Biological effectiveness on live cells of laser driven protons at dose rates exceeding 109 Gy/s

The ultrashort duration of laser-driven multi-MeV ion bursts offers the possibility of radiobiological studies at extremely high dose rates. Employing the TARANIS Terawatt laser at Queen's University, the effect of proton irradiation at MeV-range energies on live cells has been investigated at dose rates exceeding 109 Gy/s as a single exposure. A clonogenic assay showed consistent lethal effects on V-79 live cells, which, even at these dose rates, appear to be in line with previously published results employing conventional sources. A Relative Biological Effectiveness (RBE) of 1.4±0.2 at 10% survival is estimated from a comparison with a 225 kVp X-ray source.

Gemini observations of Wolf-Rayet stars in the Local Group starburst galaxy IC 10

We present Gemini-N GMOS and CFHT MOS spectroscopy of Wolf-Rayet candidates in the Local Group dwarf galaxy IC 10 that were previously identified by Massey et al. and Royer et al. From the present spectroscopic survey, the WC/WN ratio for IC 10 remains unusually high, given its low metallicity, although none of the WC9 stars suspected from narrow-band imaging are confirmed. Our spectroscopy confirms 9 newly discovered Wolf-Rayet candidates from Royer et al., whilst spectral types of 14 Wolf-Rayet stars previously observed by Massey & Armandroff are refined here. In total, there are 26 spectroscopically confirmed Wolf-Rayet stars in IC 10. All but one of the fourteen WC stars are WC4-6 stars, the exception being # 10 from Massey et al., a broad-lined, apparently single WC7 star. There are a total of eleven WN stars, which are predominantly early WN3-4 stars, but include a rare WN10 star, # 8 from Royer et al. # 5 from Massey et al. is newly identified as a transition WN/C star. Consequently, the WC/WN ratio for IC10 is 14/11similar to1.3, unusually high for a metal-poor galaxy. Re-evaluating recent photometric data of Massey & Holmes, we suggest that the true WC/WN ratio may not be as low as similar to0.3. Finally, we present ground-based finding charts for all confirmed WR stars, plus HST/WFPC2 charts for twelve cases.

Skin-reducing mastectomy and one-stage implant reconstruction with a myodermal flap: A safe and effective technique in risk-reducing and therapeutic mastectomy

Introduction: Immediate reconstruction following mastectomy for breast cancer has been shown to be oncologically safe and associated with improved psychosocial outcomes for patients. Bostwick described a technique for one-stage implant based reconstruction, combining skin-sparing mastectomy with concurrent reduction of the skin envelope. This report reviews the experience of a single centre using skin-reducing mastectomy and one-stage implant reconstruction in both early stage breast cancer and risk-reducing mastectomy, with specific reference to frequency of complications, implant loss and oncological outcomes.

Methods and results: A retrospective review was undertaken to identify women who had undergone skin-reducing mastectomy and one-stage implant reconstruction using a de-epithelialised dermal flap, between October 2008 and October 2012. One hundred and four consecutive mastectomies, with reconstruction, were performed by two surgeons on 64 patients. No complications were seen in 43.8% of patients. At three months, four implants were lost (3.8% of breast reconstructions, 6.3% of patients), due to either peri-implant infection or mastectomy skin flap necrosis. One patient required unplanned return to theatre for evacuation of a haematoma. Minor mastectomy skin flap necrosis was seen in 10 breasts (9.6% of reconstructed breasts) and superficial wound infection in 8 breasts (7.7% of reconstructed breasts). All of these complications were managed conservatively and none required operative intervention. At a median follow up of 35 months (4-53 months) there had been one episode of ipsilateral axillary nodal recurrence.

Conclusion: One-stage implant reconstruction using a myo-dermal flap technique following skin-reducing mastectomy is safe and should be considered in selected patients. Most complications are minor and will resolve with conservative management. Major complications such as implant failure or immediate reoperation, were relatively uncommon (6.3% patients, 3.8% of reconstructed breasts). Early follow-up suggests that oncological outcomes are satisfactory, but longer follow-up is required to substantiate this. (C) 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

A density functional theory study on the water formation at high coverages and the water effect in the Fischer-Tropsch synthesis

The O removal through water formation is an important process in the Fischer-Tropsch synthesis. In this study, both steps in water formation (O + H --> OH, OH + H --> H2O) are studied on the stepped Co(0001) at high coverages using density functional theory. We find the following. (i) In both O-O and O-OH co-adsorption systems, two transition states (TSs) were located for the O hydrogenation: in one TS, both O and H are on the same terrace, and in the other they are at the interface between the step edge and the terrace below. (ii) In both the O-O and O-OH co-adsorption systems, the O hydrogenation at the interface is easier (E-a = 0.32 eV in the O-O system, E-a = 1.10 eV in the O-OH system) than that on the same terrace (E-a = 1.49 eV in the O-O system, E-a = 1.80 eV in the O-OH system). (iii) In both the O-O and O-OH co-adsorption systems, only one TS for the OH hydrogenation was located, in which both OH and H are on the same terrace. (iv) Compared to the OH hydrogenation in the O-OH system (E-a = 1.46 eV), the reaction in the OH-OH system (E-a = 0.64 eV) is much easier. The barrier differences and the water effect on the Fischer-Tropsch synthesis are discussed. A possible route with low barriers for water formation is proposed.

Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: results from an open-label, multicentre phase I study.

The safety and tolerability of vandetanib (ZACTIMA; ZD6474) plus FOLFIRI was investigated in patients with advanced colorectal cancer (CRC). METHODS: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of FOLFIRI. RESULTS: A total of 21 patients received vandetanib 100 mg (n = 11) or 300 mg (n = 10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort and one DLT of hypertension (CTCAE grade 3) in the 300 mg cohort. The most common adverse events were diarrhoea (n = 20), nausea (n = 12) and fatigue (n = 10). Two patients (one in each cohort) discontinued vandetanib due to adverse events (rash, 100 mg cohort; hypertension, 300 mg cohort). There was no apparent pharmacokinetic interaction between vandetanib and FOLFIRI. Preliminary efficacy results included two confirmed partial responses in the 100 mg cohort and 9 patients with stable disease > or =8 weeks (100 mg, n = 7; 300 mg, n = 2). CONCLUSIONS: Once-daily vandetanib (100 or 300 mg) in combination with a standard FOLFIRI regimen was generally well tolerated in patients with advanced CRC.

The difficult coughing child:prolonged acute cough in children

Cough is one of the most common symptoms that patients bring to the attention of primary care clinicians. Cough can be designated as acute ( 8 weeks in duration). The use of the term 'prolonged acute cough' in a cough guideline allows a period of natural resolution to occur before further investigations are warranted. The common causes are in children with post viral or pertussis like illnesses causing the cough. Persistent bacterial bronchitis typically occurs when an initial dry acute cough due to a viral infection becomes a prolonged wet cough remaining long after the febrile illness has resolved. This cough responds to a completed course of appropriate antibiotics.

One-pot two-step mechanochemical synthesis: ligand and complex preparation without isolating intermediates

Although the use of ball milling to induce reactions between solids (mechanochemical synthesis) can provide lower-waste routes to chemical products by avoiding solvent during the reaction, there are further potential advantages in using one-pot multistep syntheses to avoid the use of bulk solvents for the purification of intermediates. We report here two-step syntheses involving formation of salen-type ligands from diamines and hydroxyaldehydes followed directly by reactions with metal salts to provide the corresponding metal complexes. Five salen-type ligands 2,2'-[1,2-ethanediylbis[(E)-nitrilomethylidyne]] bisphenol, ` salenH2', 1; 2,2'-[(+/-)-1,2-cyclohexanediylbis-[(E)-nitrilomethylidyne]] bis-phenol, 2; 2,2'-[1,2-phenylenebis( nitrilomethylidyne)]-bis-phenol, ` salphenH2' 3; 2-[[(2-aminophenyl) imino] methyl]-phenol, 4; 2,2'-[(+/-)-1,2-cyclohexanediylbis[(E)-nitrilomethylidyne]]-bis[4,6-bis(1,1-dimethylethyl)]-phenol, ` Jacobsen ligand', 5) were found to form readily in a shaker-type ball mill at 0.5 to 3 g scale from their corresponding diamine and aldehyde precursors. Although in some cases both starting materials were liquids, ball milling was still necessary to drive those reactions to completion because precipitation of the product and or intermediates rapidly gave in thick pastes which could not be stirred conventionally. The only ligand which required the addition of solvent was the Jacobsen ligand 5 which required 1.75 mol equivalents of methanol to go to completion. Ligands 1-5 were thus obtained directly in 30-60 minutes in their hydrated forms, due to the presence of water by-product, as free-flowing yellow powders which could be dried by heating to give analytically pure products. The one-armed salphen ligand 4 could also be obtained selectively by changing the reaction stoichiometry to 1 : 1. SalenH(2) 1 was explored for the onepot two-step synthesis of metal complexes. In particular, after in situ formation of the ligand by ball milling, metal salts (ZnO, Ni(OAc)2 center dot 4H(2)O or Cu(OAc)(2)center dot H2O) were added directly to the jar and milling continued for a further 30 minutes. Small amounts of methanol (0.4-1.1 mol equivalents) were needed for these reactions to run to completion. The corresponding metal complexes [M(salen)] (M = Zn, 6; Ni, 7; or Cu, 8) were thus obtained quantitatively after 30 minutes in hydrated form, and could be heated briefly to give analytically pure dehydrated products. The all-at-once ` tandem' synthesis of [Zn(salen)] 6 was also explored by milling ZnO, ethylene diamine and salicylaldehyde together in the appropriate mole ratio for 60 minutes. This approach also gave the target complex selectively with no solvent needing to be added. Overall, these syntheses were found to be highly efficient in terms of time and the in avoidance of bulk solvent both during the reaction and for the isolation of intermediates. The work demonstrates the applicability of mechanochemical synthesis to one-pot multi-step strategies.

Evaluation of the Retinal Vasculature in Hypertension and Chronic Kidney Disease in an elderly population of Irish nuns

Background: Chronic kidney disease (CKD) and hypertension are global public health problems associated with considerable morbidity, premature mortality and attendant healthcare costs. Previous studies have highlighted that non-invasive examination of the retinal microcirculation can detect microvascular pathology that is associated with systemic disorders of the circulatory system such as hypertension. We examined the associations between retinal vessel caliber (RVC) and fractal dimension (DF), with both hypertension and CKD in elderly Irish nuns.

Methods: Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study (INES) were assessed from digital photographs with a standardized protocol using computer-assisted software. Multivariate regression analyses were used to assess associations with hypertension and CKD, with adjustment for age, body mass index (BMI), refraction, fellow eye RVC, smoking, alcohol consumption, ischemic heart disease (IHD), cerebrovascular accident (CVA), diabetes and medication use.

Results: In total, 1122 (91%) participants (mean age: 76.3 [range: 56-100] years) had gradable retinal images of sufficient quality for blood vessel assessment. Hypertension was significantly associated with a narrower central retinal arteriolar equivalent (CRAE) in a fully adjusted analysis (P = 0.002; effect size= -2.16 μm; 95% confidence intervals [CI]: -3.51, -0.81 μm). No significant associations between other retinal vascular parameters and hypertension or between any retinal vascular parameters and CKD were found.

Conclusions: Individuals with hypertension have significantly narrower retinal arterioles which may afford an earlier opportunity for tailored prevention and treatment options to optimize the structure and function of the microvasculature, providing additional clinical utility. No significant associations between retinal vascular parameters and CKD were detected.

Winter Is Coming: Seasonal Variation in Resting Metabolic Rate of the European Badger (Meles meles)

Resting metabolic rate (RMR) is a measure of the minimum energy requirements of an animal at rest, and can give an indication of the costs of somatic maintenance. We measured RMR of free-ranging European badgers (Meles meles) to determine whether differences were related to sex, age and season. Badgers were captured in live-traps and placed individually within a metabolic chamber maintained at 20 ± 1°C. Resting metabolic rate was determined using an open-circuit respirometry system. Season was significantly correlated with RMR, but no effects of age or sex were detected. Summer RMR values were significantly higher than winter values (mass-adjusted mean ± standard error: 2366 ± 70 kJ⋅d-1; 1845 ± 109 kJ⋅d-1, respectively), with the percentage difference being 24.7%. While under the influence of anaesthesia, RMR was estimated to be 25.5% lower than the combined average value before administration, and after recovery from anaesthesia. Resting metabolic rate during the autumn and winter was not significantly different to allometric predictions of basal metabolic rate for mustelid species weighing 1 kg or greater, but badgers measured in the summer had values that were higher than predicted. Results suggest that a seasonal reduction in RMR coincides with apparent reductions in physical activity and body temperature as part of the overwintering strategy ('winter lethargy') in badgers. This study contributes to an expanding dataset on the ecophysiology of medium-sized carnivores, and emphasises the importance of considering season when making predictions of metabolic rate.

Modelling Future Coronary Heart Disease Mortality to 2030 in the British Isles

OBJECTIVE: Despite rapid declines over the last two decades, coronary heart disease (CHD) mortality rates in the British Isles are still amongst the highest in Europe. This study uses a modelling approach to compare the potential impact of future risk factor scenarios relating to smoking and physical activity levels, dietary salt and saturated fat intakes on future CHD mortality in three countries: Northern Ireland (NI), Republic of Ireland (RoI) and Scotland.

METHODS: CHD mortality models previously developed and validated in each country were extended to predict potential reductions in CHD mortality from 2010 (baseline year) to 2030. Risk factor trends data from recent surveys at baseline were used to model alternative future risk factor scenarios: Absolute decreases in (i) smoking prevalence and (ii) physical inactivity rates of up to 15% by 2030; relative decreases in (iii) dietary salt intake of up to 30% by 2030 and (iv) dietary saturated fat of up to 6% by 2030. Probabilistic sensitivity analyses were then conducted.

RESULTS: Projected populations in 2030 were 1.3, 3.4 and 3.9 million in NI, RoI and Scotland respectively (adults aged 25-84). In 2030: assuming recent declining mortality trends continue: 15% absolute reductions in smoking could decrease CHD deaths by 5.8-7.2%. 15% absolute reductions in physical inactivity levels could decrease CHD deaths by 3.1-3.6%. Relative reductions in salt intake of 30% could decrease CHD deaths by 5.2-5.6% and a 6% reduction in saturated fat intake might decrease CHD deaths by some 7.8-9.0%. These projections remained stable under a wide range of sensitivity analyses.

CONCLUSIONS: Feasible reductions in four cardiovascular risk factors (already achieved elsewhere) could substantially reduce future coronary deaths. More aggressive polices are therefore needed in the British Isles to control tobacco, promote healthy food and increase physical activity.

Exploiting Human Resource Requirements to Infer Human Movement Patterns for Use in Modelling Disease Transmission Systems: An Example from Eastern Province, Zambia

In this research, an agent-based model (ABM) was developed to generate human movement routes between homes and water resources in a rural setting, given commonly available geospatial datasets on population distribution, land cover and landscape resources. ABMs are an object-oriented computational approach to modelling a system, focusing on the interactions of autonomous agents, and aiming to assess the impact of these agents and their interactions on the system as a whole. An A* pathfinding algorithm was implemented to produce walking routes, given data on the terrain in the area. A* is an extension of Dijkstra's algorithm with an enhanced time performance through the use of heuristics. In this example, it was possible to impute daily activity movement patterns to the water resource for all villages in a 75 km long study transect across the Luangwa Valley, Zambia, and the simulated human movements were statistically similar to empirical observations on travel times to the water resource (Chi-squared, 95% confidence interval). This indicates that it is possible to produce realistic data regarding human movements without costly measurement as is commonly achieved, for example, through GPS, or retrospective or real-time diaries. The approach is transferable between different geographical locations, and the product can be useful in providing an insight into human movement patterns, and therefore has use in many human exposure-related applications, specifically epidemiological research in rural areas, where spatial heterogeneity in the disease landscape, and space-time proximity of individuals, can play a crucial role in disease spread.

Is the Schwabe organ a retained larval eye? Anatomical and behavioural studies of a novel sense organ in adult leptochiton asellus (Mollusca, Polyplacophora) indicate links to larval photoreceptors

The discovery of a sensory organ, the Schwabe organ, was recently reported as a unifying feature of chitons in the order Lepidopleurida. It is a patch of pigmented tissue located on the roof of the pallial cavity, beneath the velum on either side of the mouth. The epithelium is densely innervated and contains two types of potential sensory cells. As the function of the Schwabe organ remains unknown, we have taken a cross-disciplinary approach, using anatomical, histological and behavioural techniques to understand it. In general, the pigmentation that characterises this sensory structure gradually fades after death; however, one particular concentrated pigment dot persists. This dot is positionally homologous to the larval eye in chiton trochophores, found in the same neuroanatomical location, and furthermore the metamorphic migration of the larval eye is ventral in species known to possess Schwabe organs. Here we report the presence of a discrete subsurface epithelial structure in the region of the Schwabe organ in Leptochiton asellus that histologically resembles the chiton larval eye. Behavioural experiments demonstrate that Leptochiton asellus with intact Schwabe organs actively avoid an upwelling light source, while Leptochiton asellus with surgically ablated Schwabe organs and a control species lacking the organ (members of the other extant order, Chitonida) do not (Kruskal-Wallis, H = 24.82, df = 3, p < 0.0001). We propose that the Schwabe organ represents the adult expression of the chiton larval eye, being retained and elaborated in adult lepidopleurans.

Auditory cueing in Parkinson's patients with freezing of gait. What matters most: action-relevance or cue-continuity?

Gait disturbances are a common feature of Parkinson’s disease, one of the most severe being freezing of gait. Sensory cueing is a common method used to facilitate stepping in people with Parkinson’s. Recent work has shown that, compared to walking to a metronome, Parkinson’s patients without freezing of gait (nFOG) showed reduced gait variability when imitating recorded sounds of footsteps made on gravel. However, it is not known if these benefits are realised through the continuity of the acoustic information or the action-relevance. Furthermore, no study has examined if these benefits extend to PD with freezing of gait. We prepared four different auditory cues (varying in action-relevance and acoustic continuity) and asked 19 Parkinson’s patients (10 nFOG, 9 with freezing of gait (FOG)) to step in place to each cue. Results showed a superiority of action-relevant cues (regardless of cue-continuity) for inducing reductions in Step coefficient of variation (CV). Acoustic continuity was associated with a significant reduction in Swing CV. Neither cue-continuity nor action-relevance was independently sufficient to increase the time spent stepping before freezing. However, combining both attributes in the same cue did yield significant improvements. This study demonstrates the potential of using action-sounds as sensory cues for Parkinson’s patients with freezing of gait. We suggest that the improvements shown might be considered audio-motor ‘priming’ (i.e., listening to the sounds of footsteps will engage sensorimotor circuitry relevant to the production of that same action, thus effectively bypassing the defective basal ganglia).

Efficient Genotyping of KRAS Mutant Non-Small Cell Lung Cancer Using a Multiplexed Droplet Digital PCR Approach.

Droplet digital PCR (ddPCR) can be used to detect low frequency mutations in oncogene-driven lung cancer. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach to efficient mutation detection in circulating DNA. Here we report the design and optimisation of three discriminatory ddPCR multiplex assays investigating nine different KRAS mutations using PrimePCR™ ddPCR™ Mutation Assays and the Bio-Rad QX100 system. Together these mutations account for 95% of the nucleotide changes found in KRAS in human cancer. Multiplex reactions were optimised on genomic DNA extracted from KRAS mutant cell lines and tested on DNA extracted from fixed tumour tissue from a cohort of lung cancer patients without prior knowledge of the specific KRAS genotype. The multiplex ddPCR assays had a limit of detection of better than 1 mutant KRAS molecule in 2,000 wild-type KRAS molecules, which compared favourably with a limit of detection of 1 in 50 for next generation sequencing and 1 in 10 for Sanger sequencing. Multiplex ddPCR assays thus provide a highly efficient methodology to identify KRAS mutations in lung adenocarcinoma.