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Abstract  High-speed particle image velocimetry has been applied to study the flow field of an optically accessible motored direct-injection spray-guided internal combustion engine. Based on recent improvements in all-solid-state diode-pumped laser- and CMOS camera-technology a large field of view (43 × 44 mm2) was achieved at 6 kHz resulting in a temporal resolution of 1° crank angle at 1,000 rpm. This allows the investigation of the temporal evolution of large-scale flow structures. The flow field was recorded during the latter half of the compression stroke for tumble flow conditions at 500, 1,000 and 2,000 rpm. An analysis of cycle-to-cycle variations has been performed from individual and ensemble-averaged cycles. The temporal evolution of the main vortex center and the kinetic energy shows a few individual cycles with strong variations from the mean caused by a substantially different flow regime. A quantification of cyclic variations using the kinetic energy is possible. [ABSTRACT FROM AUTHOR]

Vapor−liquid−solid is a well-established process in catalyst guided growth of 1-D nanostructures, i.e., nanobelts and nanowires. The catalyst particle is generally believed to be in the liquid state during growth, and is the site for impinging molecules. The crystalline structure of the catalyst may not have any influence on the structure of the grown nanostructures. In this work, using Au guided growth of ZnO, we show that the interfaces between the catalyst droplet and the nanostructure grow in well-defined mutual crystallographic relationships. The nanostructure defines the crystallographic orientation of the solidifying Au droplet. Possible alloy, intermetallic, or eutectic phase formation during catalysis are elucidated with the help of a proposed ternary Au−Zn−O phase diagram. [ABSTRACT FROM AUTHOR]

Combined cerebellar and spinal ischemic stroke is a rare, critical condition. We report a patient with combined cerebellar and bilateral posterolateral cervical spinal cord infarction due to bilateral stenosis of the vertebral arteries. MRI is the method of choice for imaging this condition; diffusion-weighted imaging of the spinal cord gives reliable results. [ABSTRACT FROM AUTHOR]

A high dosimetric quality and short treatment time are major goals in radiotherapy planning. Intensity modulated proton therapy (IMPT) plans obtain dose distributions of great conformity but often result in long delivery times which are typically not incorporated into the optimization process. We present an algorithm to optimize delivery efficiency of IMPT plans while maintaining plan quality, and study the potential trade-offs of these interdependent objectives. The algorithm is based on prioritized optimization, a stepwise approach to implemented objectives. First the quality of the plan is optimized. The second step of the prioritized efficiency optimization (PrEfOpt) routine offers four alternatives for reducing delivery time: minimization of the total spot weight sum (A), maximization of the lowest spot intensity of each energy layer (B), elimination of low-weighted spots (C) or energy layers (D). The trade-off between dosimetric quality (step I) and treatment time (step II) is controlled during the optimization by option-dependent parameters. PrEfOpt was applied to a clinical patient case, and plans for different trade-offs were calculated. Delivery times were simulated for two virtual facilities with constant and variable proton current, i.e. independent and dependent on the optimized spot weight distributions. Delivery times decreased without major degradation of plan quality; absolute time reductions varied with the applied method and facility type. Minimizing the total spot weight sum (A) reduced times by 28% for a similar plan quality at a constant current (changes of minimum dose in the target  <1%). For a variable proton current, eliminating low-weighted spots (C) led to remarkably faster delivery (16%). The implementation of an efficiency-optimization step into the optimization process can yield reduced delivery times with similar plan qualities. A potential clinical application of PrEfOpt is the generation of multiple plans with different trade-offs for a multicriteria optimization setting. Then, the planner can select the preferred compromise between treatment time and quality for each individual patient. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the ‘classical’ phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients. [ABSTRACT FROM AUTHOR]

Dok (‘downstream-of-kinase’) family of cytoplasmic proteins play a role in signalling downstream of receptor and non-receptor phosphotyrosine kinases. Recently, a skeletal muscle receptor tyrosine kinase (MuSK)-interacting cytoplasmic protein termed Dok-7 has been identified. Subsequently, we and others identified mutations in DOK7 as a cause of congenital myasthenic syndromes (CMS), providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Here we present clinical and molecular genetic data of 14 patients from 12 independent kinships with 13 different mutations in the DOK7 gene. The clinical picture of CMS with DOK7 mutations is highly variable. The age of onset may vary between birth and the third decade. However, most of the patients display a characteristic ‘limb-girdle’ pattern of weakness with a waddling gait and ptosis, but without ophthalmoparesis. Respiratory problems were frequent. Patients did not benefit from long-term therapy with esterase inhibitors; some of the patients even worsened. DOK7 mutations have emerged as one of the major genetic defects in CMS. The clinical picture differs significantly from CMS caused by mutations in other genes, such as the acetylcholine receptor (AChR) subunit genes. None of the patients with DOK7 mutations had tubular aggregates in the muscle biopsy, implying that ‘limb-girdle myasthenia (LGM) with tubular aggregates’ previously described in literature may be a pathogenic entity distinct from CMS caused by DOK7 mutations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the precision of CT-based volumetric measurements of artificial small pulmonary nodules under ex vivo conditions. We implanted 322 artificial nodules in 23 inflated ex vivo porcine lungs in a dedicated chest phantom. The lungs were examined with a multislice spiral CT (20 mAs, collimation 16x0.75 mm, 1 mm slice thickness, 0.7 mm increment). A commercial volumetry software package (LungCARE VA70C-W; Siemens, Erlangen, Germany) was used for volume analysis in a semi-automatic and a manual corrected mode. After imaging, the lungs were dissected to harvest the nodules for gold standard determination. The volumes of 202 solitary, solid and well-defined lesions without contact with the pleura, greater bronchi or vessels were compared with the results of volumetry. A mean nodule diameter of 8.3 mm (+/-2.1 mm) was achieved. The mean relative deviation from the true lesion volume was -9.2% (+/-10.6%) for semi-automatic and -0.3% (+/-6.5%) for manual corrected volumetry. The subgroup of lesions from 5 mm to <10 mm in diameter showed a mean relative deviation of -8.7% (+/-10.9%) for semi-automatic volumetry and -0.3% (+/-6.9%) for manually corrected volumetry. We conclude that the presented software allowed for precise volumetry of artificial nodules in ex vivo lung tissue. This result is comparable to the findings of previous in vitro studies. [ABSTRACT FROM AUTHOR]

EPR-basednanometre distance measurements are becoming ever moreimportant in structural biology. Usually the distance constraintsare measured between two nitroxide spin labels. Yet, distance measurementsbetween a metal center and spin labels enable, e.g., the localizationof metal ions within the tertiary fold of biomolecules. Therefore,it is important to find methods that provide such distance informationquickly, with high precision and reliability. In the present study,two methods, pulsed electron–electron double resonance (PELDOR)and relaxation-induced dipolar modulation enhancement (RIDME), arecompared on the heme-containing and spin-labeled cytochrome P450cam.Special emphasis is put on the optimization of the dead-time freeRIDME experiment and several ways of data analysis. It turned outthat RIDME appears to be better suited for distance measurements involvingmetal ions like low-spin Fe3+than PELDOR. [ABSTRACT FROM AUTHOR]

Somatic cell nuclear transfer (SCNT) cloning requires epigenetic reprogramming of a differentiated donor cell nucleus. Incorrect reprogramming of epigenetic marks such as methylation of cytosine (5 mC) is associated with compromised development. Clones that survive into adulthood, in contrast, are assumed to be normal and are expected to be used in global food production. However, the epigenetic status of such healthy adult clones has never been investigated. We used a capillary electrophoresis technique to measure 5 mC content in leukocyte DNA from 38 healthy female clones at 1 to 8 years of age. Fibroblasts from 9 adults were used to generate 2 to 9 clones per donor. Four of the studied clone genotypes were from the Holstein breed, and 5 were from the Simmental breed. Individual 5 mC levels ranged from 4.4 to 6.9% with significant differences in mean 5 mC levels of Holstein and Simmental clones (6.50 ± 0.01% and 5.09 ± 0.02%, P< 0.001). The observed variances in 5 mC between clone genotypes of both breeds were similar (0.0204 and 0.0164), and we computed exact restricted likelihood ratio tests on the basis of linear mixed effects models to test for the presence of variability between genotypes. We found that the estimated variance in 5 mC level within clone genotypes from both breeds (0.104) was higher than the estimated variance between clone genotypes (<10-10). Three Holstein donors were analyzed for the 5 mC level of their genome together with their clones. Two donors exhibited the lowest 5 mC levels of the respective genotypes. The 5 mC level of the third nuclear donor was identical to 1 of its 8 clones, higher than 5 of them, and lower than the 2 remaining ones. This clearly demonstrates that the functional reprogramming of a given donor genotype is compatible with a highly flexible methylation status of its DNA and that genomic copies of adult animals have to be considered as epigenome variants. To quantify the contribution of SCNT to the observed variability between clones, we compared Simmental clones with female Simmental monozygotic twins of similar age that were generated by bisection of fertilized embryos. The estimated variability of 5 mC levels within 5 genotypes of clones (0.0636, n= 19) was clearly higher than in 12 twin pairs (0.0091). In clones, the estimated variability within genotypes (0.0636) was thus higher than between (<10-10) genotypes. In contrast, the variability within twin genotypes (0.0091) was lower than between twin genotypes (0.0136). Absolute deviations of 5 mC values of SCNT clones from their genotype means were 5-fold increased as compared with twins, whereas deviations of genotype means from group means were similar for clones and twins. The comparison with twins confirmed a SCNT cloning effect illustrated by a clone-specific variability of DNA methylation and provided new evidence of DNA hypermethylation by SCNT. Our data show that SCNT cloning can no longer be considered (epi)genetically neutral in apparently healthy adult animals. This raises new scientific and regulatory questions about the risks of disseminating cloned (epi)genetics into animal populations.Supported by EU (SABRE), DFG, INRA, and MRES. [ABSTRACT FROM AUTHOR]

ABSTRACTObjective:Opioid therapy is frequently associated with treatment-limiting constipation. Naloxone is an opioid antagonist with low oral systemic bioavailability. This Phase III clinical trial assessed the safety and efficacy of an oral fixed-ratio combination of oxycodone prolonged-release (PR) and naloxone PR compared with oxycodone PR in relieving opioid-induced constipation.Study design:This double-blind, multicenter trial was conducted in specialist and primary care centers in four European countries in an out-patients setting. The study included 322 adult patients with moderate-to-severe, noncancer pain requiring opioid therapy in a range of ≥20 mg/day and ≤50 mg/day oxycodone. Following a run-in phase patients were randomized to receive oxycodone PR/naloxone PR or oxycodone PR for 12 weeks. The primary outcome was improvement in constipation as measured using the Bowel Function Index (BFI). Secondary/exploratory assessments focused on pain intensity and additional bowel parameters.Trial registration:NCT00412152.Results:A significant improvement in BFI scores occurred with oxycodone PR/naloxone PR compared with oxycodone PR after 4 weeks of double-blind treatment (−26.9 vs. −9.4, respectively; p< 0.0001), observed after only 1 week of treatment and continued until study end. A significant increase in the number of complete spontaneous bowel movements and decrease in laxative use were also reported. This improvement in bowel function was achieved without compromising the analgesic efficacy of the oxycodone component; pain intensity remained constant throughout the study. The incidence of adverse events was comparable in both groups and consistent with those expected of opioid analgesics. As the study was limited to a dose range of up to 50 mg oxycodone equivalent per day, further research on higher doses would be recommended.Conclusion:The fixed-ratio combination of oxycodone PR/naloxone PR is superior to oxycodone PR alone, offering patients effective analgesia while significantly improving opioid-induced constipation. [ABSTRACT FROM AUTHOR]

This work reports the characterization of composites prepared by the association between zinc phthalocyanine (ZnPc) and titanium dioxide. These composites are better photocatalysts for wastewater decontamination mediated by solar radiation than pure TiO2, performance that remains even when reused. The UV-Vis diffuse reflectance absorption spectra show for these composites two intense absorption bands. The first covers the ultraviolet and part of the visible spectrum region until 460nm (2.7 eV), whereas the second, nonstructured, goes from 475nm until the near infrared with an absorption peak at 683nm attributed to the Q band of ZnPc. The production of additional e-/h+ pairs by these aggregates when photoexcited, their capability to act as charge carrier, the thickness and regularity of their distribution on the TiO2 surface seem to be important parameters for the performance observed for these composites. [ABSTRACT FROM AUTHOR]

We report on structural and optical properties of a (InxGa)2O3 thin film having a monotonic lateral variation of the indium content x (). The growth condition for each In content is similar allowing precise determination of the dependence of material properties on x. For low In content () the thin film has monoclinic crystal structure; for highest In contents () the cubic bixbyite phase is predominant. For intermediate alloying we observe additionally the rhombohedral InGaO3(II) crystallographic phase. The optical band-gap decreases systematically with increasing indium content and has a linear dependency on x for parts of the sample having the monoclinic phase, only. Further, properties of Pt Schottky diodes are reported for monoclinic (InxGa)2O3 and photo response measurements for [ABSTRACT FROM AUTHOR]