = 0.03) or the neonatal nursery (40.3% vs 28.4%, RR 1.42, [95% CI 1.14, 1.76], p = 0.002), and have a longer hospital stay (p = 0.001). More infants in the BGDM group had Sarnat stage 2 or 3 neonatal encephalopathy (12.9% vs 7.8%, RR 1.65, [95% CI 1.04, 2.63], p = 0.03). Conclusion: Women with BGDM and their infants had an increased risk of adverse health outcomes compared with women with a negative OGCT. Intervention strategies to reduce the risks for these women and their infants need evaluation. Trial registration: Current Controlled Trials ISRCTN00416244Hong Ju, Alice R. Rumbold, Kristyn J. Willson and Caroline A. Crowthe

Preterm birth prevention-Time to PROGRESS beyond progesterone

In a Perspective, Jane Norman and Phillip Bennett argue that it is time to explore alternatives to progesterone for preventing preterm birth

Model based dynamics analysis in live cell microtubule images

Background: The dynamic growing and shortening behaviors of microtubules are central to the fundamental roles played by microtubules in essentially all eukaryotic cells. Traditionally, microtubule behavior is quantified by manually tracking individual microtubules in time-lapse images under various experimental conditions. Manual analysis is laborious, approximate, and often offers limited analytical capability in extracting potentially valuable information from the data. Results: In this work, we present computer vision and machine-learning based methods for extracting novel dynamics information from time-lapse images. Using actual microtubule data, we estimate statistical models of microtubule behavior that are highly effective in identifying common and distinct characteristics of microtubule dynamic behavior. Conclusion: Computational methods provide powerful analytical capabilities in addition to traditional analysis methods for studying microtubule dynamic behavior. Novel capabilities, such as building and querying microtubule image databases, are introduced to quantify and analyze microtubule dynamic behavior