Benign recurrent intrahepatic cholestasis (BRIC) is a rare disorder characterized by recurrent episodes of cholestasis without permanent liver damage. Familial and sporadic cases have been described. Based on existing evidence, both autosomal-recessive and autosomal-dominant inheritance have been considered. We describe a large Dutch pedigree with 4 patients, strongly suggesting autosomal-recessive inheritance.


BACKGROUND: Rituximab-based chemotherapy is effective in inducing remissions in ~85% patients with untreated follicular lymphoma (FL). Primary treatment failure or an early relapse after first-line therapy is associated with a very poor prognosis. Recent sequencing efforts have been successful at identifying recurrent genetic events that contribute to the pathogenesis of FL, but the clinical significance of most of these events, in particular those contributing to therapeutic resistance, remain unknown. We identified a mutation in FAS (Y232*) in a patient with primary-refractory FL. FAS, a key death receptor in the extrinsic apoptotic pathway, plays a fundamental role in immune homeostasis by initiating apoptosis in lymphocytes once activated by FAS ligand (FASL) from neighboring cells. Herein, we show that mutations in FAS contribute to therapeutic resistance in FL. METHODS: We determined the incidence and clinical significance of FAS mutations in an extended cohort of 214 clinically-annotated FL biopsies. We determined the impact of the recurrent FAS(Y232*) mutation on FAS-mediated and chemotherapy-induced apoptosis in lymphoma cell lines. We measured the change in FAS and FASL expression in primary human T and B lymphocytes after exposure to chemotherapy. Finally, we cloned the murine equivalent of FAS(Y232*), Fas(Y224*), in Eu-Myc lymphoma cells and determined its effect on lymphoma growth and response to chemotherapy in immunocompetent C57BL/6 mice (n=36). RESULTS: FAS mutations were identified in 6% of FL patients. Coding FAS mutations were associated with a trend towards an earlier median time to progression (1 y versus 2.8 y, p=0.08) and an increased risk of histological transformation (p=0.036). The recurrent FAS(Y232*) mutation inhibited FAS-mediated apoptosis in cell lines but, unexpectedly, did not inhibit chemotherapy-mediated apoptosis. We hypothesized that in patients, chemotherapy induced a FAS-mediated immune response that was not modeled in vitro. Supporting this concept, we observed an increase in FASL and FAS expression on normal T and B lymphocytes, respectively, after exposure to etoposide. We injected three groups of mice with Eu-Myc lymphoma cells that differed only in their Fas genotype (Fas WT, Fas(Y224*) and an empty vector control) and monitored lymph node volumes before and after therapy. Fas(Y224*) dramatically accelerated lymphoma growth. Lymph node volumes exceeded those measured in Fas wild-type and control mice at all time points beyond the day of injection. The average maximal lymph node volume for the Fas(Y224*) group was 59.9 mm3 compared to 18.9 mm3 and 34.5 mm3 for the Fas WT and control groups, respectively (p CONCLUSION: Mutations in FAS can be clinically important in patients with FL by promoting lymphoma growth and inducing therapeutic resistance. The full malignant phenotype of FAS mutant lymphomas could only be elicited in vivo, and not in vitro, suggesting that a FAS-mediated immune response controls lymphoma growth and actively participates in chemotherapy-induced cell death. Disclosures Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding.


Objective To determine if a hybrid cardiac rehabilitation (CR) programme using the Family-Centered Empowerment Model (FCEM) as compared with standard CR will improve patient quality of life, perceived stress and state anxiety of patients with myocardial infarction (MI). Methods We conducted a randomised controlled trial in which patients received either standard home CR or CR using the FCEM strategy. Patient empowerment was measured with FCEM questionnaires preintervention and postintervention for a total of 9 assessments. Quality of life, perceived stress, and state and trait anxiety were assessed using the 36-Item Short Form Health Survey (SF-36), the 14-item Perceived Stress, and the 20-item State and 20-item Trait Anxiety questionnaires, respectively. Results 70 patients were randomised. Baseline characteristics were similar. Ejection fraction was significantly higher in the intervention group at measurements 2 (p=0.01) and 3 (p=0.001). Exercise tolerance measured as walking distance was significantly improved in the intervention group throughout the study. The quality of life results in the FCEM group showed significant improvement both within the group over time (p<0.0001) and when compared with control (p<0.0001). Similarly, the perceived stress and state anxiety results showed significant improvement both within the FCEM group over time (p<0.0001) and when compared with control (p<0.0001). No significant difference was found either within or between groups for trait anxiety. Conclusions The family-centred empowerment model may be an effective hybrid cardiac rehabilitation method for improving the physical and mental health of patients post-MI; however, further study is needed to validate these findings. Clinical Trials.gov identifier NCT02402582. Trial registration number NCT02402582.


This paper introduces a technique for improving the high-frequency performance of filter inductors and common-mode chokes by cancelling out the effects of parasitic capacitance. This technique uses additional passive components to inject a compensation current that cancels the parasitic current, thereby improving high-frequency filtering performance. Two implementation approaches for this technique are introduced. The first implementation achieves cancellation using an additional small winding on the filter inductor and a small capacitor. This approach is effective where very high coupling of the windings can be achieved or where only moderate performance improvements are required. The second implementation utilizes a small radio frequency transformer in parallel with the filter inductor to inject cancellation currents from the compensation capacitor. This technique requires an additional component (the transformer), but can provide a high degree of cancellation. Experimental results confirm the theory in both implementations.


ABSTRACT: Prior research examining the ASC 820 fair value hierarchy concludes that Level 3 fair value measurements are significantly less value-relevant than Level 1 and Level 2 fair value measurements. We reevaluate this conclusion using the closed-end fund setting, in which fair value measurements are available for substantially all assets. Contrary to prior research, we find that Level 3 fair values are of similar value relevance to Level 1 and Level 2 fair values. Our findings suggest that the results in previous research are attributable to correlated omitted variable bias arising from the absence of fair value data for most assets. JEL Classifications: M41; G12; G29. Data Availability: Data are publicly available from sources identified in the article.


Abstract Alcohol use is an important preventable and modifiable cause of non‐communicable disease, and has complex effects on the cardiovascular system that vary with dose. Observational and prospective studies have consistently shown a lower risk of cardiovascular and all‐cause mortality in people with low levels of alcohol consumption when compared to abstainers (the 'J'‐shaped curve). Maximum potential benefit occurs at 0.5 to one standard drinks (7–14 g pure ethanol) per day for women (18% lower all‐cause mortality, 95% confidence interval (CI) = 13–22%) and one to two standard drinks (14–28 g ethanol) per day for men (17% lower all‐cause mortality, 95% CI = 15–19%). However, this evidence is contested, and overall the detrimental effects of alcohol far outweigh the beneficial effects, with the risk of premature mortality increasing steadily after an average consumption of 10 g ethanol/day. Blood pressure (BP) is increased by regular alcohol consumption in a dose‐dependent manner, with a relative risk for hypertension (systolic BP > 140 mm Hg or diastolic > 90 mm Hg) of 1.7 for 50 g ethanol/day and 2.5 at 100 g/day. Important reductions in BP readings can be expected after as little as 1 month of abstinence from alcohol. Heavy alcohol consumption in a binge pattern is associated with the development of acute cardiac arrhythmia, even in people with normal heart function. Atrial fibrillation is the most common arrhythmia associated with chronic high‐volume alcohol intake, and above 14 g alcohol/day the relative risk increases 10% for every extra standard drink (14 g ethanol). Ethanol and its metabolites have toxic effects on cardiac myocytes, and alcoholic cardiomyopathy (ACM) accounts for a third of all cases of non‐ischaemic dilated cardiomyopathy. Screening people drinking alcohol above low‐volume levels and delivering a brief intervention may prevent the development of cardiovascular complications. Although people with established cardiovascular disease show improved outcomes with a reduction to low‐volume alcohol consumption, there is no safe amount of alcohol to drink and patients with ACM should aim for abstinence in order to optimize medical treatment.


The application of balanced design principles is particularly important in multifamily residential buildings. The risk of fires in apartments and condominiums is high because of the numerous kitchens, furnaces, hot water heaters, and other causes of residential fires. In addition, there is always a potential for sleeping occupants, children, and others who may be at a disadvantage for evacuating quickly. Fire safety in multifamily housing requires an understanding of the hazards involved, so that both the potential for fire and the threat to life-safety during a fire are minimized. The purpose of balanced design is to protect life and property during a fire. Death and injury from fire is caused by asphyxiation from toxic smoke and fumes; burns from direct exposure to the fire; heart attacks caused by stress and exertion; and impact due to structural collapse, explosion and falls. Life safety in multifamily housing is influenced by the design of the building, its fire protection features, and by the materials, building contents, quality of construction, and maintenance.


Abnormal muscle tone and muscle weakness are related to gait asymmetry in stroke survivors. However, the internal muscle morphological changes that occur during walking remain unclear. To address this issue, this study investigated the muscle activity of the tibialis anterior (TA) and medial gastrocnemius (MG) of both the paretic and non-paretic sides during walking in nine stroke survivors, by simultaneously capturing electromyography (EMG), mechanomyography (MMG), and ultrasound images, and using a validated novel wearable ultrasound imaging and sensing system. Statistical analysis was performed to examine the test–retest reliability of the collected data, and both the main and interaction effects of each "side" (paretic vs. non-paretic) and "gait" factors, in stroke survivors. This study observed significantly good test–retest reliability in the collected data (0.794 ≤ ICC ≤ 0.985), and significant differences existed in both the side and gait factors of the average TA muscle thickness from ultrasound images, and in the gait factors of TA and MG muscle's MMG and EMG signals (p < 0.05). The muscle morphological characteristics also appeared to be different between the paretic and non-paretic sides on ultrasound images. This study uncovered significantly different internal muscle contraction patterns between paretic and non-paretic sides during walking for TA (7.2% ± 1.6%) and MG (5.3% ± 4.9%) muscles in stroke survivors.


Aim Late Pleistocene glacial changes had a major impact on many boreal and temperate taxa, and this impact can still be detected in the present-day phylogeographic structure of these taxa. However, only minor effects are expected in species with generalist habitat requirements and high dispersal capability. One such species is the white-tailed eagle, Haliaeetus albicilla, and we therefore tested for the expected weak population structure at a continental level in this species. This also allowed us to describe phylogeographic patterns, and to deduce Ice Age refugia and patterns of postglacial recolonization of Eurasia. Location Breeding populations from the easternmost Nearctic (Greenland) and across the Palaearctic (Iceland, continental Europe, central and eastern Asia, and Japan). Methods Sequencing of a 500 base-pair fragment of the mitochondrial DNA control region in 237 samples from throughout the distribution range. Results Our analysis revealed pronounced phylogeographic structure. Overall, low genetic variability was observed across the entire range. Haplotypes clustered in two distinct haplogroups with a predominantly eastern or western distribution, and extensive overlap in Europe. These two major lineages diverged during the late Pleistocene. The eastern haplogroup showed a pattern of rapid population expansion and colonization of Eurasia around the end of the Pleistocene. The western haplogroup had lower diversity and was absent from the populations in eastern Asia. These results suggest survival during the last glaciation in two refugia, probably located in central and western Eurasia, followed by postglacial population expansion and admixture. Relatively high genetic diversity was observed in northern regions that were ice-covered during the last glacial maximum. This, and phylogenetic relationships between haplotypes encountered in the north, indicates substantial population expansion at high latitudes. Areas of glacial meltwater runoff and proglacial lakes could have provided suitable habitats for such population growth. Main conclusions This study shows that glacial climate fluctuations had a substantial impact on white-tailed eagles, both in terms of distribution and demography. These results suggest that even species with large dispersal capabilities and relatively broad habitat requirements were strongly affected by the Pleistocene climatic shifts.


To improve the efficiency of computer input, extensive research has been conducted on hand movement in a spatial region. Most of it has focused on the technologies but not the users' spatial controllability. To assess this, we analyze a users' common operational area through partitioning, including a layered array of one dimension and a spatial region array of two dimensions. In addition, to determine the difference in spatial controllability between a sighted person and a visually impaired person, we designed two experiments: target selection under a visual and under a non-visual scenario. Furthermore, we explored two factors: the size and the position of the target. Results showed the following: the 5 × 5 target blocks, which were 60.8 mm × 48 mm, could be easily controlled by both the sighted and the visually impaired person; the sighted person could easily select the bottom-right area; however, for the visually impaired person, the easiest selected area was the upper right. Based on the results of the users' spatial controllability, we propose two interaction techniques (non-visual selection and a spatial gesture recognition technique for surgery) and four spatial partitioning strategies for human-computer interaction designers, which can improve the users spatial controllability.


Imide-aryl ether ketone block copolymers were prepared and their morphology and thermal and mechanical properties investigated. Two aryl ether ketone blocks were incorporated; the first was an amorphous block derived from bisphenol–A and the second block was a semi-crystalline poly(aryl ether ether ketone) prepared from a soluble and amorphous ketimine precursor. Bis(amino) aryl ether ketone and aryl ether ketimine oligomers were prepared via a nucleophilic aromaic substitution reaction with molecular weights ranging from 6,000 to 12,000 g/mol. The oligomers were co-reacted with 4,4′-oxydianiline (ODA) and pyromellitic dianhydride (PMDA) diethyl ester diacyl chloride in N-methyl–2-pyrrolidone (NMP) in the presence of N-methylmorpholine. The copolymer compositions, determined by H-NMR, of the resulting amic ester based copolymers ranged from 8 to 50 wt % aryl ether ketone or ketimine content. Prior to imide formation, the ketimine moiety of the aryl ether ketimine block was hydrolyzed (p-toluene sulfonic acid) to the ketone form producing the aryl ether ether ketone block. Compositions of this block were maintained low to retain solubility. Solutions of the copolymers were cast and cured to effect imidization, producing clear films with high moduli (ca. 2200 MPa) and elongations (33–100%). The copolymers displayed good thermal stability with decomposition temperatures in excess of 450°C. Multiphase morphologies were observed irrespective of the co-block type, block length or composition. © 1992 John Wiley & Sons, Inc.


The aim of this article is to provide a framework for empirical research into the practice of Waldorf education with a particular emphasis on its Bildung-related aspects and to outline some of its potential contributions. Conceptually it rests on a biographical and empirical case narrative approach to Bildung in connection with MacIntyre's concept of a practice. It represents a combination of the auto/biographical approach of narrative inquiry with research into enacted and experienced curricula through extreme and paradigmatic narrative cases. The two cases presented are auto/biographical and are used to clarify and explore the implications of the argument. The conclusion highlights a number of ways in which the collection and interpretation of this kind of cases can contribute: exploring "conceptual environments", for practice development, in teacher education, making Waldorf education more accessible to "outsiders" and considering ways in which the tension between education for Bildung and effective training can be reconciled.


Semiconductor saturable absorber mirrors (SESAMs) are key devices for passive mode locking of numerous laser types and have been implemented for a variety of operational wavelengths ranging from 800 nm to 2400 nm. However, for 1560 nm the fabrication of SESAMs based on the standard AlAs/GaAs material system requires highly strained InGaAs absorber layers, which reduce the device efficiency and compromise fragile long-term performance. Here, we present SESAMs for ultrashort pulse generation at 1560 nm that are grown entirely lattice-matched to InP and thus have the potential for less structural defects and a higher operational lifetime. A highly reflective InGaAlAs-InAlAs Bragg mirror is capped with a heavily iron doped InGaAs:Fe absorber layer, which facilitates an unprecedented combination of sub-picosecond carrier lifetime and high optical quality. Therefore, the presented SESAMs show ultrafast response (τA < 1 ps), low non-saturable losses and high effective modulation depth (ΔReff ≥ 5.8%). Moreover, a nearly anti-resonant SESAM design provides high saturation and roll-over fluence (Fsat ≥ 17  µJ/cm2, F2 ≥ 21 mJ/cm2). With these SESAMs, we show self-starting and stable mode locking of an erbium doped fiber laser at 80 MHz repetition rate, providing ultrashort optical pulses at 17.5  mW average power.


Benzophenonehydrazone Schiff bases 1-25 were synthesized and their in vitro antiglycation potential has been studied. Out of twenty-five compounds, thirteen showed varying degrees of antiglycation activity with IC50 values ranging between 25.7 - 305 μM, if compared with the standard rutin (IC50 = 70.5 ± 0.50 μM). Compounds 21 (2,3- dihydroxybenzaldehyde N-(diphenylmethylene)hydrazine) IC50 = 25.7 ± 0.003 μM, 14 (diphenylmethanone N-[1-(2,4- dihydroxy-5-nitrophenyl)ethylidene]hydrazine) IC50 = 36.6 ± 0.004 μM, 6 (3,4-dihydroxybenzaldehyde N- (diphenylmethylene)hydrazine) IC50 = 49.5 ± 0.001 μM, 13 (diphenylmethanone N-[1-(2,5-dihydroxyphenyl)ethylidene] hydrazine) IC50 = 52.6 ± 0.023 μM, and 15 (diphenylmethanone N-[1-(3,4-dihydroxyphenyl)ethylidene]hydrazine) IC50 = 57 ± 0.002 μM, showed showed much better antiglycation potential superior to the standard rutin. The compounds 7 (2,5- dihydroxybenzaldehyde N-(diphenylmethylene)hydrazine) IC50 = 66 ± 0.002 μM, and 25 (diphenylmethanone N-[1-(2,5- dihydroxyphenyl)propylidene] hydrazine) IC50 = 67.9 ± 0.001 μM showed compareably good antiglycation activity to standard rutin. All compounds were characterized by spectroscopic techniques and gave satisfactory elemental analysis.


Background Objectives Systemic sclerosis (SSc) is characterised by the proof deterioration of microcirculation and the large structural changes of the microcirculatory vessels. The aim of the study was to investigate the relationship between functional and structural abnormalities of skin microcirculation in patients with systemic sclerosis (SSc). Methods Thirty patients with SSc aged 16 to 68 years (mean age 47,46 + 2,41 yrs) were included in the study. Nineteen pts had limited cutaneous SSc (lSSc), and eleven – diffuse cutaneous SSc (dSSc). The morphological changes of skin capillaries were estimated by the nailfold capillary microscopy. The skin microcirculation was evaluated by laser Doppler flowmetry (LDF). Results All studied patients showed an abnormal nailfold capillary pattern: enlargement of the capillary loop (dilated capillaries) and the loss of capillaries either diffusely or in limited areas. Depending on a degree of the nailfold capillaries changes the patients were divided into 3 groups: with mild (17 pts), moderate (14 pts) and severe (9 pts) changes. The level of basal skin blood flow in first group of the patients was 0,624 + 0,031v. In second group of the patients basal skin blood flow was 0,361 + 0,050v and there was also significantly below, when compared with first group of patients (p = 0,002). The lowest level of basal skin blood flow 0,212 + 0,063v was observed in the patients of third groups and also was significantly smaller than in the patients of first group (p < 0,001). There wasn't a statistically significant difference in basal skin blood flow levels between 2nd and 3rd groups of the patients. The level of basal skin blood flow closely correlated with number of capillaries (r = 0,73; p < 0,001). In the patients with dSSc the greater decrease of number of capillaries was observed, than in the patients with lSSc. Basal skin blood flow in dSSc was considerably below, than in lSSc (0,438 + 0,040v and 0,250 + 0,063v respectively; p = 0,02). Conclusion Thus, the microcirculation abnormalities closely correlated with structural changes of capillaries in SSc.


Groups of rats fed both choline-supplemented and choline-deficient diets were injected with methotrexate (MTX) at dose levels of 0.1 mg/kg/day and 0.2 mg/kg/day. Both doses produced lowered hepatic betaine levels in the choline-supplemented animals when compared with nontreated, pair-fed controls. Since betaine levels were very low in the livers of choline-deficient rats, MTX had no further effect on hepatic betaine in these animals. These data suggest that the betaine lowering seen in livers of choline-fed rats may be due to utilization as a means of compensating for the MTX-induced loss of N5 methyltetrahydrofolate for the vital methylation of homocysteine in methionine biosynthesis.


Achondroplasia is a rare skeletal dysplasia characterized by rhizomelic short stature, whose prevalence is about 1 per 25,000 births. For some patients with achondroplasia, excess body weight is one of the major concerns due to an impaired linear growth. Epidemiological studies revealed a premature onset of cardiovascular or cerebrovascular events in achondroplasia. An association between obesity and cardiometabolic risk factors related to cardiovascular events remains unknown in patients with achondroplasia/hypochondroplasia. This cross-sectional study investigated anthropometric measurements, body compositions and cardiometabolic risk factors in pediatric patients with achondroplasia/hypochondroplasia. Thirty-two patients with achondroplasia and ten with hypochondroplasia aged between 1.9 and 18.7 years were enrolled in this study. Half of the participants presented at least one cardiometabolic abnormality. Elevated systolic blood pressure was the most common abnormality. None of the participants developed metabolic syndrome or type 2 diabetes mellitus. Body mass index-standard deviation score and hip/height ratio were strongly correlated with percent body fat assessed by dual energy X-ray absorptiometry although no significant association was found between anthropometric measurements or body fat mass and any cardiometabolic risk factors. No significant difference in body fat mass, as well as body mass index-standard deviation score and hip/height, was found between cardiometabolically normal group and cardiometabolically abnormal groups. These results suggest that not only weight gain and hip/height changes should be monitored but also individual cardiometabolic risk factors should be evaluated to avoid cardiometabolic events in the healthcare management of pediatric patients with achondroplasia/hypochondroplasia.


CuInS2 is a chalcogenide ternary semiconductor, an efficient absorber material for solar cell application. In the present work, CuInS2 thin film (Cu/In=0.5) have deposited on pre-heated glass substrate at a growth temperature of 350˚C by cost-effective spray pyrolysis technique. The as-deposited film was annealed in vacuum at 200˚C for 1 hour. The effect of vacuum annealing on structural, optical and electrical properties of CIS thin has been investigated. Chalcopyrite structure of CIS film was confirmed by XRD analysis. Non- stoichiometric behaviour was observed by EDAX measurement demonstrating the presence of additional phases in CIS film. The absorption co-efficient of the sprayed CuInS2 film was found to be in the order of 10 4 cm -1 and the optical bandgap varies from 1.47 eV to 1.51 eV for as-deposited and annealed film respectively. Photoluminescence analysis reveals that the emission was mainly due to donor-acceptor pair transitions. The resistivity of CIS film varies extensively with annealing temperature.


Driving simulators play an important role in vehicle research. However, existing virtual reality simulators do not give users a true sense of presence. UniNet is our driving simulator, designed to allow users to interact with and visualize simulated traffic in mixed reality. It is powered by SUMO and Unity. UniNet's modular architecture allows us to investigate interdisciplinary research topics such as vehicular ad-hoc networks, human-computer interaction, and traffic management. We accomplish this by giving users the ability to observe and interact with simulated traffic in a high fidelity driving simulator. We present a user study that subjectively measures user's sense of presence in UniNet. Our findings suggest that our novel mixed reality system does increase this sensation. Author


The technique of amplitude variation with offset (AVO) allows geoscientists to extract fluid and lithology information from the analysis of prestack seismic amplitudes. Various AVO parameterizations exist, all of which involve the sum of three weighted elastic-constant terms. In present-day AVO approaches, the weighting terms involve either knowledge of the incidence angle only, or knowledge of both the incidence angle and the in situ VP/VS ratio. We have used the theory of poroelasticity to derive a generalized AVO approximation that provides the estimation of fluid, rigidity, and density parameters. We have combined two previously independent AVO formulations, thus reducing, instead of adding to, the total number of formulations. This new approach requires knowledge of a third parameter to compute the weights: the dry-rock VP/VS ratio. We have derived a new equation and applied it to model and real data sets. The new formulation has allowed us to estimate fluid properties of the reservoir in a more dire...


In this study, polymerization reaction between glycerol monostearat (1g, 0.002mol) with azelaic acid (2g, 0.005mol) carried out. Production process of this polymer is made in temperature 60-80?C and pressure (~150Pa) by using Novozym's enzyme catalyst 435 for 3 hours. Starting material is glycerol monostearat (MAG) produced through esterification reaction in temperature 60-80?C for 4 hours by using enzyme catalyst are Rhizomucor miehei and Lipozim TL IM. After that  purification of MAG carried out through winterization process by using centrifugal that separate MAG and hexane solution. It kept at 0?C for 24 hours until precipitation formed through centrifugation (3,500 rpm, 20 means, 4?C). After MAG produced, it will analyzed by HPLC and found as much as content 100% of both MAG. Further analysis are 1H and 13C NMR and FTIR to know absorption spectrum and peak produced from MAG and polymer.


Contrary to popular belief, online music services including Apple Computer Inc.'s iTunes Music Store do not turn in huge profits. In the case of Apple, out of the 99 cents that is being charged for a song, about 65 cents goes to the music label that recorded it. Another 25 cents goes for distribution costs and the rest goes to marketing, promotion, and other expenses. To make more money, many musical artists have begun selling their music on their own Web sites. Instead of going to major record labels, others are turning to one another. A prime example is MUDDA (Magnificent Union of Digitally Downloading Artists), which acts as an online collective for artists to sell their music directly to the public. There are other ways digital music will make money for its artists. One of the most sophisticated is an artist-authorized equivalent of the concert tapes that fans have always made. A new service, eMusicLive, will make a recording at a live concert and then sell it on a CD or USB key drive to departing patrons, minutes after the last encore. For more and more musicians, the fruits of new technologies may get the rent paid better than traditional recording contracts.


The Metropolis-Hastings (MH) algorithm is a way to sample a provided target distribution pi(z). It works by repeatedly sampling a separate proposal distribution T(x,x') to generate a random walk {x(t)}. We consider a modification of the MH algorithm in which T is dynamically updated during the walk. The update at time t uses the {x(t' less than t)} to estimate the product distribution that has the least Kullback-Leibler distance to pi. That estimate is the information-theoretically optimal mean-field approximation to pi. We demonstrate through computer experiments that our algorithm produces samples that are superior to those of the conventional MH algorithm.


INTRODUCTION
First-degree relatives ofcolorectal cancer patients have higher risk of disease, thus colonoscopic screening should be started at the age of 40 in this group. Goal of the study was to assess their awareness of the colorectal cancer risk factors and their compliance with colorectal cancer screening programme.

METHODS
62 patients after colorectal cancer resection and their 67 first-degree relatives (42% out of 160 addressed) answered structured questionnaire and counselling focused on colorectal cancer risk factors, and screening participation.

RESULTS
Before diagnosis of colorectal cancer only 18% of colorectal cancer patients (11/62) were aware of its risk factors, after diagnosis their awareness increased to 65% (40/62, p < 0.001). Before questionnaire 46% of first-degree relatives (31/67) were aware of colorectal cancer risk factors, after counselling awareness increased to 66% (44/67, p = 0.024). 79% (53/67) offirst-degree relatives were aware of their increased familial risk. 28% (19/67) of first-degree relatives enrolled for colorectal cancer screening. Most frequent screening method was fecal occult blood test (FOBT) in 21% (14/67) of first-degree relatives, colonoscopy was performed only in 7% (8/67) of first-degree relatives. Average age of screening participation was 53 years. 22% (15/67) of first-degree relatives refused any screening in the future.

CONCLUSIONS
We have found low awareness of colorectal cancer risk factors in colorectal cancer patients and their relatives before their diagnosis of disease respectively before their counselling. First-degree relatives are aware of their increased risk, however their screening participation is unsatisfactory. Screening is performed only in minority of first-degree relatives, often late and with inappropriate modality (FOBT). 22% of first-degree relatives refused any screening in spite of their increased colorectal cancer risk.


Impressions about the quality and reliability of products can depend as much on perceptions concerning brand and country of origin (quality cues) as on the evidence of hard data regarding performance and failure (quality attributes). Although the distinction between quality cues and quality attributes is a traditional area of research in marketing, and more specifically in the study of customer behaviour and preferences, it has not previously been investigated within the context of international technology transfer. In this paper we first use research in the machine tool sector to illustrate this country-of origin effect formation process based on surveys among UK and Chinese companies with experience of technology transfer and use of end-products. We then explore the implications for Volvo as an established Western automotive brand that has been acquired by the Chinese company Geely Automobile Holdings, and which is transferring design and manufacturing technology to enable production of new models in China as well as Europe. This uses a survey in Taiwan to establish opinions about Swedish-made and Chinese-made Volvos across a range of purchasing factors. The results reveal some important differences of opinion among nearly all these various factors.


Credit risk assessment has been one of the most appealing topics in banking and finance studies, attracting both scholars' and practitioners' attention for some time. Following the success of the Grameen Bank, works on credit risk, in particular for Small Medium Enterprises (SMEs), have become essential. The distinctive character of SMEs requires a method that takes into account quantitative and qualitative information for loan granting decision purposes. In this chapter, we first provide a survey of existing credit risk assessment methods, which shows a current gap in the existing research in regards to taking qualitative information into account during the data mining process. To address this shortcoming, we propose a framework that utilizes an XML-based template to capture both qualitative and quantitative information in this domain. By representing this information in a domain-oriented way, the potential knowledge that can be discovered for evidence-based decision support will be maximized. An XML document can be effectively represented as a rooted ordered labelled tree and a number of tree mining methods exist that enable the efficient discovery of associations among tree-structured data objects, taking both the content and structure into account. The guidelines for correct and effective application of such methods are provided in order to gain detailed insight into the information governing the decision making process. We have obtained a number of textual reports from the banks regarding the information collected from SMEs during the credit application/evaluation process. These are used as the basis for generating a synthetic XML database that partially reflects real-world scenarios. A tree mining method is applied to this data to demonstrate the potential of the proposed method for credit risk assessment.


This study shows how the theory of Frame Semantic developed by Fillmore & Baker (2010) can help to describe and analyze different kinds of frame elements of Sundanese verb evoking the 'fall down' frame. Many ways can be found in Sundanese verbs for evoking 'fall down' frame due to their variation in frame elements. This study applied a descriptive qualitative method, and the data are ten Sundanese lexis that evokes the frame 'fall down' collected as the unit of analysis. The main findings show that Sundanese verb, which evokes the 'fall down' have different frame elements. These differences of frame elements, including the part of the body, which fall down, the cause of falling and the direction of falling. Therefore, the detail frame elements in describing how the verb in Sundanese evokes the frame 'fall down' enrich the Sundanese vocabularies, which evoke the 'fall down' frame.
Keywords: frame, frame elements, frame semantic


Acoustic tracking of fishes has been conducted for several decades, but within the last 20 years technology has advanced greatly and many researchers have shifted to long-term (multi-year) passive monitoring studies as opposed to active tracking. The number of publications produced using this approach has varied over the last 20 years with dramatic increases in publications using passive telemetry data since the late 1990s. Passive monitoring has been used to address a wide array of topics including behaviorally focused research into home range analysis and presence patterns, physiological studies and technical uses of equipment or methodology. Studies have included over 80 different species including invertebrates, teleost and chondrichthyan fishes, marine reptiles and marine mammals. Research has been conducted in marine, estuarine, and freshwater systems with varying habitats and substrate. This diverse set of studies represents a wide array of research applications and uses of this technology. This text examines the use of acoustic technology and passive acoustic arrays to define where the technology began, describe past advances and comments on the future use of this technology in marine and aquatic ecology.


In this study, 43 μm 316L stainless steel and 23 μm commercial purity Fe feedstocks were used. The following coatings were made by cold spray: single component 316L, Fe, and their binary composites with nominal compositions of 20 wt.% Fe (20Fe), 50 wt.% Fe (50Fe) and 80 wt.% Fe (80Fe). The coatings were characterized (microstructure, flattening ratio, composition) and the cold sprayability metrics (DE, porosity, coating cohesion strength) were analyzed. Results show that the single component 316L coating has a much better DE and coating cohesion strength, and a slightly lower porosity as compared with the Fe coating, whereas all the composite coatings have the similar cohesion strength. Moreover, the 20Fe coating features the highest porosity and the lowest DE; 50Fe coating features the lowest porosity; and the 80Fe coating features the highest DE. To characterize the feedstock mixture composition, in addition to the usual approach of weight or volume fraction, the ratio of the 316L and Fe particle numbers in a mixture (i.e. particle number fraction), was calculated. Using this metric, the effects of the feedstock mixing composition on the cold sprayability of bimodal size 316L/Fe powder mixtures can be better explained.


The ill health and profound disadvantage of Indigenous Australians, particularly of Indigenous children, is well documented, persistent and inadequately addressed. Aboriginal and non-Indigenous professionals and advocates have long called for necessary long-term commitment to and adequate resourcing of health, housing, education, employment and development. Communities have long demanded support for structures for civil society; sustainable environments; respect for cultural diversity; investment in social and human capital; access to high-quality, appropriate child and adult education; and equality of opportunity in the face of enormous disadvantage. Reams of recommendations have been listed, skimmed, ignored and filed — any number of which, if put into practice, could have made a sustainable difference on the ground for Indigenous Australians


ABSTRACT This study contributes to the fresh food supply chain system due to the lack of carbon emissions and food waste reduction that the prior studies neglected. This study examines a fresh-food supply chain system with multiple farmers, a single processor, multi-distributor, customers, and multiple periods. This paper presents a mixed-integer linear programming to optimize total purchasing, inspection, food waste, packing, cold storage, transportation, and carbon emission costs by optimizing product inventories and deliveries. The model is also validated to provide insights into relevant industries. The results show that the total distribution cost from distributor to customers, the total purchasing cost, and total packaging cost are 38.68%; 25.87%; and 16.84%, respectively. In addition, sensitivity analyzes show that the total costs and emissions are significantly affected by the variance in temperature control, carbon punishing cost, and vehicle types. Furthermore, this research can guide the decision-makers by considering the influence of these parameters. Graphical abstract


In this work, we propose a CNN-based approach to estimate the spectral reflectance of a surface and the spectral power distribution of the light from a single RGB image of a V-shaped surface. Interreflections happening in a concave surface lead to gradients of RGB values over its area. These gradients carry a lot of information concerning the physical properties of the surface and the illuminant. Our network is trained with only simulated data constructed using a physics-based interreflection model. Coupling interreflection effects with deep learning helps to retrieve the spectral reflectance under an unknown light and to estimate the spectral power distribution of this light as well. In addition, it is more robust to the presence of image noise than the classical approaches. Our results show that the proposed approach outperforms the state of the art learning-based approaches on simulated data. In addition, it gives better results on real data compared to other interreflection-based approaches. © 2018 Optical Society of America


Knowledge about future process properties is crucial for the development of safe and economic products with load carrying structures. Real processes are influenced by uncertainty what causes scattering and deviation from assumed values. As a consequence, products are often oversized or even product failures can occur. To control uncertainty, extensive knowledge about future processes is necessary in the development process. This paper shows an approach for the representation of uncertainty in production-and usage-processes, according to scattering properties and their cause and effect relations. This approach is used as a common platform for storing, locating, comparing and reuse of knowledge about uncertain properties and their relations. The core of the proposed approach is an ontology-based information model with the ability to represent different levels of trusted information in relation to process parameters and cause and effect relations.


Since 1993, Korea Institute of Design Promotion has carried out Design Promotion Comprehensive Plan every 4 years and due to the institutes founding purpose the plans are mainly focused on enhancing quality of merchandise goods. However due to social and economic changes now enhancing quality of cultural living through design is becoming important as ever. The purpose of this paper is to find our characteristics and changes in design policies and programs to diffuse design culture in the plans. The researchers have inquired proceeding studies on cultural and design policies and also looked into cases that were carried out in Europe to diffuse design culture. By analyzing EU`s Cultural Policies four means were found: Education, Exchange, Participation, and Sharing. The results are as follows. First, in the beginning main focus was to educate people about the importance of design and what good design is, in bureaucratic ways. In the Secondary plan, reaching out to local regions begin to show in order to diffuse design culture that was and still is mainly centered around Seoul. Thirdly plan shows more exchanges but not only limited to domestic regions but international wide. In the Forth plan, participation programs and those engaging design to solve social problems are shown but still not much attention is payed to sharing.


Background: The relation of HRT (hormonal replacement therapy) with respiratory symptoms is not understood; women using HRT appear to have more respiratory symptoms but better lung function. Methods: This analysis included 1686 women 45-56 years participating in ECRHS II. Logistic and linear regressions were conducted to investigate the association between HRT (n=388) and lung function and respiratory symptoms while adjusting for BMI, age, smoking, center and height. Results: Menopausal women using HRT had higher FEV1 (adj diff 70 ml (95%CI=4 to 136)) but no increase in respiratory symptoms (OR=1.00 (0.68 to 1.48)) compared to menopausal women not using HRT. Premenopausal women using HRT had indicated more asthma symptoms (OR=1.65 (0.86 to 3.18)) and indicated lower FVC (adj diff -103 to 16)) than premenopausal women not using HRT. Conclusions: The association between HRT and respiratory health was modified by menopausal status. In this population of women in the perimenopause, HRT appeared to be beneficial for rspiratory health among menopausal women, but possibly led to adverse respiratory outcomes among those still menstruating. The conflicting evidence in the field might be due to lack of account for menopausal status when investigating effects of HRT.


In the literature, it is often assumed that traditional, control-oriented HRM systems are increasingly being replaced by commitment-based HRM systems because the latter generally result in higher firm performance. However, an HRM system's effectiveness may depend on an organisation's external and internal context, and neither control nor commitment HR systems are without disadvantages. Thus, the empirical validity of this claim is not clear ex ante. This paper analyses the empirical diffusion and determinants of control and commitment HRM systems in Germany as well as their impact on HRM outcomes and firm performance. The findings indicate that between the two extreme forms of high-control and high-commitment HRM systems, there are two hybrid forms (long-term-oriented control system and regulated commitment system) that combine elements of both 'pure' systems. Commitment HRM systems outperform the high-control HRM system concerning many HRM outcomes and firm performance measures. However, in direct comparison, the high and the regulated commitment HRM systems do not show substantially different outcomes, indicating that there is no one best way.


The electrostatic precipitator (ESP) is the most widely used of a family of air pollution control devices that primarily exploit electrical forces in the control of particulate emissions. Others are the space-charge precipitator (SCP) (where the electric precipitation field is generated by the particles being collected), the self-agglomerate (SAG) (where oppositely charged particles are induced to agglomerate by the mutual force of attraction), the charged-droplet scrubber (CDS-I) (where drops charged to one polarity collect pollutant particles charged to the opposite polarity), charged-droplet scrubber (CDS-II) (where bipolar drops collect oppositely-charged fine pollutant particles), and charged-drop precipitators (CDP) (where fields generated by charged drops are used to precipitate like-charged fine particles onto electrodes). Using gas-residence time for effective cleaning as a dominant criterion, a broad overview of the relative merits of each of these systems in the control of submicrometer particles is given. Experiments illustrate the SCP and SAG modes. The CDS and CDP configurations are modeled and tested in experiments designed to isolate the relevant collection processes. The characteristic-time approach to interrelating diverse systems identifies the electrofluidized bed (EFB) as yet another configuration, one that is especially attractive for obtaining high efficiency with extremely short residence times.


In this work, we introduce an approach for the reactive scheduling of production systems with bounded uncertain parameters. The proposed method follows a state-space representation for the scheduling problem, and relies on the use of a rolling horizon framework and multiparametric programming techniques. We show that by considering as uncertain parameters the set of variables that describe the state of the system at the beginning of the prediction horizon, we can effectively formulate a set of state-space multiparametric programming problems that are solved just once and off-line. In contrast to existing approaches, the repetitive solution of a new multiparametric problem after each disruptive event is avoided. The results of the parametric optimization are used in a rolling horizon basis without the need for online optimization. The proposed multiparametric programming rolling horizon (mp-RH) approach is applied in the scheduling problem of a network of combined heat and power units (i.e., a unit commitm...


The article studies the key concepts and theories that had been forming the basis of Chilean multilateral diplomacy in 1990-2017. The author describes the essential pillars of Chilean foreign policy towards international organizations and offers its structured model-scheme which allows getting the systematic understanding of the related phenomena.


A forthcoming experiment of low-energy elastic electron proton scattering at the new MESA facility in Mainz is planned to provide a high-precision measurement of the parity-violating polarisation asymmetry. This experiment is expected to lead to a precision determination of the weak mixing angle, competitive with Z-pole data. We discuss the challenges for theory to derive predictions with the required accuracy.


In this paper we derive homogeneous vacuum plane-wave solutions to Einstein's field equations in 4+1 dimensions. The solutions come in five different types of which three generalise the vacuum plane-wave solutions in 3+1 dimensions to the 4+1 dimensional case. By doing a Kaluza-Klein reduction we obtain solutions to the Einstein-Maxwell equations in 3+1 dimensions. The solutions generalise the vacuum plane-wave spacetimes of Bianchi class B to the non-vacuum case and describe spatially homogeneous spacetimes containing an extremely tilted fluid. Also, using a similar reduction we obtain 3+1 dimensional solutions to the Einstein equations with a scalar field.


The electron spin resonance method was employed to study the nature, concentration and kinetics of the disappearance under varying conditions of radicals produced in polyethylene by fast electron irradiation at 77°K. The predominant radical species at 77°K is the alkyl radical —CH2—ĊH—CH2—. On being warmed to room temperature it disappears rapidly, revealing a more stable unidentified radical. The kinetics of the decay at room temperature of both radicals was observed. Their stabilities were found to vary in polyethylene samples of differing physical and chemical properties. G values for these radicals are given. Comparison was made with spectra obtained under similar conditions with two pure paraffins and a pure olefin to evaluate the effect of crystallinity branching, molecular weight and unsaturation. In the olefin there is evidence for a build-up of allyl radicals due to the encounter of an alkyl radical with main chain unsaturation. This supports the view that alkyl radicals are mobile, and cross-linking occurs when two such radicals meet.


Abstract Spiroxys ankarafantsika, sp. nov. is described from Madagascar in two species of freshwater turtles, Pelusios castanoides and Pelomedusa subrufa. Spiroxys ankarafantsika differs from other species of the genus in having pseudolabial teeth only on the median lobes and no other cuticular prominences, a smooth cuticular collar, deirides as cervical minute spine-like projections, and a gubernaculum without tubes. This is the first record of a nominal species of the genus Spiroxys from the Ethiopian region.


In Gas turbine-based combined cycle power plant market, the customer conducts an economic evaluation of competitive products to decide their buying option. There are different methods to calculate the economics of a power plant like Levelized cost of electricity (LCOE), Net present value (NPV) and payback period.
 LCOE methodology is commonly used for lifecycle cost analyses for combine cycle power plant that covers cost details of the plant and plant performance over the complete lifetime of a power plant from construction to retiring. Typically, it includes a combine cycle power plant ownership costs (Total plant cost and operating & maintenance cost) and combine cycle power output and efficiency. This LCOE method is helpful to compare power generation system that use similar technologies.
 This paper encompasses the LCOE calculation method, assumptions & approach to analyze the impact of key parameters of the electrical generation cost. They key parameters includes combine cycle output, combine cycle efficiency, fuel cost, annual operating hours, capital charge factor, annual operating hours, power plant life, discount rate, nominal escalation rate, operating & maintenance cost. This paper analyses result will provide insights to the customer & Gas turbine-based OEM (Own Equipment Manufacturing) companies to focus on different area/parameters to reduce the unit cost of generating electricity.


In a character analysis of mainstream sociology in Sweden the compulsive character is found to be similar to the characteristics of the behaviour of the rigorous empiricist The choice of paradigm in Swedish sociology is seen as a reaction to smallness. The relationship between social democracy and sociology is described as an unfortunate combination of great expectations and castration anxiety. The identity crisis of sociology in the 1970's is assumed to have two possible outcomes Regression or maturation. Finally there is a vision of a Sociology, of passion.


We aimed to evaluate the Vitamin D, Vitamin B12 and Hemoglobin A1c Levels in patients with T1DM. This study is a retrospective cross-sectional study. We classified patients as <7.0% (good glycemic control) and ≥7% (poor glycemic control) based on HbA1c levels. Moreover, we divided the patients into four groups based on serum vitamin D concentrations. This study included 468 patients (257 females and 211 males) with T1DM. The present study revealed that the prevalence of vitamin D deficiency among children with T1DM was very high (49.57%). We found that the vitamin D, vitamin B12, ferritin, HGB and RBC levels were significantly lower in women than in men. The overall prevalence of poor glycemic control was 6.4%. When the groups we divided according to HbA1c levels were compared; we found that the fasting blood glucose and vitamin B12 were significantly lower, while insulin and Mg levels were significantly higher in the good glycemic control group compared to the poor glycemic control group. We found that as vitamin D increases, HbA1c, insulin and creatinine levels decrease, and vitamin B12 levels increases. The negative correlation of vitamin D levels with insulin levels (r:-0.320, p<0.01) and HbA1c levels (r:-0.187, p<0.01) was statistically significant . Our findings showed that, keeping the vitamin D levels high in T1DM patients is important in regulation of glycemic control. Considering the frequency of pernicious anemia in patients with T1DM, it is important to follow vitamin D, vitamin B12 and HbA1c levels in these patients.


The serum sodium to urinary sodium ratio divided by the (serum potassium)2 to urinary potassium ratio (SUSPPUP formula) reflects aldosterone action. We here prospectively investigated into the usefulness of the SUSPPUP ratio as a diagnostic tool in primary hyperaldosteronism. Parallel measurements of serum and urinary sodium and potassium concentrations (given in mmol/L) in the fasting state were done in 225 patients. Of them, 69 were diagnosed with primary aldosteronism (PA), 102 with essential hypertension (EH), 26 with adrenal insufficiency (AI) and 28 did not suffer from the above-mentioned disorders and were assigned to the reference group (REF). The result of the SUSPPUP formula was highest in the PA group (7.4, 4.2–12.3 L/mmol), followed by EH (3.2, 2.3–4.3 L/mmol), PA after surgery (3.9, 3.0–6.0 L/mmol), REF (3.4 ± 1.4 L/mmol) and AI (2.9 +/− 1.2 L/mmol). The best sensitivity in distinguishing PA from EH was reached by multiplication of the aldosterone to renin-ratio (ARR) with the SUSPPUP formula (92.7% at a cut off > 110 L/mmol), highest specificity was reached by the SUSPPUP determinations (87.2%). The integration of the SUSPPUP ratio into the ARR helps to improve the diagnosis of hyperaldosteronism substantially.


If social movements in West Africa are really on a rise one may use the categories of regulation theory to understand some of the backgrounds of this rise. The relatively stable formation that came into being in the 1990s with the African version of the neoliberal state at its center is coming to its end. It was able to integrate and tame social movements in its regulatory institutions. However, the rise of movements such as those against the high prices of basic necessities and those of peasants against landgrabbing and for a re-appropriation of family based agriculture are indicators of its disintegration.


A study is made of various traffic processes associated with Markovian queuing systems, and the moments of the traffic processes are analyzed. The purpose of the study is to develop a means of computing the moments efficiently so as to extend the conventional method of representing the traffic processes to a larger class of queuing systems. As an outcome of the analysis, the recurrence formulae for computing the moments including cross-covariances between multiple traffic processes are derived and expressed in terms of the infinitesimal generator, steady-state probability vector of the Markovian queuing system and a matrix describing traffic rate. The main feature of the analysis is in the utilization of the special block-partitioned structure of the matrices involved. The results are of wide application for the study of various telecommunication networks. Two examples of applications for the Markovian queuing model with batch arrivals and a multislot integrated services system are presented. >


Ambroxol (A) is used in the treatment of patients with pulmonary diseases. Apart from mucolytic activity the efficacy of A may be due to its immunomodulatory properties. The aim was to study the efficacy of A in treatment of patients with chronic obstructive pulmonary disease (COPD). Methods: The study included 52 patients with exacerbations of COPD. Bronchoalveolar lavage fluid (BALF) obtained during bronchofiberoscopy was examined for the determination of cell composition and immunoglobulins (Ig) concentration. The patients were divided into 2 groups. 25 patients with COPD received standard therapy (antibiotics, bronchodilators, glucocorticosteroids) and A inhalations. The other 27 patients received standard therapy and inhalations with placebo (sodium chloride solution). Results: In patients with COPD exacerbations the content of alveolar macrophages and the level of Ig in BALF were reduced. The use of A as a part of combined therapy for COPD exacerbation decreased the intensity of clinical symptoms, increased the level of Ig and the content of alveolar macrophages in BALF. In the case of standard therapy disorders in the local immunity and cell composition of BALF were maintained, the duration of exacerbation period was longer. Conclusion: Ambroxol administration in COPD exacerbations improved the state of local immunity and cell composition of BALF, increased the treatment efficiency.


This paper presents the application developed for humanoid robots which are used in therapy of dementia patients, as a cognitive stimulation tool. It has been created using BICA, a component oriented framework for programming robot applications, which is also described. The developed robotherapy application includes the control software onboard the robot and some tools like the visual script generator or several monitoring tools to supervise the robot behavior along the sessions. The behavior of the robot along the therapy sessions is visually programmed in a session script that allows music playing, physical movements (dancing, exercises...), speech synthesis and interaction with the human monitor. The monitoring tools allow the therapist interaction with the robot through its buttons, a tablet or a Wiimote device. Experiments with real dementia patients have been performed in collaboration with a research center in neurological diseases. Initial results show a slight (or mild) improvement in neuropsychiatric symptoms over other traditional therapy methods.


Methemoglobinemia is a condition characterized by increased level of methemoglobin in the erythrocytes and brownish cyanosis. Acquired methemoglobinemia is diagnosed by elevated methemoglobin with normal hemoglobin electrophoresis and normal NADH cytochrome b5 reductase. We report a patient who developed lethargy, confusion, and cyanosis during post-operative period. He had arterial methemoglobin level of 40.6% and oxygen saturation of 59%. No other cause could be found for his methemoglobinemia other than metoclopramide, even though it is rarely reported to cause methemoglobinemia in adults compared to infants. He had an excellent clinical response to treatment with methylene blue with which his clinical symptoms improved and the methemoglobin level returned to normal within 24 hours. Here we discuss the clinical features, diagnosis, and treatment of acquired methemoglobinemia induced by metoclopramide.


The cerebrospinal fluid (CSF) penetration of ofloxacin given orally or or intravenously was studied in cancer patients without meningitis. Each patient was assigned to a different sampling time to assess the relation between time and penetration. Ofloxacin was measured in serum and CSF by high-pressure liquid chromatography and bioassay. In addition, the bactericidal titers were measured in CSF and serum against a set of relevant bacteria. Concentrations measured by high-pressure liquid chromatography and bioassay were well correlated. Peak concentrations in CSF (0.4 to 1 microgram/ml) were observed 2 to 4 h after infusion or oral administration. Peak concentrations in serum were observed just after infusion (2 to 3.5 micrograms/ml) or 1 to 2 h after oral administration (1.7 to 4 micrograms/ml). Measured bactericidal titers were well correlated with the titers expected from the MBC and concentration. High CSF bactericidal titers were observed against Neisseria meningitidis, Haemophilus influenzae, and Escherichia coli, whereas low or no bactericidal titers were obtained against Staphylococcus aureus, Listeria monocytogenes, and Streptococcus pneumoniae.


abstract A method is presented for investigating the seismic response of multiple-story shear buildings on flexible elastic foundation media which are represented by an elastic half space. It is shown that the frequency dependent dynamic properties of the foundation medium may be assumed to be constant with respect to the frequency. This assumption leads to equations of motion with constant coefficients which are solved numerically. A study of several structure-foundation systems indicates that the flexibility of the foundation medium can increase or decrease the flexural response of the structure compared to the case of the rigid foundation.


The present study investigated how 96 children who have witnessed homicidal violence remember and report their experiences. The aims of the study were to describe the children's reporting pattern and to investigate background factors that could affect the children's reporting. Police interviews with the children were analysed regarding the amount and type of information reported, as well as frequency of denial, withholding and claims of memory loss. Results showed that the majority of children provided detailed reports about the homicidal violence they had witnessed, including critical details about the abuse. Results also revealed that the child's relationship to the perpetrator or the victim did not affect the children's reporting pattern, indicating that the children's willingness to report exceeds strong impact factors such as loyalty conflicts. These findings are applicable in different legal contexts dealing with child witnesses and can be used as guidance when interviewing children and evaluating their testimony.


: Exogenic somatotropin increases the body weight gain in the inverse dependence on the taken dose and decreases the weight of the adenohypophysis in direct dependence on the dose in thyroidectomized male rats. The content of somatotropin in the adenohypophysis and incorporation of labelled amino acids into the adenohypophysis rises under the effect of exogenic somatotropin. But when the dose of the latter is increased, these indexes drop.


The evolution of flood activity with global warming remains uncertain. To better assess flood–climate relationships, lake sediments are increasingly being investigated because they could provide regional flood histories long enough to cover past climate changes. However, site‐specific sedimentary processes may bias flood reconstructions. The aim of this article is to investigate these effects through the reconstruction of two distinct flood records from independent, neighbouring sedimentary basins of the same lake (Lake Allos in the Mediterranean French Alps), i.e. under the same climate conditions. Understanding of sedimentary processes is crucial in order to adapt the sampling strategy and the flood‐intensity proxy to each sedimentary system and, thereby, reconstruct a complete and reliable flood history. Thanks to this detailed approach, the main trends of the regional flood variability can be reproduced; i.e. periods of high flood‐frequency, ranges of flood‐frequency values and timing of the most intense events. In detail, some differences appeared associated to the various stream capacities to erode and transport flood sediments to the lake system, implying variable sensitivity of sedimentary systems in recording floods. Comparing regional flood records based on independent sedimentary systems from similar environments could thus be a complementary approach to assessing past flood intensity. Such an approach could open particularly interesting perspectives because reconstructing the long‐term evolution of flood intensity is a key challenge in the geosciences.


To implement the nutrition labeling provisions of the Patient Protection and Affordable Care Act of 2010 (Affordable Care Act or ACA), the Food and Drug Administration (FDA or we) is requiring disclosure of certain nutrition information for standard menu items in certain restaurants and retail food establishments. The ACA, in part, amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act), among other things, to require restaurants and similar retail food establishments that are part of a chain with 20 or more locations doing business under the same name and offering for sale substantially the same menu items to provide calorie and other nutrition information for standard menu items, including food on display and self-service food. Under provisions of the ACA, restaurants and similar retail food establishments not otherwise covered by the law may elect to become subject to these Federal requirements by registering every other year with FDA. Providing accurate, clear, and consistent nutrition information, including the calorie content of foods, in restaurants and similar retail food establishments will make such nutrition information available to consumers in a direct and accessible manner to enable consumers to make informed and healthful dietary choices.


: Extra-regional linkages can benefit regional development by introducing supplement resources and technologies. They also enrich the local knowledge base, keeping regions away from depression due to lock-in effects. Global - local interaction (GLI) research represents the academic effort to theorize this process by examining the interplay between a wide array of actors at multi-scales within particular territorial confines. It raises four critical questions regarding the conditions, regional differences, channels, and actors for interaction. The literature has documented that the relatedness between local and nonlocal inputs determines the probability of GLI. Local capabilities determine the extent of GLI. The literature also reveals that the leading and most lagging behind regions tend to benefit from GLI. Knowledge diffusion, foreign investment, and international trade are primary elements that support GLI. As one region continues to develop, the immigrants and nonlocal institutions may enrich the GLI. Conventionally, the literature on GLI is firm-centric. Recent advances highlight the role of individuals, such as entrepreneurs and employees. There is also increasing awareness of the non-economic agency, especially the institutional agency. Overall, an in- depth examination is still required for understanding the scales, dynamics, and agencies of GLI for regional development. Grounded in the context of China's regional restructuring and opening- up, this study proposes a framework to model GLI in China and discusses its potential for future studies.


Bone marrow-derived progenitor cells (BMPCs) as well as perivascular progenitor cells have been implicated to differentiate into vascular cells during neointima formation. The objective of this study was to assess the contribution of progenitor cells to the cellular neointimal mass. Wire-induced injury of the femoral artery was performed on chimeric C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein (EGFP). Vessels were harvested at 1, 2, 4, 6 and 16 weeks after dilation (n=8 animals per time point) and analyzed using confocal microscopy. Most of the accumulating EGFP+-cells were identified as inflammatory cells (CD45, CD68), and their number in the neointima declined from 110.81±18.98 at 2 weeks to only 5.31±2.21 at 16 weeks after dilation. Whereas very few EGFP+-cells co-expressed α-smooth muscle actin or CD31, expression of smooth muscle myosin heavy chain or von Willebrand Factor was not detected in BM-derived cells at any time point. Interestingly, a substantial expression of stem cell antigen (Sca)-1 was detected in proliferating EGFP negative cells in the adventitial layer, but only a small fraction of BM-derived cells accumulating at the arterial lesion site co-expressed Sca−1. At 4 weeks after dilation, the absolute number of adventitial Sca-1+-cells increased from 47.88±7.18 cells/slide in non-injured arteries to 158.5±16.656 cells/slide and the fraction of proliferating cells rose to 14.94% of all adventitial cells. Even though recent in vitro data have shown that perivascular progenitor cells lose Sca-1 from their cell surface when differentiating into smooth muscle-like cells, we also detected singular Sca-1+/EGFP--cells within the neointimal lesion, indicating that these cells indeed migrate toward the luminal site. In conclusion, we provide evidence that BMPCs within the neointima rarely co-express markers for vascular cells and do not contribute to the neointimal cellular mass beyond the inflammatory response. In contrast, the high proliferation rates of perivascular progenitor cells indicate a possibly substantial contribution of this cell fraction to the development of the neointimal lesion.


Thomson Reuters' Web of Science (WoS) is undoubtedly a great tool for scientiometrics purposes. It allows one to retrieve and compute different measures such as the total number of papers that satisfy a particular condition; however , it also is well known that this tool imposes several different restrictions that make obtaining certain results difficult. One of those constraints is that the tool does not offer the total count of documents in a dataset if it is larger than 100,000 items. In this article, we propose and analyze different approaches that involve partitioning the search space (using the Source field) to retrieve item counts for very large datasets from the WoS. The proposed techniques improve previous approaches: They do not need any extra information about the retrieved dataset (thus allowing completely automatic procedures to retrieve the results), they are designed to avoid many of the restrictions imposed by the WoS, and they can be easily applied to almost any query. Finally, a description of WoS Query Partitioner, a freely available and online interactive tool that implements those techniques, is presented.


OBJECTIVE
To investigate the factors that affect the outcome of pregnancies complicated with critically heart disease admitt ed to obstetric Intensive Care Unit (ICU).

METHODS
A retrospective study was conducted for 188 pregnant and postpartum patients complicated with heart disease who were admitted to the ICU in West China Second University Hospital from July 2009 to March 2013.

RESULTS
During the 4 years, there were 619 cases of pregnancy complicated with heart disease hospitalization. Among them, 188 (30.37%) patients complicated with severe heart disease were admitted to the ICU, accounting for 39.17% of the total ICU admission (480); the mean maternal age was (28.45 ± 6.08) years old and the mean gestational time was (36.03 ± 4.19) weeks. 23 (12.23%) patients received regular antenatal care in our hospital. 61 (32.45%) patients never received antenatal care before hospitalization. Among them, 5 patients were dead. The ratio for diagnosis of heart disease before pregnancy, during pregnancy and after admission were 39.89%, 25.54% and 34.57%, respectively; the most common heart diseases during pregnancy were congenital cardiac disease (80, 42.55%) and rheumatic heart disease (45, 23.94%) followed by arrhythmias (20, 10.64%). The most common complication were pulmonary arterial hypertension (51, 27.13%), arrhythmias (47, 25.00%) and severe heart failure (30, 15.96%); the cardiac function of 164 (87.23%) patients was at stage I-II and 5 (2.66% ) patients died when discharged from hospital. 151 (80.32%) patients received multidisciplinary consultation and 34 (18.09%) used central venous catheterization to control central venous pressure (CVP). 21 (11.17%) patients required mechanical ventilation. 11 (5.85%) patients required emergency life support (cardiopulmonary resuscitation 9 + electric defibrillation 3).

CONCLUSION
Pregnancy complicated with heart disease is the leading reason for admission to ICU. The congenital cardiac disease, rheumatic heart disease and arrhythmias are the main heart diseases during pregnancy. Multidisciplinary cooperation and intensive care are the key measures to improve the outcomes of patients with critically illness. It is very important for reduction of the maternal mortality rate through strengthening preconception care and antenatal care.


This project is a result of a variety of work done in the previous, the main themes for the variety of work were varied. They were about body illusion instution with its multi and complicated problem, and other problems, and other problems reated to gender aspect, political aspect, social aspect, tradition, religion, and many other. The purpose of the project was to recognize the true meaning of the borderless life after death. In order to recognized its true meaning, the traditional rituals and religion body management were used as the bases to analyze the idea of borderless life after death was perceived as a social-cultural phenomenon and as a tradition. In this project, death is defined as the borderline between the In this project, a painting –as the artwork – was chossen to express the idea of borderless life after death visually. The basic idea of borderless life after death itself was analize using relevant methodology, theories, and empirical studies. In contrast, the concept of the artwork expressing the ideas such as borderless life after death, the life of soul in the erternal realm, the travel of soul to its original realm, an death as the borderline between the zone of worldly life and the borderless borderless life after death. The use of idioms in painting such as foggy white colour, smoky white colour, and some objects are for the aesthetic purpose where as the dances in the painting symbolize the aesthetical purpose where as the dances in the painting symbolize the aesthetical values, not sadness, Altogether, these elements construct the idea of borderless life after death. In conclusion, death should not be preceive as a frightening phenomenon but as a sacred, religious, and aesthetic celebration. worldly life zone and the zone of the borderless life after death. From this pont of view tradition, death is regarded as an event to celebrete the return of the soul to the eternal realm. It can be verivied by the fact that  there are many artistic symbols representing death , thus making it as new realty.


Objective
To assess the malaria transmission risk in the border area of Yunnan Province and provide evidence for adjustment of malaria intervention and elimination strategies.

Method
Data concerning malaria prevalence, vector distribution, and institutional intervention capacity were collected in 197 towns of 20 counties in the border area of Yunnan Province during 2012-2014. The malaria transmission potential index (TPI), intervention capacity index (ICI) and malaria risk index (MRI) were calculated for each town, based on the criteria formulated by a professional committee. The towns were categorized according to the indices aforementioned. The risk map was created with GIS software.

Results
Based on the TPI, the 197 towns comprised of 2 grade-I towns (including Nabang in Yingjiang and Banlao in Cangyuan) with high transmission potential, 11 grade-II towns with moderate transmission potential and 184 grade-III towns with low transmission potential. Based on the ICI, the 197 towns comprised of 4 grade-III towns (including Zhongke in Ximen, Zhonghe and Diantan in Tengchong, and Menghan in Jinghong) with a weak control capacity, 20 grade-II towns with a moderate control capacity and 173 grade-I towns with a strong control capacity. Based on the MRI, the 197 towns comprised of 2 grade-I towns (including Nabang in Yingjiang, and Banlao in Cangyuan) with a high transmission risk level, 12 grade-II towns with a moderate level and 183 grade-III towns with a low level distributed in 20 counties.

Conclusion
The grade I or II towns with moderate and high transmission risk constitute <5% of the 197 towns in the border area, suggesting a relatively low level of malaria transmission risk in most counties.


Following surgery for early breast cancer, the standard of care for postmenopausal women is adjuvant therapy with any combination of radiation therapy, endocrine therapy, chemotherapy and/or targeted therapy. Clinicians rely on many tools, including guidelines, to make these treatment decisions. Such guidelines include the St Gallen consensus statement, the American Society of Clinical Oncology guidelines and the National Comprehensive Cancer Network guidelines, as well as various regional and national guidelines. Recommendations may vary, because different methods and criteria were used to assess the strength of supporting data. This article provides an overview of global guidelines for the adjuvant treatment of breast cancer and points out the major differences. Ongoing changes are highlighted, particularly those regarding the adjuvant endocrine treatment of postmenopausal women with breast cancer. While previous guidelines recommended tamoxifen alone, all major guidelines now recommend using third-generation aromatase inhibitors either in sequence with tamoxifen or as upfront treatment.


Neuron activity alters the state of white matter in the mammalian brain. [Also see Research Article by Gibson et al.] As we learn and experience the world around us, our brains are remodeling neuronal pathways. Is this remodeling only a property of neurons, or are other brain cell types also adapting and contributing to learning? A substantial proportion of cells in the mammalian brain are oligodendrocytes and their precursors (collectively called oligodendroglia). Oligodendrocytes generate multiple myelin sheaths, lipid-rich extensions of specialized plasma membrane that spirally coat condensed layers around neurons. This insulation facilitates rapid nerve conduction, increasing velocities of neuron signals 10-fold (1) by restricting current flow to the small gaps between sheaths—the nodes of Ranvier. More than half of the human brain is composed of myelinated nerves ("white matter"). With such extensive myelinated neural networks, it raises the questions: Do the myelin-producing oligodendrocytes in the brain also adapt as neural circuits are modified in response to activity, and does adaptation of oligodendrocytes then affect the underlying neural circuits? On page 487 of this issue, Gibson et al. (2) provide new evidence to address how neuron activity may promote oligodendroglia changes.


The rate of acid production and end-products from sorbitol were measured under anaerobic conditions in washed-cell suspensions of oral strains of Lactobacillus casei subsp. casei and Lactobacillus casei subsp. rhamnosus. The enzymatic activities were assayed in cell extracts of these strains. The cells fermented sorbitol to lactate, formate, ethanol and acetate under anaerobic conditions. Exposure of the cells to air (oxygen) led to inactivation of pyruvate formate-lyase and inhibition of anaerobic sorbitol fermentation. In the presence of acetate, air-exposed cells fermented sorbitol with a concomitant consumption of acetate and production of ethanol and lactate. Acetate also enhanced acid production from sorbitol in cells kept under anaerobic conditions and resulted in formation of lactate and ethanol. Cell extracts of all the strains had NADH-coupled acetate-reducing activity, which consisted of sequential reactions of acetate kinase, phosphotransacetylase, acylating aldehyde dehydrogenase and alcohol dehydrogenase. These findings indicate that oral lactobacilli can utilize acetate as an electron acceptor for maintaining their intracellular redox balance during anaerobic sorbitol fermentation in the absence of pyruvate formate-lyase activity.


BACKGROUND
Orofacial pain, headaches, and neck pain are very common pain conditions in the general population and might be associated in their pathophysiology, although this is not yet clarified. The development and validation of a prediction inventory is important to minimize risks. Most recent questionnaires have not focused on pain, but pain is the common symptom in temporomandibular disorders, headaches, and neck pain. It is necessary to provide tools for these conditions.

OBJECTIVES
The purpose of this study is to present the development and analysis of the factorial structure and psychometric properties of a new self-administered questionnaire (Craniofacial Pain and Disability Inventory [CF-PDI]) designed to measure pain, disability, and functional status of the mandibular and craniofacial regions.

STUDY DESIGN
Multicenter, prospective, cross-sectional, descriptive survey design. A secondary analysis of the reliability of the measures was a longitudinal, observational study.

SETTING
A convenience sample was recruited from a hospital and 2 specialty clinics in Madrid, Spain.

METHODS
The study sample consisted of 192 heterogeneous chronic craniofacial pain patients. A sub-sample of 106 patients was asked to answer the questionnaire a second time, to assess the test-retest reliability. The development and validation of the CF-PDI were conducted using the standard methodology, which included item development, cognitive debriefing, and psychometric validation. The questionnaire was assessed for the following psychometric properties: internal consistency (Cronbach's α); floor and ceiling effects; test-retest reliability (Intraclass Correlation Coefficient [ICC]; Bland and Altman method); construct validity (exploratory factor analysis); responsiveness (standard error of measurement [SEM] and minimal detectable change [MDC]); and convergent validity (Pearson correlation coefficient), by comparing visual analog scale (VAS), the Tampa Scale for Kinesiophobia (TSK-11), the Pain Catastrophizing Scale (PCS), the Neck Disability Index (NDI), and the Headache Impact Test-6 (HIT-6). Multiple linear regression analysis was used to estimate the strength of the associations with theoretically similar constructs.

RESULTS
The final version of the CF-PDI consists of 21 items. Exploratory factor analysis revealed 2 factors ("pain and disability" and "jaw functional status"), both with an eigenvalue greater than one, explaining 44.77% of the variance. Floor or ceiling effects were not observed. High internal consistency of the CF-PDI (Cronbach's α: 0.88) and also of the 2 subscales (Cronbach's α: 0.80 - 0.86) was confirmed. ICC was found to be 0.90 (95% confidence interval [CI] 0.86 - 0.93), which was considered to be excellent test-retest reliability. The SEM and MDC were 2.4 and 7 points, respectively. The total CF-PDI score showed a moderate correlation with most of the assessed questionnaires (r = 0.36 - 0.52) and a strong correlation with the NDI (r = 0.65; P < 0.001). The NDI, VAS, and TSK-11 were predictors of CF-PDI.

LIMITATIONS
Only self-reported measures were considered for convergent validity. Future research should use physical tests to explore the clinical signs relating to pain and disability.

CONCLUSION
The CF-PDI showed good psychometric properties. Based on the findings of this study, the CF-PDI can be used in research and clinical practice for the assessment of patients with craniofacial pain.


According to the features of optical fiber localizer image,a precise measurement method for detecting the geometry character based on Hough transform was proposed.After energy field edges being detected,geometry element equations of circularity and lines were obtained by improved Hough transform,then the accurate geometry characters such as the position of points of intersection were obtained.The experiment results show that this method can be applied to other geometry character detection problems in noise included image,and the algorithm is efficient and robust.


Meru Betiri forest in Jember contains a lot of medicinal plants. Irvingia malayana (Pauh Kijang), which is one of the medicinal plants found, has been proven as an antimalarial. However, phytochemical and antimalarial studies of Irvingia malayana have never been carried out. This study was conducted for an antimalarial Drug Discovery through phytochemical study by isolating the roots, stems, and leaves of Irvingia malayana. From the analysis using FTIR, H-NMR, and GC-MS, it was concluded that the compound in the ethyl acetate extract of Irvingia malayana stem was terpenoids that was included in silymarin group as well as other plants in the genus Irvingia. The melting point of Irvingia malayana isolate was 120-121oC with white crystals. Statistical result of in vivo study showed that each group was significantly different. On day 4 after administration, IC50 showed was 11,827 mg/kgBW and day 3 was 6,927 mg/kgBW. Therefore, 3 days is the maximum duration of administration in reducing plasmodium and shows the most excellent activity as antimalarial. In in vitro study, IC50 of Irvingia malayana (62.855 ug/ml) has weak activity of antiplasmodium compared to chloroquine positive controls containing IC50 (1,114x10-3 ug/ml). Based on the data of in vivo and in vitro antimalarial activities, the compound had no antimalarial activity because the extract consisted of many components that possessed many possible synergetic mechanisms of antimalarial if compared to single compound.Keywords:


The use of corrosion inhibitors is an important method to retard the process of metallic attack by corrosion. The construction of mathematical models from theoretical-computational and experimental data obtained for different molecules is one of the most attractive alternatives in the analysis of corrosion prevention, whose objective is to define those molecular characteristics that are common in high-performance corrosion inhibitors. This review includes data of corrosion inhibitors evaluated in different media, the most commonly studied molecular descriptors, and some examples of mathematical models generated by different researchers.


Objectives: To describe the trends in and determinants of HIV testing and positivity at genitourinary medicine (GUM) clinics and in general practice (GP) in England between 1990 and 2000. Methods: Data on all first HIV specimens from GUM and GP clinics and tested at seven sentinel laboratories were related to key demographic, clinical, and behavioural variables. Results: During the observation period, 202 892 eligible first HIV tests were reported. 90% (182 746) of specimens were from GUM clinics, of which 55% were from heterosexuals, 12% from men who have sex with men (MSM), and 3% from injecting drug users (IDU). In contrast, only 3% of GP specimens were from MSM and 13% from IDUs. The total number of first HIV tests increased threefold between 1990 and 2000. Overall, 1.6% of GUM and 0.9% of GP first testers were diagnosed HIV positive. In GUM clinics, HIV positivity was highest among heterosexuals who have lived in Africa (11.7%), MSM (6.9%), and IDUs (2.8%) and lowest among heterosexuals with no other specified risk (0.3%). Consistently lower prevalences were observed in GP settings. HIV positivity among GUM first testers declined in MSM, from 13.6% in 1990 to 5.2% in 2000 (p<0.01), and in IDUs, from 7.5% in 1990 to 2.0% in 2000 (p = 0.03). Prevalence remained constant in the groups heterosexually exposed to HIV infection. Conclusions: HIV testing in GUM settings increased over the decade, with a concomitant reduction in HIV positivity among MSM and IDUs. Increased testing among heterosexual first testers overall was not associated with declining positivity.


Touch interactions are now ubiquitous, but few tools are available to help designers quickly prototype touch interfaces and predict their performance. For rapid prototyping, most applications only support visual design. For predictive modelling, tools such as CogTool generate performance predictions but do not represent touch actions natively and do not allow exploration of different usage contexts. To combine the benefits of rapid visual design tools with underlying predictive models, we developed the Storyboard Empirical Modelling tool (StEM) for exploring and predicting user performance with touch interfaces. StEM provides performance models for mainstream touch actions, based on a large corpus of realistic data. Our tool provides new capabilities for exploring and predicting touch performance, even in the early stages of design. This is the demonstration of our accompanying paper1.


Motion blur is one of the most common degradation artifacts in dynamic scene photography. This paper reviews the NTIRE 2020 Challenge on Image and Video Deblurring. In this challenge, we present the evaluation results from 3 competition tracks as well as the proposed solutions. Track 1 aims to develop single-image deblurring methods focusing on restoration quality. On Track 2, the image deblurring methods are executed on a mobile platform to find the balance of the running speed and the restoration accuracy. Track 3 targets developing video deblurring methods that exploit the temporal relation between input frames. In each competition, there were 163, 135, and 102 registered participants and in the final testing phase, 9, 4, and 7 teams competed. The winning methods demonstrate the state-of-the-art performance on image and video deblurring tasks.


Despite tremendous effort, the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) remains poor and therapy options are limited. Recent advances in chemotherapeutic schemes have increased the survival of PDAC patients by a few months only. So far, the success of immunotherapy seen in other cancer types could not be transferred to PDAC. Our group has demonstrated that single agent RIG-I-like helicase (RLH)-targeting immunotherapy induces an anti-tumoral immune response and improves survival in a PDAC mouse model dependent on the induction of immunogenic cell death. In addition, we and others were able to show that tumor cell death induction by RLH ligands is partially dependent on the induction of the pro-apoptotic BH3-only proteins PUMA and NOXA. In the current study we aim at improving therapy response using a combinatorial chemo-immunotherapy (CIT) approach.Tumor cell death induction by gemcitabine, oxaliplatin and 5-fluoruracil (5-FU) alone or in combination with RLH ligands was evaluated in the murine cell line Panc02. The induction of PUMA and NOXA was measured by real-time PCR. The capability of chemo-immunotherapy -induced tumor cell death to activate splenic CD8a+dendritic cells (DC) as well as to induce antigen uptake and cross-presentation was investigated in vitro. Therapeutic efficacy was evaluated in vivo using an orthotopic PDAC mouse model.Gemcitabine, oxaliplatin and 5-FU induced dose-dependent tumor cell death in vitro. however, only gemcitabine lead to an induction of the pro-apoptotic proteins PUMA and NOXA. Simultaneous treatment with gemcitabine and RLH-ligand increased cell death induction without affecting the cytokine secretion substantially. CD8a+ DC activation upon RLH-therapy was not affected by chemotherapy. Of note, antigen uptake as well as T cell priming was increased by chemo-immunotherapy. Most importantly, the survival of orthotopic PDAC bearing mice was significantly prolonged in the chemo-immunotherapy group compared to single agent treatment.Gemcitabine treatment of PDAC induces PUMA and NOXA expression which leads to mitochondrial priming and sensitization towards RLH-induced cell death. chemo-immunotherapy increases the cross-presentation capability of DC in vitro and prolongs the survival of PDAC bearing mice. chemo-immunotherapy is therefore an attractive combinatorial therapeutic approach in PDAC.The project was supported by the Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 179062510 and 329628492 - SFB 1321 as well as the Förderprogramm für Forschung und Lehre (FöFoLe) funded by the Ludwig-Maximilians-Universität München.P. Metzger: None. H.T. Bourhis: None. M. Stieg: None. D. Böhmer: None. S. Endres: None. P. Düwell: None. L.M. König: None. M. Schnurr: None.


Credit: Archives of Bernard Fisher

The US surgeon Bernard Fisher has died at the age of 101. As chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP) he undertook the landmark studies that ended mutilating radical mastectomy and, for primary breast cancer, established preoperative and postoperative chemotherapy and tamoxifen as adjuvant treatments. Fisher, who worked at the University of Pittsburgh, was widely credited with launching the scientific approach, where breast cancer treatments were based on results from research using large scale randomised clinical trial methods. He was one of the first translational clinicians to recognise that laboratory investigations and clinical trials were inexorably linked.

"Bernard Fisher was a titan. His research improved and extended the lives of untold numbers of women with breast cancer. His work overturned the dominant paradigm of cancer progression and, to the benefit of all, demonstrated the systemic nature of metastasis," says Arthur Levine, senior vice chancellor for health sciences at the University of Pittsburgh School of Medicine.

"Women in the US should erect a statue to Bernie because he changed breast cancer surgery from the horrendous Halsted operation (involving the breast being removed, the muscle wall denuded, and lymph drainage disrupted) to a more compassionate procedure resulting in far less morbidity," says Vincent DeVita, professor of medicine at the Yale Cancer Center, who was the director of the National Cancer Institute from 1980 to 1988.

In 1957 the career of Fisher, who at the time was researching liver regeneration and the metastatic spread of tumour, changed direction when he received a phone call from his former mentor, Isidor S Ravdin, requesting attendance at a meeting at the National Institutes of Health to discuss the creation of the Surgical Adjuvant Chemotherapy Breast Project, later known as the National Surgical Adjuvant Breast and Bowel Project. "I wasn't the least bit …


The article discusses the issues of developing an effective strategic approach to promoting IT products via the Internet on a B2C market to attain marketing goals. The study provides insights into the peculiarities and essential differences in marketing activities on a B2B and B2C markets along with revealing the specifics of using Internet marketing tools in a consumer market subject to specific features of an information technology product and a particular phase of a consumer's purchase decision. The findings demonstrate that IT products are characterized by high degree of innovation and technological complexity which differentiates them from products in other areas of business. It is argued that the promotion of IT products on the Internet imposes a strategic approach to the selection of advertising channels and formats to ensure effective communication and achieving marketing goals. It is important that this process shall rely on the results of marketing research including the research on target audiences, competitors activities, and the effectiveness of particular tools for selecting advertising channels and formats that will ultimately contribute to reaching marketing goals. In this context, using Internet marketing tools for IT products is critical to build an effective communication system in the framework of a customer conversion funnel. It is noted that the use of Internet marketing instruments by software companies also has certain specifics driven by the conversion funnel and differentiation characteristics which make it differ from other areas of the IT market. The study findings highlight a significant role of a video format in building brand knowledge as well as in achieving conversion goals. The research results have important implications to IT companies, in particular to mobile applications developers, which can be utilized in designing product promotion strategies or while launching a new product into the market.