Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 5 Σεπτεμβρίου 2016
Heat treatment, microstructure and properties of 75Cr1 steel, for use in heavy loaded elements
This study aims to optimize the heat treatment of tool steel 75Cr1 which is used for heavy loaded elements in transmissions. A salt bath was used to quench and temper the steel at different temperatures. Mechanical tests and microstructural characterization were done to define the heat treatment parameters corresponding to the optimal performance of the elements. Optical microscopy, electron back scatter diffraction and x-ray diffraction were used to characterize the microstructure, while tensile tests and toughness tests were employed to determine the mechanical properties after different heat treatments. It was found that the yield strength decreases with increasing annealing temperature and that the toughness decreases with increasing annealing time and temperature. The changes of the mechanical properties are discussed in relation with the thermal treatment and the corresponding microstructures.
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A novel method for the measurement of accurate degenerative chain transfer coefficients: proof of concept and experimental validation
A novel method is presented to determine transfer coefficients in degenerative reversible addition fragmentation chain transfer (RAFT) polymerization from experimental dispersity data. Both the exchange reactivity with the small RAFT agent (CTA; C-tr,C-0) and the macro-RAFT agent (C-tr) can be measured at specific monomer conversions. The method is able to capture for the first time a possible intrinsic or apparent chain length dependency of C-tr(0) or thus the RAFT addition rate coefficient, an outstanding challenge in the mechanistic understanding of RAFT polymerization up to high monomer conversion. In its development stage, the method has been theoretically evaluated via the simulation of test cases in the absence and presence of artificial error. Experimental data at 353 K for azobis(isobutyronitrile) (AIBN) initiated RAFT polymerization of methyl methacrylate (MMA) with cyano-2-propyl dithiobenzoate (CPDB) as a small RAFT agent are successfully analyzed with the novel method. A highly accurate value of 20 is obtained for the exchange with CPDB. For the RAFT exchange with the macro-RAFT agent, an approximate but higher value of 76 is obtained and no chain length dependency is detected. The method is implemented in a spreadsheet, including a step by step explanation of the input parameters.
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Evaluation of acute Ni bioavailability models for model and non-model species
An 'average animal' bioavailability model and an 'average Crustacean' BLM for predicting acute Ni toxicity to vertebrate and invertebrate species was developed. The 'average animal' model was based on a weighted average of the existing invertebrate (D. magna, C. dubia and D. pulex BLMs) and vertebrate (fish model) bioavailability models. The developed 'average animal' bioavailability model has a log-linear pH effect (SpH=0.162) which is superimposed on a classic BLM-type Ca2+ and Mg2+ competition effect. The 'average Crustacean' model was based on a arithmetic average of the existing invertebrate BLMs (D. magna, C. dubia and D. pulex BLMs). The developed 'average Crustacean' BLM has a classic BLM-type structure with a Ca2+ and Mg2+ competition effect. The 'average animal' model and the 'average Crustacean' BLM were shown to accurately predict acute Ni toxicity for 5 invertebrate species. Furthermore, the models predicted Ni toxicity to L. minor more accurate than the existing algae models. The 'average animal' model predicted also acute Ni toxicity to 2 vertebrate species with reasonable accuracy. Therefore, these models can both be used to normalize Ni toxicity data of animals in risk assessment procedures. The 'average Crustacean' BLM, however, depicts the effect of pH on acute Ni toxicity to daphnids better than the 'average animal' bioavailability model.
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A survey of substance use for cognitive enhancement by university students in the Netherlands
Background: Pharmacological cognitive enhancement, using chemicals to change cellular processes in the brain in order to enhance one's cognitive capacities, is an often discussed phenomenon. The prevalence among Dutch university students is unknown. Methods: The study set out to achieve the following goals: (1) give an overview of different methods in order to assess the prevalence of use of prescription, illicit and lifestyle drugs for cognitive enhancement (2) investigate whether polydrug use and stress have a relationship with cognitive enhancement substance use (3) assessing opinions about cognitive enhancement prescription drug use. A nationwide survey was conducted among 1572 student respondents of all government supported Dutch universities. Results: The most detailed level of analysis use of specific substances without a prescription and with the intention of cognitive enhancement shows that prescription drugs, illicit drugs and lifestyle drugs are respectively used by 1.7, 1.3, and 45.6% of the sample. The use of prescription drugs and illicit drugs is low compared to other countries. We have found evidence of polydrug use in relation to cognitive enhancement. A relation between stress and the use of lifestyle drugs for cognitive enhancement was observed. We report the findings of several operationalizations of cognitive enhancement drug use to enable comparison with a wider variety of previous and upcoming research. Conclusions: Results of this first study among university students in the Netherlands revealed a low prevalence of cognitive enhancement drug use compared to other countries. Multiple explanations, such as a difference in awareness of pharmacological cognitive enhancement among students, accessibility of drugs in the student population and inclusion criteria of enhancement substances are discussed. We urge enhancement researchers to take the different operationalizations and their effects on the prevalence numbers into account.
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Therapeutic and prophylactic uses of invertebrates in contemporary Spanish ethnoveterinary medicine
Zootherapeutic practices in ethnoveterinary medicine are important in many socio-cultural environments around the world, particularly in developing countries, and they have recently started to be inventoried and studied in Europe. In light of this, the purpose of this review is to describe the local knowledge and folk remedies based on the use of invertebrates and their derivative products in contemporary Spanish ethnoveterinary medicine. An overview in the fields of ethnozoology, ethnoveterinary medicine and folklore was made. Automated searches in the most important databases were performed. All related works were examined thoroughly and use-reports were obtained from 53 documentary sources. The traditional use of 18 invertebrate species and five ethnotaxa and a total of 86 empirical remedies based on the use of a single species was recorded. The two most relevant zoological groups were found to be insects and molluscs. A broad diversity of body parts or derivative products have been and are used to treat or prevent ca. 50 animal diseases or conditions, in particular diseases of the skin and subcutaneous tissue, different infectious livestock diseases, and disorders of the eye and adnexa. Cattle, sheep and equines form the group of domestic animals in which the greatest number of remedies are mentioned. In addition, seven magical remedies and practices are documented. In comparison with other culturally related areas, this is a rich heritage. The use-reports included here will help in the search for new and low-cost drugs for treating livestock and alternative materials for pharmaceutical purposes, future research addressing the validation of the effects and the development of organic farming.
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Vitamin D receptor gene associations with pulmonary tuberculosis in a Tibetan Chinese population
Background: The vitamin D receptor (VDR) mediates the immunological function of vitamin D3, which activates macrophages, and vitamin D deficiency has been linked to tuberculosis risk. Single nucleotide polymorphisms (SNPs) in VDR may influence the function of vitamin D and susceptibility to tuberculosis. Methods: This study included 217 patients with pulmonary tuberculosis (PTB) and 383 healthy subjects in a Tibetan Chinese population living in and near Xi'an. Association analyses of SNPs in VDR were performed with the SPSS 17.0 statistical packages, SNP stats software, Haploview software package (version 4.2), and the SHEsis software platform. Results: Our results revealed a correlation between three SNPs (rs11574143, odds ratio [OR]: 1.47, 95 % confidence interval [CI]: 1.11 - 1.94, p = 0.006, p-adjust = 0.030; rs11574079, OR: 0.48, 95 % CI: 0.25 - 0.92, p = 0.023, p-adjust = 0.115; rs11168287, OR: 2.55, 95 % CI: 2.00 - 3.25, p = 1.730E-14, p-adjust = 0.865E-13) and PTB based on Chi-square tests. We observed the allele "A" of rs11574143 and rs11168287 increased the PTB risk and the allele "A" of rs11574079 provided a protective effect against PTB. Conclusions: The goal of this study was the identification of putative associations between five SNPs (rs11574143, rs7975232, rs11574079, rs3819545 and rs11168287) in VDR and susceptibility to PTB. Our findings demonstrated associations between VDR polymorphisms and PTB development.
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Traditional knowledge and use of wild mushrooms by Mixtecs or Ñuu savi, the people of the rain, from Southeastern Mexico
Background: Mexico is an important global reservoir of biological and cultural richness and traditional knowledge of wild mushrooms. However, there is a high risk of loss of this knowledge due to the erosion of traditional human cultures which is related with the rapid acculturation linked to high migration of rural populations to cities and the U.S.A., and the loss of natural ecosystems. The Mixtec people, the third largest native group in Mexico only after the Nahua and the Maya, maintain ancient traditions in the use and knowledge of wild mushrooms. Paradoxically, there are few studies of the Mixtec ethnomycology. This study shows our ethnomycological research, mainly focused on knowledge and use of wild mushrooms in communities of the Mixteca Alta, in southeastern Mexico. We hypothesized that among the studied communities those with a combination of higher vegetation cover of natural pine and oak forests, lower soil erosion and higher economic margination had a greater richness and knowledge of wild mushrooms. Our study therefore aimed to record traditional knowledge, use, nomenclature and classification of wild mushrooms in four Mixtec communities and to analyze how these aspects vary according to environmental and cultural conditions among the studied communities. Methods: In order to analyze the cultural significance of wild mushrooms for the Mixtec people, 116 non-structured and semi-structured interviews were performed from 2009 to 2014. Information about the identified species, particularly the regional nomenclature and classification, their edibility, toxicity and ludic uses, the habitat of useful mushrooms, traditional recipes and criteria to differentiate between toxic and edible species, and mechanisms of knowledge transmission were studied. The research had the important particularity that the first author is Mixtec, native of the study area. A comparative qualitative analysis between the richness of fungal species used locally and the official information of the natural vegetation cover, soil erosion and economic marginalization in each of the studied communities was conducted. Results: A total of 106 species of mushrooms were identified growing in pine and oak forest, deciduous tropical forest and grassland; among the identified mushrooms we recorded 26 species locally consumed, 18 considered toxic, 6 having ludic uses and the remaining 56 species not being used in the studied areas but some of them having potential as food (56 species) or medicine (28 species). We recorded that 80, 22 and 4 species are ectomycorrhizal, saprotrophic and parasites, respectively. Our study shows that a complex and accurate knowledge related with the use, nomenclature, classification, ecology, gastronomy of wild mushrooms has been developed by Mixtecs; and that there is a relation between natural vegetation cover, lower soil erosion and higher economic marginalization and richness, knowledge and use of mushrooms in the studied communites. Conclusion: Our study showed that conservation and adaptation of ancestral mycological knowledge survives mainly through oral transmition, maintenance of cultural identity, forest protection, preservation native language and also paradoxically through the current socieconomical marginality among the Mixtec people. We also found that those studied communities with a combination of higher vegetation cover of natural pine and oak forests, lower soil erosion and higher economic marginalization showed a greater richness and knowledge of wild mushrooms. Use and sustainable management of wild mushrooms can be an alternative for local integrated development, but local knowledge and traditional worldview should be included into the regional programs of Mixtec biocultural conservation.
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IJMS, Vol. 17, Pages 1479: Roles of Voltage-Gated Tetrodotoxin-Sensitive Sodium Channels NaV1.3 and NaV1.7 in Diabetes and Painful Diabetic Neuropathy
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Quality control of involved field radiotherapy in the HD 13 and HD 14 trials
Abstract
Introduction
As part of the foundation of the German Hodgkin Study Group (GHSG) in 1978, a central radiotherapy (RT) reference centre was established to evaluate and to improve the quality of treatment. During the study generations, the quality assurance programs (QAP) were continued and adapted to the demands of each study. The purpose of this article is to demonstrate the results of the fifth study generation and to compare them to the previous findings.
Methods
With the start of the fourth GHSG study generation (HD10–12), a central prospective review of all diagnostic images was established to create an individual treatment plan for each early stage study patient. The quality of involved field RT was retrospectively evaluated by an expert panel of radiation oncologists. In the fifth study generation (HD13–15), the retrospective review of radiotherapy performed was refined and the results were compared with the findings of the fourth generation.
Results
The expert panel analyzed the RT planning and application of 1037 (28 %) patients (HD13 n = 465, HD14 n = 572). Simulation films were available in 85 % of cases and verification films in 87 %. RT was assessed as major violation in 46 % (HD13 = 38 %, HD14 = 52 %), minor violation in 9 % (HD13 = 9 %, HD14 = 9 %) and according to the protocol in 45 % (HD13 = 52 %, HD14 = 38 %).
Conclusion
The value for QAP of RT within the GHSG trials is well known. Still there were several protocol violations. In the future, the QAP program has to be adapted to the requirements of "modern RT" in malignant lymphoma.
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Enhanced XOR activity in eNOS-deficient mice: Effects on the nitrate-nitrite-NO pathway and ROS homeostasis
Publication date: Available online 5 September 2016
Source:Free Radical Biology and Medicine
Author(s): Maria Peleli, Christa Zollbrecht, Marcelo F. Montenegro, Michael Hezel, Jianghong Zhong, Erik G. Persson, Rikard Holmdahl, Eddie Weitzberg, Jon O. Lundberg, Mattias Carlström
Xanthine oxidoreductase (XOR) is generally known as the final enzyme in purine metabolism and as a source of reactive oxygen species (ROS). In addition, this enzyme has been suggested to mediate nitric oxide (NO) formation via reduction of inorganic nitrate and nitrite. This NO synthase (NOS)-independent pathway for NO generation is of particular importance during certain conditions when NO bioavailability is diminished due to reduced activity of endothelial NOS (eNOS) or increased oxidative stress, including aging and cardiovascular disease. The exact interplay between NOS- and XOR-derived NO generation is not fully elucidated yet. The aim of the present study was to investigate if eNOS deficiency is associated with changes in XOR expression and activity and the possible impact on nitrite, NO and ROS homeostasis.Plasma levels of nitrate and nitrite were similar between eNOS deficient (eNOS−/−) and wildtype (wt) mice. XOR activity was upregulated in eNOS−/− compared with wt, but not in nNOS−/−, iNOS−/− or wt mice treated with the non-selective NOS inhibitor l-NAME. Following an acute dose of nitrate, plasma nitrite increased more in eNOS−/− compared with wt, and this augmented response was abolished by the selective XOR inhibitor febuxostat. Livers from eNOS−/− displayed higher nitrite reducing capacity compared with wt, and this effect was attenuated by febuxostat. Dietary supplementation with nitrate increased XOR expression and activity, but concomitantly reduced superoxide generation. The latter effect was also seen in vitro after nitrite administration. Treatment with febuxostat elevated blood pressure in eNOS−/−, but not in wt mice. A high dose of dietary nitrate reduced blood pressure in naïve eNOS−/− mice, and again this effect was abolished by febuxostat. In conclusion, eNOS deficiency is associated with an upregulation of XOR facilitating the nitrate-nitrite-NO pathway and decreasing the generation of ROS. This interplay between XOR and eNOS is proposed to play a significant role in NO homeostasis and blood pressure regulation.
Graphical abstract
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Chain transfer in degenerative RAFT polymerization revisited: a comparative study of literature models
Under the validity of the degenerative transfer mechanism, the activation/deactivation process in reversible addition-fragmentation chain transfer (RAFT) polymerization can be formally quantified by transfer coefficients, depending on the chemical structure of the participating radicals and dormant species. In the present work, the different literature methods to experimentally determine these RAFT transfer coefficients are reviewed and theoretically re-evaluated. The accuracy of each method is mapped for a broad range of reaction conditions and RAFT transfer reactivities. General guidelines on when which method should be applied are formulated.
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Adaptation and standardization of a Western tool for assessing child development in non-Western low-income context
Background: Due to lack of culturally relevant assessment tools, little is known about children's developmental profiles in low income settings such as Ethiopia. The objective of this study was to adapt and standardize the Denver II for assessing child development in Jimma Zone, South West Ethiopia. Methods: Culture-specific test items in Denver II were modified. After translation into two local languages, all test items were piloted and fine-tuned. Using 1597 healthy children 4 days to 70.6 months of age, the 25, 50, 75 and 90 % passing ages were determined for each test item as milestones. Milestones attainment on the adapted version and the Denver II were compared on the 90 % passing age. Reliability of the adapted tool was examined. Results: A total of 36 (28.8 %) test items, mostly from personal social domain, were adapted. Milestones attainment ages on the two versions differed significantly on 42 (34 %) test items. The adapted tool has an excellent inter-rater on 123 (98 %) items and substantial to excellent test-retest reliability on 119 (91 %) items. Conclusions: A Western developmental assessment tool can be adapted reliably for use in low-income settings. Age differences in attaining milestones indicate a correct estimation of child development requires a population-specific standard.
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A light activated reaction manifold
We introduce an efficient reaction manifold Where the rate of a thermally induced ligation can be controlled by a photonic field via two competing reaction channels. The effectiveness of the reaction manifold is evidenced by following the transformations of macro molecular chain termini via high-resolution mass spectrometry and subsequently by selective block copolymer formation. The light controlled reaction manifold consists of a so-called o-quinodimethane species, a photocaged diene, that reacts in the presence of light with suitable enes in a Diets Alder reaction and undergoes a transformation into imines with amines in the absence of light. The chemical Selectivity of the manifold is controlled by the amount of ene present in the. reaction and can be adjusted from 100% imine formation (0% photo product) to 5% imine formation (95% photo product). The reported light-controlled reaction manifold is highly attractive because a simple external field is used to switch the selectivity of specific reaction channels.
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First principles kinetic study on the effect of zeolite framework on 1-butanol dehydration
Understanding the role of zeolite topology in defining its catalytic performance is of prime importance for the development of catalytic processes. Herein, a first-principles-based microkinetic study of 1-butanol dehydration is used to illustrate the effect of different zeolites (i.e., H-FAU, H-ZSM-5, H-ZSM-22, and H-FER) on the dehydration activity and product selectivity. Under identical reaction conditions, microkinetic simulations show significant variation in dehydration rates and butene/ether selectivity profiles within the different zeolites. H-ZSM-5 has the highest catalytic activity, whereas H-FAU and H-FER exhibit a higher butene selectivity. In the large pore H-FAU, the weaker dispersive stabilization of the dimer makes the butene formation by monomolecular direct dehydration via a concerted anti elimination compete with di-n-butyl ether formation. In H-FER, steric constraints due to partial confinement of the protonated di-n-butyl ether in the 8-MR channel decrease its stability, favoring its further decomposition to butene via a concerted syn elimination of butanol. On the other hand, the higher ether selectivity in H-ZSM-5 and H-ZSM-22 is rationalized on the basis of a higher stability for adsorbed ether and a higher activation barrier for ether decomposition. In addition to the effect of the zeolite framework, this study further highlights the pivotal role of the reaction conditions in determining the most abundant reaction intermediate, dominant reaction paths, and underlying reaction mechanisms. In general, for all four zeolites, an increase in reaction temperature and a decrease in butanol feed partial pressure favors direct dehydration of butanol to butene (via butanol monomer). However, a decrease in reaction temperature and increase in butanol feed partial pressure favors dimer-mediated dibutyl ether formation. An increase in conversion favors direct dehydration and dibutyl ether decomposition to butene.
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Entre verbe et adverbe: grammaticalisation et dégrammaticalisation du marqueur épistémique umeengo/umeenga en kirundi (bantou, JD62)
La présente étude concerne l'évolution sémantique et formelle d'un adverbe épistémique du kirundi, umeengo/umeenga, les deux formes constituant des variantes libres. Elle est une des premières études s'inscrivant en linguistique de corpus pour les langues bantoues, une démarche rarement adoptée pour cette famille de langues, de même qu'elle étudie une catégorie grammaticale généralement négligée dans les études linguistiques, c'est-à-dire l'adverbe. Nous décrivons les différents emplois de umeengo/umeenga : comme adverbe, mais aussi comme comparatif, et dans les emplois du verbe qui en émerge à l'étape suivante dans son évolution. Ses origines sont éclairées par un indice retrouvé en kinyarwanda, langue proche du kirundi, ainsi que dans la variante dialectale du kirundi parlée à l'ouest du Burundi, dans la région de l'Imbo. D'après ces éléments, il apparaît que cet adverbe est formé par univerbation, plus précisément par fusion d'un verbe conjugué, umenya (du verbe meny « connaître ») et du quotatif ngo « que ». Dans la suite du processus, à partir de cet adverbe épistémique, se forme un nouveau verbe, meeng « croire ; penser », différent de celui du départ, tant dans le sens qu'au niveau de la forme. Une telle évolution au sein de l'adverbe, qui naît d'un verbe et débouche lui-même à la naissance d'un autre verbe, est rare dans les langues du monde, de là l'intérêt de notre analyse. Dans cette étude, nous nous interrogeons sur la nature des processus à l'œuvre. Nous montrons que les changements structurels et sémantiques par lesquels l'adverbe umeengo/umeenga s'est formé sont à mettre sur le compte de la grammaticalisation. Dans le même ordre d'idée, nous analysons la formation du verbe meeng à partir de l'adverbe comme le résultat d'une dégrammaticalisation.
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Differences in environmental preferences towards cycling for transport among adults: a latent class analysis
Background: Increasing cycling for transport can contribute to improve public health among adults. Micro- environmental factors (i.e. small-scaled street-setting features) may play an important role in affecting the street's appeal to cycle for transport. Understanding about the interplay between individuals and their physical environment is important to establish tailored environmental interventions. Therefore, the current study aimed to examine whether specific subgroups exist based on similarities in micro-environmental preferences to cycle for transport. Methods: Responses of 1950 middle-aged adults (45–65 years) on a series of choice tasks depicting potential cycling routes with manipulated photographs yielded three subgroups with different micro-environmental preferences using latent class analysis. Results: Although latent class analysis revealed three different subgroups in the middle-aged adult population based on their environmental preferences, results indicated that cycle path type (i.e. a good separated cycle path) is the most important environmental factor for all participants and certainly for individuals who did not cycle for transport. Furthermore, only negligible differences were found between the importances of the other micro-environmental factors (i.e. traffic density, evenness of the cycle path, maintenance, vegetation and speed limits) regarding the two at risk subgroups and that providing a speed bump obviously has the least impact on the street's appeal to cycle for transport. Conclusions: Results from the current study indicate that only negligible differences were found between the three subgroups. Therefore, it might be suggested that tailored environmental interventions are not required in this research context.
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A corpus-driven account of the noun classes and genders in Northern Sotho
This article offers a distributional corpus analysis of the Northern Sotho noun and gender system. The aim is twofold: first, to assess whether the existing descriptions of the noun class system in Northern Sotho are corroborated by information provided by the analysis of a large electronic corpus for this language, with specific reference to singular-plural pairings, and second, to present a number of novel visualisation aids to characterise a noun class system (in a radar diagram) and a noun gender system (using a two-directional weighted representation) for Northern Sotho in particular, and for any Bantu language in general. The findings include the discovery of two new genders in Northern Sotho (i.e. class pairs 1/6 and 3/10), and also indicate that the Northern Sotho noun class system, and by extension any one for Bantu, should be seen as dynamic.
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Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP
Background: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity. Methods: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression. Results: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old. Conclusion: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype.
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Ni-EXTEND: extending the chronic nickel BLM from pH 8.2 to pH 8.7 and validation of the BLM-normalized HC5(50%) for Ni against the ecological effects observed in a 4-month microcosm experiment
In this study, we investigated if the pH range of the chronic nickel BLM could be extended above pH 8.2, by investigating effects of increasing pH on Ni toxicity to various aquatic species. Ni toxicity expressed as dissolved Ni concentration was at least similar or increased when increasing the pH from 8.2 to 8.7. However, Ni toxicity expressed as free Ni2+ activity was higher at pH 8.7 compared to pH 8.2 for all tested species. All existing Ni BLMs had the tendency to underestimate toxicity at pH 8.7. Hence, it is clear that the BLMs developed for pH<8.2, are not suitable for extrapolation to pH 8.7 and that they should be modified in terms of pH slope. A modified BLM which takes in account a mean pH slope for the invertebrates and another for plants/algae predicted Ni toxicity most accurately and without bias. As a consequence, a two-step procedure is proposed to normalize toxicity data (and calculate HC5) for target waters with pH>8.2. First, Normalize all NOECs to pH 8.2, using the BLMs that have been shown valid for pH up to 8.2, next extend the NOECs normalized from pH 8.2 to the target pH using a mean invertebrate SpH = 1.36 for all invertebrates and a mean SpH = 0.97 for all plants and algae. The NOECs from step 2 can subsequently be used to fit an SSD and calculate an HC5. This procedure is relatively simple and results in realistic normalized HC5s, that are also unbiased (i.e. neither over or under-conservative). The HC5(50%) normalized to the conditions of the microcosm experiment is protective of the overall community-level dynamics observed in a previously reported mesocosm experiment.
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Long live the liver: immunohistochemical and stereological study of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells of male and female rats throughout ageing
Abstract
Male/female differences in enzyme activity and gene expression in the liver are known to be attenuated with ageing. Nevertheless, the effect of ageing on liver structure and quantitative cell morphology remains unknown. Male and female Wistar rats aged 2, 6, 12 and 18 months were examined by means of stereological techniques and immunohistochemical tagging of hepatocytes (HEP), liver sinusoidal endothelial cells (LSEC), Kupffer cells (KC) and hepatic stellate cells (HSC) in order to assess the total number and number per gram of these cells throughout life. The mean cell volume of HEP and HSC, the lobular position and the collagen content of the liver were also evaluated with stereological techniques. The number per gram of HSC was similar for both genders and was maintained throughout ageing. The mean volume of HSC was also conserved but differences in the cell body and lobular location were observed. Statistically significant gender differences in HEP were noted in young rats (females had smaller and more binucleated HEP) but were attenuated with ageing. The same occurred for KC and LSEC, since the higher number per gram in young females disappeared in older animals. Liver collagen increased with ageing but only in males. Thus, the numbers of these four cell types are related throughout ageing, with well-defined cell ratios. The shape and lobular position of HSC change with ageing in both males and females. Gender dimorphism in HEP, KC and LSEC of young rat liver disappears with ageing.
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The versatility of the mitochondrial presequence processing machinery: cleavage, quality control and turnover
Abstract
Mitochondria play a key role in several metabolic and cell biological pathways and have attracted increasing attention due to their implication in life-span, ageing and human diseases. Mitochondrial proteases have a special role in these multiple biological functions, as they are involved in the regulation of various processes, e.g., mitochondrial protein biogenesis and quality control, mitochondrial dynamics, mitophagy and programmed cell death. The mitochondrial presequence processing machinery serves the particular purpose of maturing the majority of incoming precursor proteins by presequence cleavage, to ensure a stable mature protein by trimming of intermediate N-termini and to remove free toxic targeting peptides.
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Risk factors for active bleeding from colonic angiodysplasia confirmed by colonoscopic observation
Abstract
Purpose
Colonic angiodysplasia is an important cause of lower gastrointestinal bleeding in the elderly. Here, we investigated the risk factors for bleeding from colonic angiodysplasia seen at endoscopy.
Methods
We conducted a retrospective case-control study by reviewing records of 435 patients with angiodysplasia at colonoscopy from November 2006 to November 2015 in our hospital. To identify risk factors for active bleeding, the following were analyzed: age, sex, comorbidities, use of antithrombotic drugs and non-steroidal anti-inflammatory drugs, and the size and location of the lesions.
Results
Among the 435 patients, active bleeding from angiodysplasia was observed at endoscopy in 29 patients (6.7 %). Using multivariate analysis, we identified advanced age (odds ratio 5.15, 95 % confidence interval, 1.61–16.5), comorbidity of heart disease (6.88, 1.04–45.5), use of anticoagulant drug (4.22, 1.21–14.7), multiple lesions (6.67, 1.77–25.2), and small lesions (≤5 mm) (17.7, 4.90–64.0) as independent and significant risk factors for active bleeding. Actively bleeding colonic angiodysplasia lesions were very small in most cases (1–2 mm, 24/29, 83 %) and predominantly located in the right-side colon (26/29, 90 %). All of the 29 patients with active bleeding were successfully and safely treated endoscopically, but re-bleeding occurred in nine patients (31 %, 9/29) during the follow-up period of 2–84 months.
Conclusions
Multiple and small colonic angiodysplasia lesions in patients of advanced age, with heart disease, or receiving anticoagulants have increased risk for bleeding. We should be aware that small colonic angiodysplasia lesions in the right-side colon at colonoscopy in these patients may be a source of bleeding.
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Dry-powder inhalers in patients with persistent airflow limitation: usability and preference
Abstract
Background
Inhalation devices represent per sé critical factors because they can affect the therapeutic outcomes independently of the drug used. The role of patients' usability and preference (PUP) for Dry Powder Inhalers (DPIs) is high indeed because they can influence the extent of the adherence to treatment and the therapeutic outcomes.
Aim of the study was to assess and compare the PUP of three different DPIs in out-patients with persistent airflow limitation due to asthma or COPD.
Methods
The PUP of three different DPIs (Breezhaler; Genuair; Handihaler) were investigated by means of the Handling Questionnaire in out-patients with persistent airflow limitation needing an inhalation therapy. Patients had to report their preference before and after the nurse's instruction on the handling of each device. The nurse had also to note the critical steps during the patient's procedure for actuation; to count the number of attempts needed for actuating the device properly, and to measure the time (in sec.) required for these procedures. Data were collected up to three attempts per device.
Statistics: Welch test was used for normal distributed variables, while the Wilcoxon test for not normal distributed variables. The χ 2 test and the ANOVA test were also used. Univariate and multivariate regressions were also performed in order to investigate the effect of patients' characteristics and of technical differences of each device on their proper use.
Results
Three hundred thirty-three consecutive out-patients (age range 55–58 years, and well matched for gender), with persistent airway limitation of different severity were investigated, suffering from bronchial asthma (n = 175) or from chronic obstructive pulmonary disease (COPD) (n = 158). In particular, 127 patients (38 %) tested the three DPIs, while 110 (33 %) tested Breezhaler and Genuair, and 96 (29 %) Breezhaler and Handihaler. More than 50 % of patients who tested all devices preferred the Genuair and perceived this device as the easiest to use. The nurse's judgement confirmed their opinion. When compared to the other two DPIs, Genuair proved the least problematic either according to the patients' judgement and to the nurse's opinion. Mean number of attempts aimed to achieving the first proper actuation was lower with Genuair than with Breezhaler and Handihaler (1.5 vs 2.5–2.6, p < 0.0001). Finally, Genuair also proved the easiest to use and the least problematic according to the nurse judgement (0.0001), the most easily learned (0.0001), and that one with a successful rate of more than 56 % at the first attempt. Breezhaler and Handihaler needed an average of about one additional attempt to be used properly (p < 0.0001), and their usability proved significantly more difficult (OR of successful rate between 0.15 and 0.17, p < 0.001). In general, older patients needed more attempts to perform their first proper inhalation; their successful rate was lower, and they needed more time to learn how to use devices properly: with Genuair these differences were minimized.
Conclusions
The possibility of grading objectively the performance of different DPIs in terms of their usability and therapeutic convenience in daily life represents a crucial operational opportunity to pursue. To note that a substantial discrepancy exists between the patients' belief "at glance" and the patients' effective usability with can be registered with some devices. From a general point of view, devices requiring less manual actions for their actuation confirmed their better usability and proper handling after less attempts. In particular, Genuair came out as the most preferred DPI also when several different aspects of preference and usability are assessed objectively and compared.
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Silica-Coated Nonstoichiometric Nano Zn-Ferrites for Magnetic Resonance Imaging and Hyperthermia Treatment
Large-scale and reproducible synthesis of nanomaterials is highly sought out for successful translation into clinics. Flame aerosol technology with its proven capacity to manufacture high purity materials (e.g., light guides) up to kg h−1 is explored here for the preparation of highly magnetic, nonstoichiometric Zn-ferrite (Zn0.4Fe2.6O4) nanoparticles coated in situ with a nanothin SiO2 layer. The focus is on their suitability as magnetic multifunctional theranostic agents analyzing their T2 contrast enhancing capability for magnetic resonance imaging (MRI) and their magnetic hyperthermia performance. The primary particle size is closely controlled from 5 to 35 nm evaluating its impact on magnetic properties, MRI relaxivity, and magnetic heating performance. Most importantly, the addition of Zn in the flame precursor solution facilitates the growth of spinel Zn-ferrite crystals that exhibit superior magnetic properties over iron oxides typically made in flames. These properties result in strong MRI T2 contrast agents as shown on a 4.7 T small animal MRI scanner and lead to a more efficient heating with alternating magnetic fields. Also, by injecting Zn0.4Fe2.6O4 nanoparticle suspensions into pork tissue, MR-images are acquired at clinically relevant concentrations. Furthermore, the nanothin SiO2 shell facilitates functionalization with polymers, which improves the biocompatibility of the theranostic system.
Highly magnetic nanoparticles are made by scalable flame aerosol technology combining properties crucial for diagnostics (magnetic resonance imaging) and therapeutics (magnetic hyperthermia). This allows for the simultaneous imaging and treatment of cells while the superior magnetic performance of the nanoparticles drastically reduces their required dose.
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Biomimicking Platelet–Monocyte Interactions as a Novel Targeting Strategy for Heart Healing
In patients who survive myocardial infarction, many go on to develop congestive heart failure (CHF). Despite ongoing efforts to develop new approaches for postinfarction therapy, there are still no effective therapeutic options available to CHF patients. Currently, the delivery of cardioprotective drugs relies entirely on passive uptake via the enhanced permeability and retention (EPR) effect which occurs in proximity to the infarction site. However, in ischemic disease, unlike in cancer, the EPR effect only exists for a short duration postinfarction and thus insufficient for meaningful cardioprotection. Splenic monocytes are recruited to the heart in large numbers postinfarction, and are known to interact with platelets during circulation. Therefore, the strategy is to exploit this interaction by developing platelet-like proteoliposomes (PLPs), biomimicking platelet interactions with circulating monocytes. PLPs show strong binding affinity for monocytes but not for endothelial cells in vitro, mimicking normal platelet activity. Furthermore, intravital multiphoton imaging shows that comparing to plain liposomes, PLPs do not aggregate on uninjured endothelium but do accumulate at the injury site 72 h postinfarction. Importantly, PLPs enhance the targeting of anti-inflammatory drug, cobalt protoporphyrin, to the heart in an EPR-independent manner, which result in better therapeutic outcome.
Currently, the delivery of cardioprotective drugs relies entirely on passive uptake via the enhanced permeability and retention (EPR) effect which occurs in proximity to the infarction site. Novel platelet-like proteoliposomes have been developed to employ mobilized splenic monocytes as "shuttle buses" in the blood stream to carry therapeutics to the infarcted heart without relying on the EPR effect.
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From The Mine to Cancer Therapy: Natural and Biodegradable Theranostic Silicon Nanocarriers from Diatoms for Sustained Delivery of Chemotherapeutics
Drug delivery using synthetic nanoparticles including porous silicon has been extensively used to overcome the limitations of chemotherapy. However, their synthesis has many challenges such as lack of scalability, high cost, and the use of toxic materials with concerning environmental impact. Nanoscale materials obtained from natural resources are an attractive option to address some of these disadvantages. In this paper, a new mesoporous biodegradable silicon nanoparticle (SiNP) drug carrier obtained from natural diatom silica mineral available from the mining industry is presented. Diatom silica structures are mechanically fragmented and converted into SiNPs by simple and scalable magnesiothermic reduction process. Results show that SiNPs have many desirable properties including high surface area, high drug loading capacity, strong luminescence, biodegradability, and no cytotoxicity. The in-vitro release results from SiNPs loaded with anticancer drugs (doxorubicin) demonstrate a pH-dependent and sustained drug release with enhanced cytotoxicity against cancer cells. The cells study using doxorubicin loaded SiNPs shows a significantly enhanced cytotoxicity against cancer cells compared with free drug, suggesting their considerable potential as theranostic nanocarriers for chemotherapy. Their low-cost manufacturing using abundant natural materials and outstanding chemotherapeutic performance has made them as a promising alternative to synthetic nanoparticles for drug delivery applications.
New chemotherapeutic nanocarrier based on luminescent silicon nanoparticles (SiNPs) generated from low-cost, natural silica diatom mineral rocks obtained from the mine industry featuring outstanding pH-dependent and extended drug delivery capabilities, biodegradability, biocompatibility, cell internalization, and theranostic properties is presented. Their low manufacturing cost using abundant natural materials, environmentally friendly, and cost-effective processes shows that these SiNPs have a potential to replace existing synthetic nanocarriers for broad drug delivery applications.
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Hemoglobin-Conjugated Gelatin Microsphere as a Smart Oxygen Releasing Biomaterial
In this study, a novel micrometric biomaterial acting as a cyclic oxygen releasing system is designed. Human hemoglobin (Hb) is conjugated to the surface of gelatin microspheres (GM) to produce gelatin hemoglobin oxygen depot (G-HbOD). G-HbOD is obtained by means of two different conjugation strategies. The degree of conjugation of GM surfaces in terms of free amino groups by using HPLC is first evaluated. By following the strategy A (G-HbOD_A), Hb is conjugated to GM by means of the formation of a polyurethane linker. In the strategy B (G-HbOD_B) the conjugation occurs via amide bound formation. Physical and morphological differences between G-HbOD_A and G-HbOD_B are investigated by means of Fourier Transform Infrared Spectroscopy (FTIR), Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). Differences in oxygen uptake/release kinetics are found depending on the conjugation strategy and it is proved that G-HbOD works under repeated cycles in microfluidic chip. Moreover, G-HbOD is also able to work as oxygen depot in the early stages of 3D cell cultures.
Gelatin hemoglobin oxygen depot (G-HbOD) is obtained by conjugating human hemoglobin to the surface of gelatin microsphere. G-HbODs are able to catch and release oxygen in cyclic manner. It is proved that G-HbOD sustains cell viability in 3D cell culture under hypoxic condition. G-HbOD would be used in would healing process, in vitro tissue engineering, and in tissue-on-chip system as well.
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An alternative approach to the calculation and analysis of connectivity in the world city network
The purpose of this paper is to contribute to the empirical 'world city network' (WCN) literature by proposing an analytical framework that considers the significance of the positions of cities in the urban networks created by multinational corporations. To this end, we introduce an approach in which network centrality measures are interpreted against a randomized baseline model that retains the network's original degree distribution. Our framework is applied to Taylor's (2001 Geographical Analysis 33 181-194) specification of world cities being 'interlocked' through the office networks of globalized service firms. We thereby develop a new analytical take on Taylor's specification by using a primary-linkage algorithm that produces a one-mode directed graph based on the initial two-mode city and firm network data. We then randomize the resultant empirical network with a bootstrapping simulation approach, and compare the simulated parameters of this null model with our empirical network parameter, that is, betweenness centrality. We show the potential and limitations of our framework by discussing the position of cities such as Tokyo, Sydney, Melbourne, Almaty, and Karachi, which seem to hold more strategic and valuable positions than is suggested in Taylor's analyses. We discuss the wider significance of our approach by showing that the analytical strategy of interpreting measures against a randomized baseline model can also be adopted in other WCN approaches, including those using other data sources and network-related measures.
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Naturally Dried Graphene Aerogels with Superelasticity and Tunable Poisson's Ratio
A novel natural drying (ND) strategy for low-cost and simple fabrication of graphene aerogels (GA) is highlighted. The as-formed NDGA exhibit ultralarge reversible compressibility (99%) and tunable Poisson's ratio behaviors (−0.30 < ν < 0.46), which suggests promising applications as soft actuators, soft robots, sensors, deformable electronic devices, drug release, thermal insulator, and protective materials.
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Spoofing voice verification systems with statistical speech synthesis using limited adaptation data
Source:Computer Speech & Language
Author(s): Ali Khodabakhsh, Amir Mohammadi, Cenk Demiroglu
State-of-the-art speaker verification systems are vulnerable to spoofing attacks using speech synthesis. To solve the issue, high-performance synthetic speech detectors (SSDs) for known attack methods have been proposed recently. Here, as opposed to developing new detectors, we investigate new attack strategies. Investigating new techniques that are specifically tailored for spoofing attacks that can spoof the voice verification system and are difficult to detect is expected to increase the security of voice verification systems by enabling the development of better detectors. First, we investigated the vulnerability of an i-vector based verification system to attacks using statistical speech synthesis (SSS) with a particular focus on the case where the attacker has only a very limited amount of data from the target speaker. Even with a single adaptation utterance, the false alarm rate was found to be %23. Still, SSS-generated speech is easy to detect [1, 2] which dramatically reduces its effectiveness. For more effective attacks with limited data, we propose a hybrid statistical/concatenative synthesis approach and show that hybrid synthesis significantly increases the false alarm rate in the verification system compared to the baseline SSS method. Moreover, proposed hybrid synthesis makes detecting synthetic speech more difficult compared to SSS even when very limited amount of original speech recordings are available to the attacker. To further increase the effectiveness of the attacks, we propose a linear regression method that transforms synthetic features into more natural features. Even though the regression approach is more effective at spoofing the detectors, it is not as effective as the hybrid synthesis approach in spoofing the verification system. An interpolation approach is proposed to combine the linear regression and hybrid synthesis methods which is shown to provide the best spoofing performance in most cases.
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