Articoli di riviste sul tema "17.24 sociolinguistics: other"

Richard Gregory was a pioneer of cognitive psychology. Much of his scientific work involved the development and interpretation of visual illusions, which he used as a tool to work out the perceptual mechanisms involved in the way that the visual world is normally perceived. He was also an inventor, developing a technique for viewing microscopic objects in three dimensions, and a method for taking sharp telescope images through an unstable atmosphere. He was a man of great charm, enthusiasm and wit, who listed his hobbies as punning and pondering. He was to become an outstanding public communicator of scientific ideas. He gave the Royal Institution Christmas Lectures (‘The intelligent eye’) in 1967, was a founder member of the Experimental Psychology Society, set up his own journal, Perception , in 1972, and in 1978 founded the Exploratory, a hands-on science centre in Bristol. His work on illusions and his interest in painting led to a collaboration with the art historian Sir Ernst Gombrich, resulting in the book Illusion in nature and art (1973) and an exhibition at the Institute of Contemporary Art. Other books included Mind in science (1981) and The Oxford companion to the mind (1987), for which he was both editor and a major contributor. The book for which he is best known is the wonderfully accessible Eye and brain , whose five editions (1966–1997) and many translations have inspired students of all ages.

PURPOSE To describe the incidence and significance of clonal evolution patterns. PATIENTS AND METHODS We analyzed 264 patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed clonal evolution between 1967 and 1993. RESULTS The median survival time following clonal evolution was 19 months. Factors associated with worse survival (P < .01) were as follows: chromosome 17 abnormality or chromosomal translocations other than Ph, high percentage of abnormal metaphases, longer time to clonal evolution, and presence of other accelerated-phase features. A recursive partitioning technique (CART) identified different risk groups. The best group (37 patients; no chromosome 17 abnormality, abnormal metaphases < 16%, and interval to clonal evolution < or = 24 months) had an estimated median survival time of 54 months. The worst two groups included 27 patients with chromosome 17 abnormalities and > or = 36% abnormal metaphases (estimated median survival time, 6 months), and 22 patients with other accelerated features and > or = 16% abnormal metaphases (estimated median survival time, 7 months). The intermediate group had an estimated median survival time that ranged from 13 to 24 months. Prior interferon therapy evaluated within risk groups showed a significant survival advantage only in the intermediate-risk group. A multivariate analysis showed similar results, and identified the following independent poor prognostic variables: chromosome 17 abnormality, percentage of abnormal metaphases (cutoff, 24%), longer time to clonal evolution (cutoff, 24 months), other accelerated-phase features, and no prior interferon therapy. Patients with none, one, two, three, or more of the first four features had median survivals times of 51, 24, 14, and 7 months, respectively. CONCLUSION The prognostic significance of clonal evolution in CML is not uniform and is related to the specific abnormality, time to its development, its predominance in metaphases, and the presence of other accelerated features, and it may be modified by specific therapies.

Background: The role of steroids to mitigate the deleterious effects of pediatric cardiopulmonary bypass (CPB) remains a matter of debate; therefore, we aimed to assess preferences in administering corticosteroids (CSs) and the use of other anti-inflammatory strategies in pediatric cardiac surgery. Methods: A 19-question survey was distributed to consultants in pediatric cardiac anesthesia from 12 centers across the United Kingdom and Ireland. Results: Of the 37 respondents (37/60, 62%), 24 (65%) use CSs, while 13 (35%) do not use steroids at all. We found variability within 5 (41%) of the 12 centers. Seven consultants (7/24, 29%) administer CSs in every case, while 17 administer CSs in selected cases only (17/24, 71%). There was variability in the dose of steroid administration. Almost all consultants (23/24, 96%) administer a single dose at induction, and one administers a two-dose regimen (1/24, 4%). There was variability in CS indications. Most consultants (24/37, 66%) use modified ultrafiltration at the conclusion of CPB. Fifteen consultants (15/32, 47%) report the use of aprotinin, while only 3 use heparin-coated circuits (3/24, 9%). Conclusions: We found wide variability in practice in the administration of CSs for pediatric cardiac surgery, both within and between units. While most anesthetists administer CSs in at least some cases, there is no consensus on the type of steroid, the dose, and at which patient groups this should be directed. Modified ultrafiltration is still used by most of the centers. Almost half of consultants use aprotinin, while heparin-coated circuits are infrequently used.

The Routledge Handbook of language and culture represents a comprehensive study on the inextricable relationship between language and culture. It is structured into seven parts and 33 chapters. Part 1, Overview and historical background, by Farzad Sharifian, starts with an outline of the book and a synopsis of research on language and culture. The second chapter, John Leavitt’s Linguistic relativity: precursors and transformations discusses further the historical development of the concept of linguistic relativity, identifying different schools’ of thought views on the relation between language and culture. He also tries to demystify some misrepresentations held towards Boas, Sapir, and Whorf’ theories (pp. 24-26). Chapter 3, Ethnosyntax, by Anna Gladkova provides an overview of research on ethnosyntax, starting from the theoretical basis laid by Sapir and Whorf and investigates the differences between a narrow sense of ethnosyntax, which focuses on cultural meanings of various grammatical structures and a broader sense, which emphasises the pragmatic and cultural norms’ impact on the choice of grammatical structures. John Leavitt presents in the fourth chapter, titled Ethnosemantics, a historical account of research on meaning across cultures, introducing three traditions, i.e. ‘classical’ ethnosemantics (also referred to as ethnoscience or cognitive anthropology), Boasian cultural semantics (linguistically inspired anthropology) and Neohumboldtian comparative semantics (word-field theory, or content-oriented Linguistics). In Chapter 5, Goddard underlines the fact that ethnopragmatics investigates emic (or culture-internal) approaches to the use of different speech practices across various world languages, which accounts for the fact that there exists a connection between the cultural values or norms and the speech practices peculiar to a speech community. One of the key objectives of ethnopragmatics is to investigate ‘cultural key words’, i.e. words that encapsulate culturally construed concepts. The concept of ‘linguaculture’ (or languaculture) is tackled in Risager’s Chapter 6, Linguaculture: the language–culture nexus in transnational perspective. The author makes reference to American scholars that first introduced this notion, Paul Friedrich, who looks at language and culture as a single domain in which verbal aspects of culture are mingled with semantic meanings, and Michael Agar, for whom culture resides in language while language is loaded with culture. Risager himself brought forth a new global and transnational perspective on the concept of linguaculture, i.e. the use of language (linguistic practice) is seen as flows in people’s social networks and speech communities. These flows enhance as people migrate or learn new languages, in permanent dynamics. Lidia Tanaka’s Chapter 7, Language, gender, and culture deals with research on language, gender, and culture. According to her, the language-gender relationship has been studied by researchers from various fields, including psychology, linguistics, and anthropology, who mainly consider gender as a construct that preserves inequalities in society, with the help of language, too. Tanaka lists diachronically different approaches to language and gender, focusing on three specific ones: gender stereotyped linguistic resources, semantically, pragmatically or lexically designated language features (including register) and gender-based spoken discourse strategies (talking-time imbalances or interruptions). In Chapter 8, Language, culture, and context, Istvan Kecskes delves into the relationship between language, culture, and context from a socio-cognitive perspective. The author considers culture to be a set of shared knowledge structures that encapsulate the values, norms, and customs that the members of a society have in common. According to him, both language and context are rooted in culture and carriers of it, though reflecting culture in a different way. Language encodes past experience with different contexts, whereas context reflects present experience. The author also provides relevant examples of formulaic language that demonstrate the functioning of both types of context, within the larger interplay between language, culture, and context. Sara Miller’s Chapter 9, Language, culture, and politeness reviews traditional approaches to politeness research, with particular attention given to ‘discursive approach’ to politeness. Much along the lines of the previous chapter, Miller stresses the role of context in judgements of (im)polite language, maintaining that individuals represent active agents who challenge and negotiate cultural as well as linguistic norms in actual communicative contexts. Chapter 10, Language, culture, and interaction, by Peter Eglin focuses on language, culture and interaction from the perspective of the correspondence theory of meaning. According to him, abstracting language and culture from their current uses, as if they were not interdependent would not lead to an understanding of words’ true meaning. David Kronenfeld introduces in Chapter 11, Culture and kinship language, a review of research on culture and kinship language, starting with linguistic anthropology. He explains two formal analytic definitional systems of kinship terms: the semantic (distinctions between kin categories, i.e. father vs mother) and pragmatic (interrelations between referents of kin terms, i.e. ‘nephew’ = ‘child of a sibling’). Chapter 12, Cultural semiotics, by Peeter Torop deals with the field of ‘semiotics of culture’, which may refer either to methodological instrument, to a whole array of methods or to a sub-discipline of general semiotics. In this last respect, it investigates cultures as a form of human symbolic activity, as well as a system of cultural languages (i.e. sign systems). Language, as “the preserver of the culture’s collective experience and the reflector of its creativity” represents an essential component of cultural semiotics, being a major sign system. Nigel Armstrong, in Chapter 13, Culture and translation, tackles the interrelation between language, culture, and translation, with an emphasis on the complexities entailed by translation of culturally laden aspects. In his opinion, culture has a double-sided dimension: the anthropological sense (referring to practices and traditions which characterise a community) and a narrower sense, related to artistic endeavours. However, both sides of culture permeate language at all levels. Chapter 14, Language, culture, and identity, by Sandra Schecter tackles several approaches to research on language, culture, and identity: social anthropological (the limits at play in the social construction of differences between various groups of people), sociocultural (the interplay between an individual’s various identities, which can be both externally and internally construed, in sociocultural contexts), participatory-relational (the manner in which individuals create their social–linguistic identities). Patrick McConvell, in Chapter 15, Language and culture history: the contribution of linguistic prehistory reviews research in this field where historical linguistic evidence is exploited in the reconstruction and understanding of prehistoric cultures. He makes an account of research in linguistic prehistory, with a focus on proto- and early Indo-European cultures, on several North American language families, on Africa, Australian, and Austronesian Aboriginal languages. McConvell also underlines the importance of interdisciplinary research in this area, which greatly benefits from studies in other disciplines, such as archaeology, palaeobiology, or biological genetics. Part four starts with Ning Yu’s Chapter 16, Embodiment, culture, and language, which gives an account of theory and research on the interplay between language, culture, and body, as seen from the standpoint of Cultural Linguistics. Yu presents a survey of embodiment (in embodied cognition research) from a multidisciplinary perspective, starting with the rather universalistic Conceptual Metaphor Theory. On the other hand, Cultural Linguistics has concentrated on the role played by culture in shaping embodied language, as various cultures conceptualise body and bodily experience in different ways. Chapter 17, Culture and language processing, by Crystal Robinson and Jeanette Altarriba deals with research in the field of how culture influence language processing, in particular in the case of bilingualism and emotion, alongside language and memory. Clearly, the linguistic and cultural character of each individual’s background has to be considered as a variable in research on cognition and cognitive processing. Frank Polzenhagen and Xiaoyan Xia, in Chapter 18, Language, culture, and prototypicality bring forth a survey of prototypicality across different disciplines, including cognitive linguistics and cognitive psychology. According to them, linguistic prototypes play a critical part in social (re-)cognition, as they are socially diagnostic and function as linguistic identity markers. Moreover, individuals may develop ‘culturally blended concepts’ as a result of exposure to several systems of conceptual categorisation, especially in the case of L2 learning (language-contact or culture-contact situations). In Chapter 19, Colour language, thought, and culture, Don Dedrick investigates the issue of the colour words in different languages and how these influence cognition, a question that has been addressed by researchers from various disciplines, such as anthropology, linguistics, cognitive psychology, or neuroscience. He cannot but observe the constant debate in this respect, and he argues that it is indeed difficult to reach consensus, as colour language occasionally reveals effects of language on thought and, at other times, it is impervious to such effects. Chapter 20, Language, culture, and spatial cognition, by Penelope Brown concentrates on conceptualisations of space, providing a framework for thinking about and referring to objects and events, along with more abstract notions such as time, number, or kinship. She lists three frames of reference used by languages in order to refer to spatial relations, i.e. a) an ‘absolute’ coordinate system, like north, south, east, west; b) a ‘relative’ coordinate system envisaged from the body’s standpoint; and c) an intrinsic, object-centred coordinate system. Chris Sinha and Enrique Bernárdez focus on, in Chapter 21, Space, time, and space–time: metaphors, maps, and fusions, research on linguistic and cultural concepts of time and space, starting with the seminal Conceptual Metaphor Theory (CMT), which they denounce for failing to situate space–time mapping within the broader patterns of culture and world perspective. Sinha and Bernárdez further argue that although it is possible in all cultures for individuals to experience and discuss about events in terms of their duration and succession, the specific words and concepts they use to refer to temporal landmarks temporal and duration are most of the time language and culture specific. Chapter 22, Culture and language development, by Laura Sterponi and Paul Lai provides an account of research on the interplay between culture and language acquisition. They refer to two widely accepted perspectives in this respect: a developmental mechanism inherent in human beings and a set of particular social contexts in which children are ‘initiated’ into the cultural meaning systems. Both perspectives define culture as “both related to the psychological make-up of the individual and to the socio-historical contexts in which s/he is born and develops”. Anna Wierzbicka presents, in Chapter 23, Language and cultural scripts discusses representations of cultural norms which are encoded in language. She contends that the system of meaning interpretation developed by herself and her colleagues, i.e. Natural Semantic Metalanguage (NSM), may easily be used to capture and convey cultural scripts. Through NSM cross-cultural experiences can be captured in a thorough manner by using a reduced number of conceptual primes which seem to exist in all languages. Chapter 24, Culture and emotional language, by Jean-Marc Dewaele brings forth the issue of the relationship between language, culture, and emotion, which has been researched by cultural and cognitive psychologists and applied linguists alike, although with some differences in focus. He considers that within this context, it is important to see differences between emotion contexts in bilinguals, since these may lead to different perceptions of the self. He infers that generally, culture revolves around the experience and communication of emotions, conveyed through linguistic expression. The fifth part starts with Chapter 25, Language and culture in sociolinguistics, by Meredith Marra, who underlines that culture is a central concept in Interactional Sociolinguistics, where language is considered as social interaction. In linguistic interaction, culture, and especially cultural differences are deemed as a cause of potential miscommunication. Mara also remarks that the paradigm change in sociolinguistics, from Interactional Sociolinguistics to social constructionism reshaped ‘culture’ into a more dynamic as well as less rigid concept. Claudia Strauss’ Chapter 26, Language and culture in cognitive anthropology deals with the relationship between human society and human thought/thinking. The author contends that cognitive anthropologists may be subdivided into two groups, i.e. ones that are concerned with the process of thinking (cognition-in-practice scholars), and the others focusing on the product of thinking or thoughts (concerned with shared cultural understandings). She goes on to explore how different approaches to cognitive anthropology have counted on units of language, i.e. lexical items and their meanings, along with larger chunks of discourse, as information, which may represent learned cultural schemata. Part VI starts with Chapter 27, Language and culture in second language learning, by Claire Kramsch, in which she makes a survey of the definition of ‘culture’ in foreign language learning and its evolution from a component of literature and the arts to a more comprehensive purport, that of culturally appropriate use of language, along with an appropriate use of sociopragmatic and pragmalinguistic norms. According to her, in the postmodern era, communication is not only mere transmission of information, it represents construal and positioning of the self and of self-identity. Chapter 28, Writing across cultures: ‘culture’ in second language writing studies, by Dwight Atkinson focuses on the usefulness of culture in second-language writing (SLW). He reviews several approaches to the issue: contrastive rhetoric (dealing with the impact of first-language patterns of text organisation on writers in a second language), or even alternate notions, like‘ cosmopolitanism’, ‘critical multiculturalism’, and hybridity, as of late native culture is becoming irrelevant or at best far less significant. Ian Malcolm tackles, in Chapter 29, Language and culture in second dialect learning, the issue of ‘standard’ Englishes (e.g., Standard American English, Standard Australian English) versus minority ‘non-standard’ speakers of English. He deplores the fact that in US specialist literature, speaking the ‘non-standard’ variety of English was associated with cognitive, cultural, and linguistic insufficiency. He further refers to other specialists who have demonstrated that ‘non-standard’ varieties can be just as systematic and highly structured as the standard variety. Chapter 30, Language and culture in intercultural communication, by Hans-Georg Wolf gives an account of research in intercultural education, focusing on several paradigms, i.e. the dominant one, investigating successful functioning in intercultural encounters, the minor one, exploring intercultural understanding and the ‘deconstructionist, and or postmodernist’. He further examines different interpretations of the concepts associated with intercultural communication, including the functionalist school, the intercultural understanding approach and a third one, the most removed from culture, focusing on socio-political inequalities, fluidity, situationality, and negotiability. Andy Kirkpatrick’s Chapter 31, World Englishes and local cultures gives a synopsis of research paradigm from applied linguistics which investigates the development of Englishes around the world, through processes like indigenisation or nativisation of the language. Kirkpatrick discusses the ways in which new Englishes accommodate the culture of the very speech community which develops them, e.g. adopting lexical items to express to express culture-specific concepts. Speakers of new varieties could use pragmatic norms rooted in cultural values and norms of the specific new speech community which have not previously been associated with English. Moreover, they can use these new Englishes to write local literatures, often exploiting culturally preferred rhetorical norms. Part seven starts with Chapter 32, Cultural Linguistics, by Farzad Sharifian gives an account of the recent multidisciplinary research field of Cultural Linguistics, which explores the relationship between language and cultural cognition, particularly in the case of cultural conceptualisations. Sharifian also brings forth illustrations of how cultural conceptualisations may be linguistically encoded. The last chapter, A future agenda for research on language and culture, by Roslyn Frank provides an appraisal of Cultural Linguistics as a prospective path for research in the field of language and culture. She states that ‘Cultural Linguistics could potentially create a paradigm that “successfully melds together complementary approaches, e.g., viewing language as ‘a complex adaptive system’ and bringing to bear upon it concepts drawn from cognitive science such as ‘distributed cognition’ and ‘multi-agent dynamic systems theory’.” She further asserts that Cultural Linguistics has the potential to function as “a bridge that brings together researchers from a variety of fields, allowing them to focus on problems of mutual concern from a new perspective” and most likely unveil new issues (as well as solutions) which have not been evident so far. In conclusion, the Handbook will most certainly serve as clear and coherent guidelines for scholarly thinking and further research on language and culture, and also open up new investigative vistas in each of the areas tackled.

Russia's military aggression against Ukraine has globally transformed the media landscape. Facing global challenges, the world's media began to continuously publicize the unacceptable violations and catastrophic Russian armed aggression consequences. On February 24, 2022, Russia attacked Ukraine, and these events prompted both Ukrainian and global journalists to refocus on wartime conditions. This work is a compilation of theoretical and methodological approaches that may be useful for the study of the discourse transformations within media discourse. The work is time-limited, but it is during the period in question that the “language issue” roared throughout the pages. The idea of combining the concept of discourse, sociolinguistics, and lexico-semantics to understand the discursive and linguistic event was proposed. These methodologies were grouped around ideas that recognize the relevance of English-language mass media. To study a linguistic event such as the Ukrainian war, the empirical part aimed to illustrate how proceedings such as guilt, linguistic conflict, can be investigated by methods of discourse analysis and other linguistic phenomena. Such a constructivist approach develops the working hypothesis that nomination (as a discursive record) varies according to the work and sociopolitical stakes of the speaker.

Abstract We performed observations of the HC3N (24–23, 17–16, 11–10, 8–7) lines towards a sample consisting of 19 Galactic massive star-forming regions with the Arizona Radio Observatory 12 m and Caltech Submillimeter Observatory 10.4 m telescopes. HC3N (24–23, 17–16, 11–10, 8–7) lines were detected in sources except for W 44, where only HC3N (17–16, 11–10) were detected. Twelve of the nineteen sources showed probable line wing features. The excitation temperatures were estimated from the line ratio of HC3N (24–23) to HC3N (17–16) for 18 sources and are in the range 23– 57 K. The line widths of higher-J transitions are larger than lower-J ones for most sources. This indicates that the inner dense warm regions have more violent turbulence or other motions (such as rotation) than outer regions in these sources. A possible cutoff tendency was found around LIR ∼ 106 L⊙ in the relation between LIR and full width at half maximum line widths.

The deployment of the innate immune system in humans is essential to protect us from infection. Human cathelicidin LL-37 is a linear host defense peptide with both antimicrobial and immune modulatory properties. Despite years of studies of numerous peptides, SK-24, corresponding to the long hydrophobic domain (residues 9–32) in the anionic lipid-bound NMR structure of LL-37, has not been investigated. This study reports the structure and activity of SK-24. Interestingly, SK-24 is entirely helical (~100%) in phosphate buffer (PBS), more than LL-37 (84%), GI-20 (75%), and GF-17 (33%), while RI-10 and 17BIPHE2 are essentially randomly coiled (helix%: 7–10%). These results imply an important role for the additional N-terminal amino acids (likely E16) of SK-24 in stabilizing the helical conformation in PBS. It is proposed herein that SK-24 contains the minimal sequence for effective oligomerization of LL-37. Superior to LL-37 and RI-10, SK-24 shows an antimicrobial activity spectrum comparable to the major antimicrobial peptides GF-17 and GI-20 by targeting bacterial membranes and forming a helical conformation. Like the engineered peptide 17BIPHE2, SK-24 has a stronger antibiofilm activity than LL-37, GI-20, and GF-17. Nevertheless, SK-24 is least hemolytic at 200 µM compared with LL-37 and its other peptides investigated herein. Combined, these results enabled us to appreciate the elegance of the long amphipathic helix SK-24 nature deploys within LL-37 for human antimicrobial defense. SK-24 may be a useful template of therapeutic potential.

This paper considers the degree to which events that intensify partying increase sexual assault. Estimates are based on panel data from campus and local law enforcement agencies and an identification strategy that exploits plausibly random variation in the timing of Division 1 football games. The estimates indicate that these events increase daily reports of rape with 17–24-year-old victims by 28 percent. The effects are driven largely by 17–24-year-old offenders and by offenders unknown to the victim, but we also find significant effects on incidents involving offenders of other ages and on incidents involving offenders known to the victim. (JEL I23, J16, K42, Z13)

SUMMARY The purpose of this study was to evaluate the retention rates of a fissure sealant placed using different adhesive protocols over 24 months. Twenty-four subjects with no restorations or caries received fissure sealants (Clinpro Sealant, 3M ESPE) placed using different adhesive protocols. A total of 292 sealants were placed as follows by two previously calibrated dentists using a table of random numbers (n=73): group I, acid-etch/without adhesive; group II, with a self-etch adhesive (Adper Easy Bond, 3M ESPE); group III, with an etch-and-rinse adhesive (Adper Single Bond 2, 3M ESPE); group IV, with acid + self-etch adhesive (Adper Easy Bond). Two other calibrated examiners independently evaluated the sealants at baseline and at six-, 12-, 18-, and 24-month recalls. Each sealant was evaluated in terms of caries formation being present or absent and retention using the following criteria: 1 = total retention, 2 = partial loss, and 3 = total loss. Pearson's χ2 test was used to evaluate differences in retention rates among the sealants for each evaluation period. At the end of 24 months, total retention rates were 57.5%, 27.4%, 84.9%, and 76.7% in the acid-etch, self-etch adhesive, etch-and-rinse adhesive, and acid + self-etch adhesive groups, respectively. Although there were no statistically significant differences between the retention rates among the adhesive protocols at 6 months (p=0.684), significant differences were observed at the 12-, 18-, and 24-month evaluations. At 24 months, the lowest retention rates were observed in the self-etch group (p&lt;0.05). No caries development was observed in any of the groups. The retention rate of sealants placed using self-etch adhesive was poor compared with the other groups.

Abstract Jesus begins his ministry with appeals to Elijah and the widow, making bold and controversial claims about the true beneficiaries of the kingdom of God (Luke 4:25–26; cf. 1 Kgs 17:8–24). Although commentators recognize subsequent allusions to this episode throughout Luke-Acts, these are generally noted in passing and in isolation from each other. This article draws from recent studies that examine “redundant” narrations in the Lukan narrative, applying the same methodology to the phenomenon of the narrator’s repetitive reappropriation of a given OT episode. In examining repeated appeals to the Zarephath account within the Lukan narrative (Luke 4:26; 7:11–17; Acts 9:32–43; 20:7–12; cf. 1 Kgs 17:17–24), it is argued that these passages, when linked together, create a literary arc that spans almost the entirety of Luke-Acts. Viewed as a whole, this arc highlights the unfolding understanding of the true people of God in Lukan theology.

Androgens act in concert with vitamin D to influence reabsorption of calcium. However, it is unclear whether androgens directly regulate vitamin D homeostasis or control other cellular events that are related to vitamin D metabolism. To examine whether the expression of vitamin D-related genes in mouse kidney is driven by androgens or androgen-dependent effects, the androgen receptor and other sex steroid receptors were monitored in orchidectomized mice treated with 5α-dihydrotestosterone (DHT). Our results revealed that exposing orchidectomized mice to DHT inhibited the expression of progesterone receptor (Pgr) with or without estrogen receptor α expression, the latter was confirmed by ER-positive (MCF7 and T47D) or -negative (PCT) cells analysis. The loss of Pgr in turn decreased the expression of renal 24-hydroxylase via transcriptional regulation because Cyp24a1 gene has a progesterone receptor-binding site on promoter. When male kidneys preferentially hydroxylate 25-hydroxyvitamin D3 using 24-hydroxylase rather than 25-hydroxyvitamin D3-1-alpha hydroxylase, DHT suppressed the Pgr-mediated 24-hydroxylase expression, and it is important to note that DHT increased the blood 25-hydroxyvitamin D3 levels. These findings uncover an important link between androgens and vitamin D homeostasis and suggest that therapeutic modulation of Pgr may be used to treat vitamin D deficiency and related disorders.

Background:Spondyloarthritis (SpA) refers to a heterogeneous group of disorders with clinical features that can include axial and peripheral arthritis, inflammatory bowel disease, uveitis, and psoriasis. Several cytokines including interleukin (IL)-12/23, IL-17 and tumor necrosis factor (TNF) are involved in pathogenesis of SpA. It is assumed that TNF is the upstream cytokine in the cytokine cascade (Schett, et al., 2013).Objectives:To investigate whether TNF inhibitors decrease serum IL-12/23 and IL-17 levels in patients with SpA.Methods:Serum were obtained from 23 SpA patients (AS, 10 patients; PsA, 13 patients) enrolled in this study, at baseline, 24 and 48 weeks of TNF inhibitor treatment. Serum IL-12/23 and IL17 levels were measured using LEGEND MAX Human IL-12/IL-23 (p40) ELISA Kit (BioLegend) and Human IL-17A ELISA kit (Invitrogen), respectively. IL-6 levels, the other downstream cytokine, was measured using Lumipulse G600II (FUJIREBIO) as a control.Results:Any significant reduction in IL-12/23 levels (143.9±143.6 pg/mL at baseline, 156.3±117.1 pg/mL at 24 weeks and 139.3±118.1 pg/mL at 48 weeks), as well as that in IL-17 levels (13.6±51.9 pg/mL at baseline, 12.3±41.4 pg/mL at 24 weeks and 11.6±39.2 pg/mL at 48 weeks) were not observed in 23 SpA patients. On the other hand, serum IL-6 levels were significantly decreased after treatment (4.0±4.2 pg/mL at baseline; 1.8±1.4 pg/mL,p=0.002, at 24 weeks; 1.6±1.9 pg/mL,p=0.0002at 48 weeks. Pain-VAS was significantly reduced at 24 and 48 weeks compared with that at baseline. No significant differences in serum levels of analyzed cytokines were observed in the AS group compared with the PsA group at baseline (IL-12/23 levels: 110.8±70.0 vs.169.3±180.3 pg/mL,p=0.28; IL-17 levels: 26.8±78.6 vs. 3.4±7.6pg/mL,p=0.08).Conclusion:TNF inhibitors did not alter serum IL-12/23 and IL-17 levels but reduced IL-6 levels in patients with SpA. These results imply that IL-12/23 and IL-17 expression might be regulated by alternative pathways.References:[1]Schett, et al. Toward a cytokine-based disease taxonomy. Nat Med. 2013 Jul; 19 (7):822-4Disclosure of Interests:Miho Murakami Grant/research support from: Chugai, Eisai, Consultant of: Chugai, Norihiro Nishimoto Grant/research support from: Chugai, Eisai, Consultant of: Chugai, Speakers bureau: Chugai, Eisai, AYUMI, Mitsubishi Tanabe, AbbVie, Novartis, Nippon Kayaku, TOWA, Astellas, Kyowa Kirin

This study investigated the effect of experimentally-induced cholestasis in the rat on the structure and function of the zona fasciculata, the glucocorticoid secretory region of the adrenal cortex. Wistar-Furth rats (200-250g) were assigned to three groups: bile duct ligated (BDL), Sham operated (Sham) and unmodified normal control (NC). On day 14, serum bilirubin and liver histology were performed to confirm cholestasis in BDL animals together with basal 24 hour 17-hydroxycorti-costeroid excretion, adrenal histology and zona fasciculata ultrastructure in all experimental groups. Following this laparotomy, structural and functional studies were repeated on day 15 to evaluate the response of the gland to surgically induced stress. Basal 24 hr. 17-hydroxycorticoid steroid excretion was elevated in BDL animals (26.9 ±3.2 μ g/24 hr) with respect to Sham (10.4 ± 2.3) and NC groups (13.5 ± 3.2) (p <0.05). Adrenal histology and ultrastructural studies demonstrated excessive accumulation of vesicles laden with glucocorticoid biogenic precursors. Following surgical stress 24 hr 17 OH corticosteroid excretion increased in all groups: BDL (31.0 ± 3.0 μg/24 hr) vs Sham (15.6 ± 1.8) and NC (14.5 ± 2.4) Moderate alterations in zona fasciculata architecture were seen following surgery in all groups. Cholestasis induces overactivity of the zona fasciculata of the adrenal cortex, and may modify the normal metabolic responses to surgical and other stresses.

ABSTRACT The activities of garenoxacin, ciprofloxacin, levofloxacin, moxifloxacin, trovafloxacin, amoxicillin-clavulanate, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 20 anaerobes were tested. At two times the MIC, garenoxacin was bactericidal against 19 of 20 strains after 48 h and against 17 of 20 after 24 h. Other drugs, except clindamycin (which gave lower killing rates), gave killing rates similar to those for garenoxacin.

Abstract Abstract 875 Introduction: Childhood AMKL has heterogeneous clinical presentations with two major subcategories: AMKL in patients with Down syndrome (DS-AMKL) and AMKL in patients without DS (non-DS-AMKL). Related to DS-AMKL is the transient abnormal myelopoiesis (TAM), observed in neonates with DS, is considered to be a self-limited leukemia in most cases; only 20% of TAM patients develop AMKL within 4 years. The pathogenetic relationship is further illustrated by the presence of somatic mutations of GATA1 gene in children with both TAM and DS-AMKL. However, progression from TAM to AMKL may require acquisition of additional genetic alterations. Furthermore, little is known about the kinds of genetic alterations involved in the pathogenesis of non-DS-AMKL. Patients and methods: To investigate the mechanism of leukemogenesis, we comprehensively analyzed the molecular lesions in childhood AMKL (DS-AMKL, N=24; non-DS-AMKL, N=13; TAM, N=17) using single nucleotide polymorphism array (SNP-array) and mutation analysis of 9 genes, including GATA1, JAK3, JAK2, p53, FLT3, N-RAS, KIT, MPL and ASXL1. The diagnosis of TAM and AMKL was based on morphology, histopathology, the expression of megakaryocyte-specific antigens (CD41, CD42 or CD61) and/or the French-American-British (FAB) classification. The diagnosis of DS was confirmed by conventional cytogenetic analysis. Bone marrow or blood samples were obtained from the patients with TAM and AMKL at diagnosis after obtaining informed consent for banking and molecular analyses from the children's parents. Mutational screen was performed using Sanger sequencing of PCR amplified DNA. A high-density Affymetrix 6.0 SNP-array was used for karyotyping and copy number changes. Results: SNP array analysis revealed somatic gains other than trisomy 21 in 11/11 of DS-AMKL and in 7/12 of non-DS-AMKL, respectively including recurrent duplication of 1q in 4/11 patients with DS-AMKL (Table 1). Deletions were found in 8/11 and 5/12 of DS-AMKL and non-DS-AMKL, respectively. They included del(13p) in 2/11 patients with DS-AMKL and 1/12 with non-DS-AMKL, and del(17p) in 1/11 patients with DS-AMKL and 1/12 with non-DS-AMKL. A hemizygous p53 mutation was found in the DS-AMKL patient with del(17p). Uniparental disomy was found in 2 patients with DS-AMKL. The frequencies of the gene mutations in the DS-AMKL, non-DS-AMKL and TAM patients were distributed as follows: GATA1 (24/24, 1/13, 17/17, respectively), JAK3 (3/24, 1/13, 1/17, respectively), JAK2V617F (1/24, 0/13, 0/17, respectively), p53 (3/24, 0/13, 1/17, respectively), and ASXL1 (0/24, 1/13, 0/17, respectively) (Table 1). Mutations in the other genes were not detected. Two patients with DS-AMKL who had bone marrow samples at the TAM stage did not have additional gene mutations other than GATA1 mutations. Four gene mutations (GATA1, JAK3, JAK2, p53) were found in 1 patient with DS-AMKL, who did not respond to conventional chemotherapy and died of disease progression. The ASXL1 gene mutation was found in 1 patient with non-DS-AMKL who had additional chromosome abnormality t(1;22)(p13;q13) in his leukemic cells. Conclusions: Considering the different patterns of molecular lesions, DS-AMKL needs to be classified into a different category than non-DS-AMKL. Disclosures: No relevant conflicts of interest to declare.

It is widely recognized not only that Luke was a literary artist but that his literary methods involved specifically Hellenistic approaches and techniques. The primary purpose of this article is to indicate that the enigmatic relationship of part of Luke's text (7. 11–17, the raising of the widow's son) to part of the LXX text (1 Kgs 17. 17–24, Elijah's raising of the widow's son) is aliteraryrelationship, a relationship which is the result of a sophisticated and coherent process of dramatization and christianization. The article is also intended to suggest briefly that this literary relationship is to be understood, in considerable part, in light of the Hellenistic literary practice known asimitatio, and that the practice ofimitatiomay be an important clue in detecting and unravelling other areas of Luke's sources.

293 Background: We report the safety and clinical activity of CaboNivo and CaboNivoIpi in pts with mUC and other GU tumors. Methods: Part I included 4 dose levels (DLs) (Cabo PO daily and Nivo IV q2wk): DL1 Cabo40/Nivo1, DL2 Cabo40/Nivo3, DL3 Cabo60/Nivo1, DL4 Cabo 60/Nivo3. Part II included 3 DLs (Cabo PO daily, plus NivoIpi IV q3 wk x 4 doses then Nivo q2wk): DL5 Cabo 40/Nivo1/Ipi1, DL6 Cabo40/Nivo3/Ipi1, DL7 Cabo 60/Nivo3/Ipi 1. Tumors were assessed for overall response rate (ORR) by RECIST 1.1. Adverse events (AEs) were graded (G) by NCI-CTCAE v4.0. Results: From 7/22/15-10/14/16, 40pts [mUC N=14/(plasmacytoid N=1); bladder urachal N=4; bladder squamous cell carcinoma (bSCC) N=2; germ cell tumor (GCT) N=4; castrate-resistant prostate cancer (CRPC) N=9/(neuroendocrine prostate N=1); sarcomatoid renal cell carcinoma (sRCC) N=1; trophoblastic tumor N=1); sertoli cell tumor N=1; and penile SCC N=4] were treated. Median age was 58 (range 31-77); 36 (90%) were male. AEs related to study drugs with [1] CaboNivo included G3 hyponatremia 4/24 (17%), hypophosphatemia 4/24 (17%), lipase increase 3/24 (13%), dehydration 2/24 (8%), diarrhea 2/24 (8%), fatigue 2/24 (8%), HTN 2/24 (8%), thromboembolic event 1/24 (4%), rash 1/24 (4%), chest pain 1/24 (4%), amylase increase 1/24 (4%), hyperthyroid 1/24 (4%), proteinuria 1/24 (4%), thrombocytopenia 1/24 (4%); and G4 pyelonephritis 1/24 (4%); [2] CaboNivoIpi included G3 hypophosphatemia 2/16 (13%), lipase increase 2/16 (13%), fatigue 1/16 (6%), ALT increase 1/16 (6%), and HTN 1/16 (6%). There were 2/40 (5%) G3 immune-related AEs: 1 aseptic meningitis/CaboNivo; and 1 colitis/CaboNivoIpi. There were no G5 toxicities, or DLTs. 38 pts were evaluable for response. ORR was 12/38 (32%): 1 CR (bSCC); 11 PRs (5 mUC, 1 sRCC, 1 urachal, 1 bSCC, 1 CRPC, 2 penile). SD 20/38 (53%); 9/11 responses were ongoing and 26/39 (67%) pts remain on study. Conclusions: CaboNivo and CaboNivoIpi were well tolerated with no DLTs. Responses were seen at all DLs. The recommended dose for Part I is Cabo40/Nivo3 and for Part II is Cabo40/Nivo3/Ipi1. Rare tumors such as bSCC, urachal, and penile cancer demonstrated responses. Clinical trial information: NCT02496208.

BackgroundLimited dosing guidelines exist for overweight children (≈30% pediatric population). This prospective study examines the pharmacokinetics (PK) of pantoprazole (CYP2C19 substrate) in overweight vs. normal-weight children.MethodsUsing TaqMan techniques, 51 children (6–17 yrs) were genotyped for CYP2C19 loss-of-function (*2, *3, *4) and gain-of-function (*17) alleles. After a single oral dose of pantoprazole (1.2 mg/kg lean body weight), 10 plasma samples were collected over 8hrs, pantoprazole/metabolite concentrations measured by HPLC-UV, and PK parameters generated via non-compartmental methods. Using a two-tailed unpaired t-test, parameters were compared between overweight/obese (n=24) and normal-weight (n=25) children, and the effect of CYP2C19 genotype (*1/*1, n=24; *1/*17, n=15; *1/*2, n=7; *2/*17, n=3; *2/*2, n=2) on drug disposition was analyzed using a one-way ANOVA; α=0.05.ResultsDose-adjusted AUCtot, CL/F and other PK parameters were not significantly different between overweight/obese and normal-weight children. Independent of weight, mean AUCtot for pantoprazole was 2-fold greater in children with 1 loss-of-function vs. 1 gain-of-function allele (p=0.01). CL/F was increased only in children with *1/*17 genotype compared to all other genotypes (p<0.03), except *2/*17. In children with *1/*1 genotype (n=24), CL/F was significantly reduced (0.25±0.1 vs. 0.41±0.23 L/h/kg; p<0.05) and AUCtot increased (5.3±3.5 vs. 3.1±1.5 mg*h/L; p=0.05) in overweight/obese vs. normal-weight children. AUCtot was significantly increased in obese vs. normal-weight children (8.1±4.6 vs. 3.1±1.5 mg*h/L; p<0.05), with a positive correlation observed between AUCtot and BMI (r2=0.4; p=0.01).ConclusionsCYP2C19 genotype appears to be the primary determinant of pantoprazole PK in children, whereas BMI may explain individual variability within genotype groups.

Background:Schnitzler’s syndrome is an autoinflammatory disease characterized by monoclonal gammopathy and recurrent episodes of urticaria accompanied by clinical and laboratory signs of acute inflammation. Although the exact pathogenic mechanisms have not been fully clarified, the role of Interleukin-1 seems to be central.Objectives:To describe clinical features and therapeutic approach in patients with Schnitzler’s Syndrome.Methods:Retrospective analysis of an Italian multicenter cohort. Data are expressed as the median (IQR).Results:The clinical data of 24 patients from 9 centers (median follow-up 6 years [2-10]; median age at diagnosis 56.5 years [51.25-64.25]) were collected. The median diagnostic delay was 2 years (0-10); the diagnosis was made consensually at the onset of symptoms in 4 cases. The main clinical and laboratory features are shown in Table 1. Therapeutic response was evaluable in 20 patients: all received corticosteroids (CS; 25mg/day [25-50]); in one case, a good clinical response was observed. Eight patients were initially treated with colchicine: in 3 cases it was effective in controlling symptoms and reducing the dose of CS; other 8 patients were treated with csDMARDs (n:1 [1-2]): only 1 patient had a good response to cyclosporin.Table 1.Clinical and laboratory featuresChronic Urticarial Rash, n (%)24/24 (100)Pruritus, n (%)17/24 (71)Intermittent fever, n (%)23/24 (96)Arthralgia/Arthritis, n (%)20/24 (83)Bone pain, n (%)8/24 (33)Weight loss, n (%)9/24 (38)Angioedema, n (%)4/24 (17)Lymphoadenopathy, n (%)7/24 (29)Hepatomegaly, n (%)3/24 (12)Splenomegaly, n (%)3/24 (12)Neuropathy, n (%)4/24 (17)Raised ESR or CRP, n (%)24/24 (100)Leukocytosis, n (%)17/24 (71)Anemia, n (%)9/24 (38)Monoclonal GammopathyIgG λ, n (%)5/22 (23)IgG κ, n (%)6/22 (27)IgM λ, n (%)1/22 (5)IgM κ, n (%)12/22 (55)Bence Jones Protein, n (%)6/23 (26)A bDMARD was initiated in 15 patients. In 7 of the 14 patients initially treated with anakinra this therapy was continued with benefit whereas in the other 7 patients the treatment was discontinued for primary inefficacy (1 patient), secondary inefficacy (3 patients) and adverse events (3 patients; 2 injection site reaction, 1 severe allergic reaction). After anakinra discontinuation, 5 patients were treated with canakinumab with a good response in 3 cases and a partial response in 1 case (persistent arthritis); 1 patient died during the treatment. No response was observed in 3 patients treated with TNF inhibitors as a 2ndor 3rdline bDMARDs, as well as in 1 case initially treated with tocilizumab (in which a good response was afterwards obtained with canakinumab). bDMARDs were associated with a csDMARD in 2 patients (methotrexate and methotrexate + cyclosporine).In one case monoclonal gammopathy evolved into Multiple Myeloma and the patient died 15 years after the onset of symptoms. Idiopathic myelofibrosis and myelodysplasia were found in one and in two patients, respectively.Conclusion:In most cases csDMARDs and bDMARDs like anti-IL6 and anti-TNFα were not able to control the disease. In contrast, in some cases, a good response to colchicine was observed; refractory patients may be successfully treated with anti-IL1 agents. Patients should be supervised for possible evolution towards lymphoproliferative disease.Disclosure of Interests:None declared

The data of visual measurements of the magnetic field in sunspots umbra, obtained in four observatories during 24 cycles of solar activity, are compared. Magnetic field strength modules with averaging over each observatory are analyzed. The measurements taken in the Astronomical Observatory of the University of Kyiv (KAO) were used as base, where 170 spots were measured on average 4 times each at intervals of one to two daysduring the group passing through the solar disk. Measurements of the Ural, Crimean and Mount Wilson Observatory, performed within 24 hours of observation in the KAO, are used in the study. It was found that the average value of the magnetic field per cycle, obtained from the data of three observatories UrAO, CrAO and KAO, was 26.0 ± 0.3, 25.0 ± 0.2 and 25.2 ± 0.2 cT, respectively. They differ by no more than 3 standard errors, while the Mount Wilson Observatory gives a significantly lower magnetic field – 23.8 ± 0.1 cT. This result is confirmed by the work of R. Rezaei et al., 2015, which compares the visual measurements in Mount Wilson with Tenerife Infrared Polarimeter (TIP) and Facility InfRared Spectropolarimeter (FIRS) for the 23rd and 24th cycle of solar activity. The average magnetic field value for observations of TIP and FIRS in 24 cycles is 26.0 cT, which is slightly higher than we obtained from the visual observations of three observatories, while MtW shows a few centitesla less. The mean square error of the average per cycle of the magnetic field, based on the data of TIP and FIRS is 0.2 cT, so the difference with the MtW is reliable. An understatement of the measured intensity of the magnetic field of the spots requires a revision of the measurement calibration in Mount Wilson. The data of the Crimean Astrophysical Observatory can be considered reference for subsequent comparisons with the results of observations of other observatories. For the calculation of the annual index Bsp of magnetic fields of sunspot size 22-44 Mm, the data of visual measurements of all 4 observatories are traditionally used. We have found that variations in the magnetic field of sunspots are the same as in previous cycles: the peak occurs in the second-third years after the maximum number of spots. The average for the 24 cycle Bsp index is 24.9 ± 0.3 сT, which allows us to consider this magnetic cycle as moderately strong. Reduction of the sunspots magnetic field in 2018 to 23 cT allows it to expect in 2019 the highest near-ground level of galactic cosmic rays in the last half century.

Abstract The Th17 response has been associated with autoimmune diseases in patients and in animal models. IL-17A is recognized as the Th17 signature cytokine and IL-17A-producing T cells are pathogenic effectors in models of autoimmunity, including experimental autoimmune uveitis (EAU). Paradoxically, however, injection of IL-17 ameliorates EAU (PMID: 19234216). Using a model of spontaneous uveitis in IRBP T cell receptor transgenic R161H mice, we investigated their susceptibility on the IL-17A−/− background. Surprisingly, IL-17A−/− R161H mice developed essentially undiminished uveitis and IL-17−/− R161H T cells, polarized to Th17 and infused into wild type recipients, induced similar disease to IL-17A sufficient R161H T cells. Interestingly, IL-17A−/− R161H T cells polarized under Th17 conditions produced elevated amounts of other Th17-related cytokines, i.e. IL-17F, GM-CSF and IL-22. Supplementing these cultures with recombinant IL-17A normalized the elevated production of these cytokines. RNAseq analysis revealed that IL-17A−/− T cells expressed lower levels of IL-24 compared to their IL-17A sufficient counterparts. Mechanistic studies indicated a negative feedback loop where IL-17A induces Th17 cells to produce IL-24, which subsequently suppresses production of Th17 lineage cytokines. Finally, injection of recombinant IL-24 ameliorated adoptive Th17-induced EAU, and conversely, silencing IL-24 expression in Th17 cells increased their pathogenicity and enhanced disease severity. Our data suggest that: (a) IL-17A exerts a negative feedback on uveitogenic Th17 cells via IL-24 production, and (b) IL-24 limits the expression of other Th17-related cytokines and controls their pathogenicity.

Abstract The 90-Kda heat shock protein (Hsp90), together with a number of other chaperones are involved in normal cellular differentiation and cancerogenesis. Hsp90 is implicated in the conformational maturation of a large variety of protein kinases. We have shown its overexpression in a series of 116 acute myeloid leukemias (AML). Geldanamycin and its analogue 17-AAG selectively block the activities of Hsp90, but do not interact with other members of the Hsp family. The objective of the study was to test the effect of 17-AAG on cell lines (Jurkat, U-937, HL60, HL60R : resistant to daunorubicin (DNR), and KG1a) and on 24 AML samples tested positive for Hsp90 (14 strongly positive and 10 moderately positive). CD34+ cells from bone marrow donors were used as controls. Cells were maintained in liquid culture in the presence or absence of 17-AAG. Moreover hematopoietic and leukemic progenitor assays were performed in semi-solid media containing or not 17-AAG. CD34+ cells were non affected by 17-AAG. Jurkat, U937, HL60 were partially sensitive to 17-AAG. Addition of low dose DNR to 17-AAG induced an apoptotic death in 48 hours in all samples, including HL60R. KG1a (exhibiting high HSP90 levels) was more sensitive to 17-AAG alone with a death rate of 100% at higher doses. A similar effect was observed in AML samples : 17-AAG induced cell death in all 14 cases highly positive for HSP90, but a partial death in 5 cases, and no death in 5 cases mildly positive for HSP90. DNR increased apoptosis in only 5/10 of these cases. The other 5 patients were also positive for bcl-2. When they were first incubated with 17-AAG and then treated with bcl-2 antisens oligodeoxynucleotides (bcl-2AS), a complete apoptosis was obtained. So, in the 10 samples with moderate HSP90 expression a synergystic effect was found when a combination of 17-AAG with either chemotherapy or bcl -2AS was used. While normal progenitors were not affected by 17-AAG, leukemic progenitors were completed inhibited in the 14 patients who responded to 17-AAG in liquid culture. This apoptosis was caspase -3 dependant. Finally, we investigated the implication of the ERK signal pathway in Jurkat line and in 14/24 17-AAG responder samples using an ERK inhibitor (PD98059). When this inhibitor was added prior to 17-AAD and DNR, the apoptotic effect was completely inhibited. So, ERK signal pathway may interfere with the Hsp90 function. In conclusion, these results raise the possibility that Hsp90 antagonists represent a novel antileukemic strategy in sequential addition to conventional chemotherapy

The register is a part of language variations that is appeared in a different groups of society. A different way of speaking can carry different social meanings. A group of society may have a different form of language that surely has a different meaning. This research aims to find out the form of the registers used by Indonesian casters in an online game (Mobile Legends: Bang-Bang) and to describe the function of registers that are used by Indonesian casters in an online game (Mobile Legends: Bang-Bang). Based on the analysis that has been carried out, there are 43 register data used by Indonesian casters in the final mobile legends (Indonesia vs the Philippines). The classification of register forms is divided into lingual units of words, and lingual units of phrases. Based on the lingual unit of a single word includes 19 data, and the lingual unit of the phrase consists of 24 data. Then, there are three register functions used by Indonesian casters in mobile legends, namely: a) usage of registers to make communication more effective; b) the use of registers intends to attract the interest of language users in communicating; c) the existence of a register can distinguish one language from another. It is suggested to the interested parties who want to conduct another research in the same field to research other types of online games such as jargon, code mixing, code switching, slang, language variations, and various other interesting topics in the field of sociolinguistics.

The research is dedicated to the study of the concept of “gender” in linguistics. The concept of “gender” includes a set of social and cultural norms that have been transformed in the process of evolution from biological to socio-psychological category. Subsequently, the gender of a person from a biological characteristic was transformed into a socio-psychological characteristic, which is considered as a socio-cultural, discursive and psycholinguistic phenomenon. Currently, a new branch of linguistics, linguistic gender studies or gender linguistics, is studying the differences between the sexes. Gender self-identification is part of the cognitive resources of both the individual and society. Accordingly, gender can be seen as a dimension, as a parameter of research in many sciences. In addition, the recognition of the theory of distinction allows a more reasonable statement of the principle of interdisciplinarity in gender studies. This approach is typical both at the level of research of specific problems and at the level of substantiation of gender asymmetry in general. The concept of gender is included in the linguistic description in order to emphasize the social aspects of gender and related cultural traditions and stereotypes that are fixed by language and in the most direct way affect behavior and self-identification, the study of this phenomenon certainly deserves close attention linguopragmatics, theories of communication and language influence, sociolinguistics and a number of other linguistic sciences. As the results of research in the field of gender have shown, the special literature pays great attention not only to specific facts, but also to terminology in this area of knowledge.

Abstract Objective The purpose of this study was to evaluate the two year clinical performance of posterior composite restorations in endodontically treated premolars and molars using a hybrid composite (Filtek Z-250, 3M ESPE) and a total etch bonding system (Single Bond, 3M ESPE). Method and Materials Thirty-nine class II restorations in endodontically treated premolars (n=11) and molars (n=28) of 27 patients (14 female, 13 male, mean age 36.51) in 16 maxillar and 23 mandibular teeth were placed by one operator. Restorations were evaluated by two experienced investigators at baseline, 12 months, and 24 months according to the modified United States Public Health Service (USPHS) criteria that included retention, color match, marginal discoloration, secondary caries, anatomic form, marginal adaptation, and surface texture. All restorations were able to be evaluated at baseline, 12 months, and 24 months. Results Paired samples t-test showed only marginal discoloration showed a statistically significant difference (p<0.05) at the end of 24 months, and no other significant differences were observed for the other variables examined over the duration of the study. None of the restored teeth showed periapical pathology at the end of 24 months. Conclusion At two years, limited deterioration in marginal discoloration was detected. The clinical performance of posterior composite restorations in endodontically treated teeth using Filtek Z250 was found clinically acceptable after two years. Citation Can Say E, Kayahan B, Ozel E, Gokce K, Soyman M, Bayirli G. Clinical Evaluation of Posterior Composite Restorations in Endodontically Treated Teeth. J Contemp Dent Pract 2006 May;(7)2:017-025.

AbstractObjectiveTo determine the impact of BMI on post-operative outcomes and resource utilization following elective total hip arthroplasty (THA).DesignA retrospective cohort analysis on all primary elective THA patients between 1996 and 2004. Primary outcomes investigated using regression analyses included length of stay (LOS) and costs (US dollars).SettingMayo Clinic Rochester, a tertiary care centre.SubjectsPatients were stratified by pre-operative BMI as normal (18·5–24·9 kg/m2), overweight (25·0–29·9 kg/m2), obese (30·0–34·9 kg/m2) and morbidly obese (≥35·0 kg/m2). Of 5642 patients, 1362 (24·1 %) patients had a normal BMI, 2146 (38·0 %) were overweight, 1342 (23·8 %) were obese and 792 (14·0 %) were morbidly obese.ResultsAdjusted LOS was similar among normal (4·99 d), overweight (5·00 d), obese (5·02 d) and morbidly obese (5·17 d) patients (P= 0·20). Adjusted overall episode costs were no different (P= 0·23) between the groups of normal ($17 211), overweight ($17 462), obese ($17 195) and morbidly obese ($17 655) patients. Overall operative and anaesthesia costs were higher in the morbidly obese group ($5688) than in normal ($5553), overweight ($5549) and obese ($5593) patients (P= 0·03). Operating room costs were higher in morbidly obese patients ($3418) than in normal ($3276), overweight ($3291) and obese ($3340) patients (P< 0·001). Post-operative costs were no different (P= 0·30). Blood bank costs differed (P= 0·002) and were lower in the morbidly obese group ($180) compared with the other patient groups (P< 0·05). Other differences in costs were not significant. Morbidly obese patients were more likely to be transferred to a nursing home (24·1 %) than normal (18·4 %), overweight (17·9 %) or obese (16·0 %) patients (P= 0·001 each). There were no differences in the composite endpoint of 30 d mortality, re-admissions, re-operations or intensive care unit utilization.ConclusionsBMI in patients undergoing primary elective THA did not impact LOS or overall institutional acute care costs, despite higher operative costs in morbidly obese patients. Obesity does not increase resource utilization for elective THA.

Abstract Objectives Patients with congenital adrenal hyperplasia (CAH) require lifelong replacement therapy with glucocorticoids. Optimizing hydrocortisone therapy is challenging, since there are no established cortisol concentration targets other than the cortisol circadian rhythm profile. 17-hydroxyprogesterone (17-OHP) concentrations are elevated in these patients and commonly used to monitor therapy. This study aimed to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of cortisol using 17-OHP as a biomarker in pediatric patients with CAH and to assess different hydrocortisone dosing regimens. Methods Cortisol and 17-OHP concentrations from 30 CAH patients (7–17 years of age) receiving standard hydrocortisone replacement therapy (5–20 mg) twice (n = 17) or 3 times (n = 13) daily were used to develop a PK/PD model. Sequentially, simulated cortisol concentrations for clinically relevant 3- and 4-times daily dosing regimens were compared with cortisol and 17-OHP target ranges and to concentrations in healthy children. Results Cortisol concentration-time profiles were accurately described by a 2-compartment model with first-order absorption and expected high bioavailability (82.6%). A time-delayed model with cortisol-mediated inhibition of 17-OHP synthesis accurately described 17-OHP concentrations. The cortisol concentration inhibiting 50% of 17-OHP synthesis was 48.6 nmol/L. A 4-times-daily dosing better attained the target ranges and mimicked the cortisol concentrations throughout the 24-hour period than 3-times-daily. Conclusions A PK/PD model following hydrocortisone administration has been established. An improved dosing regimen of 38% at 06:00, 22% at 12:00, 17% at 18:00, and 22% at 24:00 of the daily hydrocortisone dose was suggested. The 4-times-daily dosing regimen was superior, avoiding subtherapeutic cortisol concentrations and better resembling the circadian rhythm of cortisol.

From the flowers of Bombax ceiba L. (Family: Bombacaceae) twenty-four compounds were isolated and identified, including ten flavonoids, quercetin (1), quercetin-3- O-β-D-glucopyranoside (2), quercetin-3- O-β-D-glucuronopyranoside (3), rutin (4), sexangularetin-3- O-sophoroside (5), vitexin (6), isovitexin (7), vicenin 2 (8), kaempferol-3- O-rutinoside (18), and kaempferol-3- O-β-D-glucuronopyranoside (23); three xanthones, isomangiferin (9), mangiferin (10), and 7- O-methyl mangiferin (11); four coumarins, esculetin (12), scopoletin (13), fraxetin (14), and scopolin (21); and seven other compounds, blumenol C glucopyranoside (15), benzyl-β-D-glucopyranoside (16), phenylethyl rutinoside (17), protocatechulic acid (19), chlorogenic acid (20), methyl chlorogenate (22) and vanillic acid (24). Among these, 13 compounds (3, 5, 6, 9, 11, 14, 15, 16, 17, 18, 22, 23 and 24) were isolated for the first time from B. ceiba.

In a two-year prospective study of patients hospitalized because of community-acquired pneumonia, the incidence of legionellosis was found to be 3.8% (17/442 cases). After S. pneumoniae, M. pneumoniae and influenzae viruses, legionellae were the fourth most frequently identified pneumonia agents. We evaluated the clinical data from 41 cases with legionellosis, 17 diagnosed in this prospective study and 24 prior to the study. The age range of all patients (22 women, 19 men) was 24-78 yrs (median 61.3 yrs), 14 of 41 cases (34.1%) had extrapulmonary organ involvement. Twelve patients (29.3%) died. The fatality rate was 4.5% (1/22 cases) in patients treated with erythromycin, and 57.9% (11/19 cases) in patients treated with other antibiotics. Antibiotics effective in legionellosis should be added to the routine therapy of community-acquired pneumonia when this aetiology can not be excluded.

A multiplex PCR was developed to detect all true serotypes of Streptococcus suis. This multiplex PCR was composed of four reaction sets. The first set identified nine serotypes (serotypes 1/2, 1, 2, 3, 7, 9, 11, 14 and 16), the second set identified eight serotypes (serotypes 4, 5, 8, 12, 18, 19, 24 and 25), the third set identified seven serotypes (serotypes 6, 10, 13, 15, 17, 23 and 31), and the last set identified five serotypes (serotypes 21, 27, 28, 29 and 30). This assay correctly detected serotypes 2, 5, 14 and 24 in human isolates, and serotypes 1, 2, 1/2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17, 19, 24, 28 and 31 in pig isolates from Thailand. No cross-reaction was observed with other bacterial species. Our multiplex PCR was able to simultaneously amplify a DNA mixture of reference Streptococcus suis serotypes. This assay should be useful for serotype surveillance of human and pig isolates of Streptococcus suis.

This study aims to determine how effective the direct instruction model is in improving the understanding of VII E grade students of MTs Wali Songo Ngabar Putri in Hadith subjects through the application of the direct instruction method or direct instruction method. The research subjects were class VII E MTs Wali Songo Putri Ngabar, totaling 24 female students.. This research is a classroom action research method (CAR) which consists of two cycles with the design of each cycle consisting of four stages, namely the first stage is planning, the second stage is acting (implementing), observing and the third stage is reflecting. Research data is obtained during action research until the final assessment of the action. The results showed that the results of the initial test after the action in the first cycle of 24 students there were 13 students (54.17%) declared complete, while for the other 11 students (45.83%) were declared incomplete. In the second cycle the number of students who completed as many as 20 students (83.3%), while the other 4 students had not completed (16.7%). Thus, it can be proven that the application of the direct instruction model in Hadith subjects for class VII E MTs Wali Songo Ngabar Putri about sneezing etiquette and yawning manners have a positive impact on increasing student understanding.

Objective: To assess the frequency of alopecia areata associated with other autoimmune disorder in a tertiary care hospital. Study Design: Prospective Cross Sectional study. Setting: Department of Dermatology GHAQ/DHQ Teaching Hospital/Sahiwal Medical College, Sahiwal. Period: January 2020 to December 2020. Material & Methods: A total of 24 patients fulfilling criteria were entered in the study. After taking informed consent, demographic data was recorded. History was taken and general physical and systemic examination was performed. Laboratory investigations were carried out where needed, for determination of factors associated with alopecia areata. Results: This study comprised of 24 patients with male n=12 (50%) and female n=12 (50%) in equal ratio 1:1. Mean age of patients of alopecia areata with SD was 19.75 ± 9.90 years. Most of the study patients were unmarried n=17 (70.8%). More than two third of patients had mild and moderate severity of disease n=18 (75%). Most common autoimmune disorder associated with alopecia areata was Diabetes Mellitus n=6 (20.9%) followed by atopic dermatitis n=3 (12.5%), anemia n=3 (12.5%) and thyroid disorders (hypothyroidism and hyperthyroidism) n=2 (8.3%). The p value in various autoimmune diseases was found to be non-significant. (> 0.05). Conclusion: Patients presenting with alopecia areata may have associated other autoimmune disorders which needs to be investigated, thus helping in the management of disease.

This essay attends to the relationship between our ethnic, social, and cultural identities, and the creation of the new communal identity embodied in the Christian community. Drawing upon six New Testament texts – Ephesians 2:11–22; Galatians 3:27–28; 1 Corinthians 7:17–24 and 10:17; 1 Peter 2:9–11; and Revelation 21:24–26 – it is argued that the creation of a new and prime identity in Christ does not abrogate other creaturely identities, even as it calls for the removal of such as boundary markers. Catholicity, in other words, is intrinsically related to the most radical particularity, and demands an ongoing work of discernment and of judgement vis-à-vis the gospel itself. Those baptized into Christ are now to live in the reality of Christ who is both the boundary and center of their existence, a boundary which includes all humanity in its cultural, ethnic, gendered, social and historical particularities. 本文关注的是种族、社会及文化身份与具体化的基督教新群体身份的创造之间的关系。从新约里的六段经文里 – 弗2:11–22; 加3:27–28; 林前7:17–24; 10:17; 彼前2:9–11; 启21:24–26 – 本文辩称在基督里新造的身份，即使会抹去其存在的边界线，但并不废除其被造身份的特殊性。换句话说，大公教会本质上与最根本的个体性有关，需要透过福音本身作出持续不断的辨明与判断。那些在基督里受洗了的，现在活在他们存在的边界和中心，这边界包括了所有带着文化、种族、性别、社会及历史个体性的人类。 Este ensayo se ocupa de la relación entre nuestras identidades étnicas, sociales y culturales y la creación de una nueva identidad comunal encarnada en la comunidad cristiana. Basado en seis pasajes del Nuevo Testamento: Efesios 2: 11–22; Gálatas 3: 27–28; 1 Corintios 7: 17–24 y 10:17; 1 Pedro 2: 9–11 y Apocalipsis 21: 24–26 se argumenta que la creación de una identidad nueva y principal en Cristo no anula otras identidades del ser humano, aún cuando pide que se eliminen tales barreras. La catolicidad, en otras palabras, está intrínsecamente relacionada con la particularidad más radical, y exige un trabajo continuo de discernimiento y de juicio frente al evangelio mismo. Los bautizados en Cristo ahora deben vivir en la realidad de Cristo quien es a la vez el límite y el centro de sus existencias, un límite que incluye a toda la humanidad en sus particularidades culturales, étnicas, de género, sociales e históricas. This article is in English.

We searched for newborn calf carcasses of migratory barren-ground caribou (Rangifer tarandus groenlandicus) in June 1982 in the Northwest Territories. On 17 June, we found 34 calves killed by wolves (Canis lupus), clumped in a 3-km2 area. The calves had been killed apparently within minutes of each other and about 24 h before being found. Wolves had not fed on 17 of the carcasses and had only partially eaten the other 17. Ground observations illustrate the speed of and efficiency with which wolves can kill calves: a single wolf killed three calves on one occasion and three and possibly four calves on a second occasion at average kill rates of 1 calf/min, and 1 calf/8 min or 1 calf/6 min between the first and last deaths. We attributed the surplus killing of newborn caribou calves to their high densities and their vulnerability on the calving grounds. We recommend that a distinction be made between "surplus killing" and "excessive killing" by predators.

ABSTRACT The finding that the rat adrenal zona glomerulosa cell shows specific sensitivity to stimulation by α-MSH and related peptides has been confirmed both in vivo and in vitro, raising the possibility that α-MSH may have a physiological role in the control of glomerulosa function and aldosterone secretion. To define more closely the structural features which confer the specificity of the glomerulosa response, other ACTH derived peptides have been tested for their specificity of actions on rat adrenal cells in vitro. The peptides tested were ACTH(5–24), ACTH(1–12), ACTH(1–14), ACTH(1–15), ACTH1–16) and ACTH(1–17). Their actions were compared with those of α-MSH and ACTH(1–24). All of the ACTH-derived peptides stimulated glomerulosa corticosterone production with sensitivities similar to that of α-MSH; minimum effective concentration was 10 nmol/l. Also, like α-MSH, the shorter ACTH peptides stimulated aldosterone production only relatively weakly in these cells from animals on normal sodium intake. Only ACTH(5–24), ACTH(1–16) and ACTH(1–17) stimulated fasciculata/reticularis cells at concentrations up to 1 μmol/l. The actions of all of the shorter peptides were thus unlike those of ACTH(1–24) which stimulates both cell types with approximately equal sensitivity, and which furthermore strongly stimulates aldosterone production. The data suggest that the 18–24 region of the ACTH molecule contains the signal for a fasciculata/ reticularis response, and the region 1–13 that for glomerulosa specificity. They confirm the view that, in the rat, α-MSH itself may be the specific pituitary glomerulosa-stimulating agent which much experimental work has predicted. They also indicate that synthetic ACTH(1–17) analogues should be used with caution. J. Endocr. (1986) 109, 275–278

In this study, 24 sedentary first-year male university students aged 17 to 24 yr. were assigned to one of four groups. Three of the groups underwent a 6-wk. training program consisting of a 30-min. bicycle ergometer ride, three times per week. A fourth group acted as a control. The experimental groups trained at workload intensities corresponding to predetermined heart rates of 125, 140, and 155 bpm, respectively. Analysis of scores indicated that changes in aerobic capacity occurred only if the intensity of training exceeded a minimal level. Essentially, these results replicated data from other studies.

The genus Hylodes Fitzinger is composed of diurnal frogs that live associated to lotic streams in forests (Lingnau et al. 2008; Silva & Benmaman 2008). In Brazil, this genus occurs from the states of Espírito Santo to Rio Grande do Sul (Lingnau et al. 2008; Frost 2011). Hylodes currently comprises 24 species (Frost 2011) distributed in four species groups (Heyer 1982): glaber; lateristrigatus; mertensi; and nasus. Hylodes ornatus (Bokermann) are included in “Hylodes lateristrigatus” species group with other 17 species (Silva & Benmaman 2008; Canedo & Pombal 2007). Fourteen out of 24 species of Hylodes have their larvae described (Pirani et al. 2011).

El presente trabajo analiza la responsabilidad patrimonial del Estado juez establecida en el art. 121 CE. En él se describen los precedentes históricos de este artículo 121 de la CE, su posterior desarrollo legislativo, la interpretación jurisprudencial de dichas normas, que se considera reductora y palmariamente inconstitucional desde la perspectiva sistemática del conjunto que forman los artículos 17, 24 y los citados 106.2 y 121 de la CE; finalmente se comparan estos elementos con los de otros estados europeos y se termina con concretas propuestas interpretativas y de lege ferenda.This paper analyses the patrimonial responsibility of the Judicial Power established in art. 121 Spanish Constitution. The paper describes the historical precedents of article 121 CE, the legislative development, the jurisprudential interpretation of it, which it could be considered unconstitutionally from the systematic perspective of the articles 17, 24, 106.2 and 121 CE; finally, there are a comparative analysis with other European countries and some reform proposals.

A new species, Dollfusentis salgadoi n. sp., is described from Eugerres plumieri, Bahía de Chetumal, Quintana Roo, México. The new species is most similar to D. bravoae, but has 17–19 hooks per longitudinal row on the proboscis (excluding the ventral crescent), longer lemnisci (2250±391, n=44), testes that are longer and wider (322±38, n= 25 long and 176±29, n= 25 wide), and a uterine bell that is smaller (289±61, n= 23 long and 80±24, n= 23 wide). Dollfusentis bravoae has 16–17 hooks per longitudinal row on the proboscis, shorter lemnisci (2015±516, n=9), testes that are shorter and not as wide (218±46, n= 6 long and 136±24, n= 6), and a uterine bell that is larger (321±64, n= 4 long and 78±33, n= 4 wide). Adults of all other known species of the genus inhabit the intestine of their host, but adults of D. salgadoi n. sp. inhabit the rectum of its host.

Floristic sampling was carried out in Serra do Japi Biological Reserve, Jundiaí, state of São Paulo, Brazil, including physiognomies of semideciduous montane forest, a type of forest formation within the Atlantic Forest domain. Six hundred and sixty one species distributed in 129 families were recorded; the ten most diverse phanerogam families were: Asteraceae (56 species), Fabaceae (37), Rubiaceae (29), Poaceae (25), Solanaceae (24), Cyperaceae (19), Euphorbiaceae (19), Orchidaceae (19), Melastomataceae (17), and Piperaceae (17). The addition of 322 species from other floristic surveys increased the number of species of Serra do Japi to 976, distributed in 141 families. Compared to other floristic surveys carried out in the Atlantic Forest, our results highlight the floristic diversity of the study area and the importance of preserving the vegetation of this highly urbanized region.

ObjectiveTo describe the main syndrome and clinical course in a large cohort of patients with anti–Ri-associated paraneoplastic neurologic syndrome (Ri-PNS).MethodsTwenty-year retrospective nationwide study and systematic review of the literature.ResultsThirty-six patients with complete clinical information were identified (median age 66 years, range: 47–87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1–64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54–0.85]), at 24 months 62% (95% CI [0.41–0.78]), and at 36 months 47% (95% CI [0.25–0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort.ConclusionsRi-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.

Objective To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. Design Retrospective review. Patients Women with CAIS identified from our database. Results The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1–53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. Conclusions In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone.

Objective: To analyze the efficacy of endoscopic dacryocystorhinostomy (DCR) with marsupialization of the lacrimal sac compared with other techniques of endoscopic dacryocystorhinostomy. Material and methods: Clinical chart review. Patients with lacrimal sac pathologies and endoscopic DCR with or without marsupialization of the lacrimal sac were included from 2011 to 2015. The outcome measurements were absence of ocular symptoms and permeability of the lacrimal sac. Results: A total of 24 patients were evaluated, 17 women and 7 men, average age was 47 years. Seven patients underwent DCR with marsupialization, 17 patients underwent other endoscopic techniques. Average follow-up was 18 months. The efficacy (absence of symptoms and permeability of the lacrimal sac) of the DCR technique with marsupialization was 71%, without significant difference compared to other techniques (p = 0.686). Conclusion: Similar results were found in the different types of endoscopic DCR techniques. More studies are needed to corroborate our results.

Abstract Background Langerhans cell histiocytosis (LCH) is a heterogeneous disease whose myriad manifestations result from accumulation of Langerhans cells in a variety of organs most commonly including skin, bone, central nervous system, liver, lymph nodes, and bone marrow. The disease can affect people of any age. Treatment is primarily driven by disease extent and organ involvement and can range from focused radiation or surgery to multi-agent chemotherapy. There is a relatively high recurrence rate following complete remissions with conventional chemotherapy. In the first-time-in-human (FTIH) study of the oral pan-AKT inhibitor afuresertib (GSK2110183), in patients with hematologic malignancies, a patient with refractory multi-system LCH experienced a prolonged period (> 3 years) of clinical benefit on 125mg oral once daily afuresertib. This observation led to the evaluation of the use of afuresertib in patients with LCH. Methods This single-arm, open-label trial was designed to evaluate the efficacy and safety of afuresertib, administered at 125 mg once daily, in adults and adolescents with relapsed/refractory LCH and adults with treatment-naïve LCH. Secondary objectives included pharmacokinetics. Diagnosis of LCH was confirmed by pathology review of archival tissue. The Histiocyte Society criteria were used for response evaluation at three and six months with safety and pharmacokinetic assessments performed at pre-specified intervals. BRAF status from archival tissue was evaluated by Sanger sequencing. Results 17 patients (16 adults, 10 females) were enrolled; median age was 38 years (15-75). 3/17 patients had isolated pulmonary disease, 1/17 had single-system multifocal-bone disease, 1/17 had single-system skin disease, and 12/17 had multi-system disease. Seven patients were treatment-naïve; 10 had relapsed/refractory disease, including the one adolescent. The most frequent (>20% of patients) adverse events (AEs), regardless of causality, were nausea (59%), fatigue (59%), upper respiratory infection (47%), diarrhea (47%), dyspepsia (35%), bone pain (39%), asthenia (24%), memory impairment (24%), decreased appetite (24%) and vomiting (24%). Most AEs were Grade 1 or 2 in severity; no Grade 4 AEs were reported and no Grade 3 AEs occurring in more than 1 subject were reported. 6/17 (35%) had afuresertib dose modifications (interruption or reduction). Afuresertib plasma concentrations in the adult patients were similar to values seen in adult patients with other hematologic malignancies in the FTIH study. Following a single dose, the concentration-time profile in the adolescent patient was similar to adults in the FTIH study (Tmax = 3h: Cmax 229 ng/ml: AUC24 = 3893 ng*h/mL). 15 patients had archival tissues collected for BRAF testing; 13 had DNA suitable for analysis. 2/13 was BRAF V600E mutant and 11/13 were BRAF wild type. Upon evaluation of the all-treated patient population, 5/17 (29%) patients were reported as better at the three and/or six month disease assessment. Among the 5 responders, three were treatment-naïve and two had relapsed/refractory disease. The median duration on study for all patients was 214 (44-426) days. For the 5 patients who responded, the median duration on study was 372 (255-426) days. Conclusion The pharmacokinetic and safety profile of afuresertib in patients with LCH was consistent with that observed in patients with other hematologic malignancies evaluated in the FTIH study. Afuresertib was active in patients with both treatment-naïve and relapsed/refractory disease. Additional evaluation, including molecular profiling, may be warranted alone or in combination with BRAF inhibitors or established therapies for LCH to determine the optimal population of patients with LCH who might benefit from afuresertib Disclosures: Vassallo: GlaxoSmithKline: Research Funding. Oliff:GlaxoSmithKline: Employment. Morris:GlaxoSMithKline: Employment. Reedy:GlaxoSmithKline: Employment. Portnoy:GlaxoSmithKline: Stock, prior employee Other. Smith:GlaxoSmithKline: Employment, Equity Ownership. Noble:GlaxoSmithKline: Employment, stock Other. Murnane:GlaxoSmithKline: Employment, stock Other. Szabo:GlaxoSmithKline: Employment. Heaney:Novartis: Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onconova: Research Funding; Incyte: Consultancy, Research Funding.

Introduction. The treatment of children with multidrug-resistant and extensively drug-resistant tuberculosis (MDR / XDR-TB) is a difficult task due to many factors: the duration of treatment, the lack of drugs with children’s dosages, age restrictions (according to the drug instructions).Purpose of the study. To assess the efficacy and safety of regimen with the inclusion of bedaquiline in children and adolescent with respiratory tuberculosis with drug-resistant tuberculosis.Materials and methods. The study is prospective, cohort, non-comparative from the period 2017–2019. We included 24 patients aged 5 to 17 years with MDR-TB (established or suspected) began regimen containing bedaquiline for 24 weeks. The duration of observation of patients included in the study was 24 months.Results. We can state a sufficient level of safety of using the latter for 24 weeks: adverse events presumably associated directly with the intake of bedaquiline were noted in only 1 patient out of 24 (4.2%; 95% CI 0.7-20.3). The efficacy of a regimen containing bedaquiline in combination with other anti-tuberculosis reserve drugs is beyond doubt: positive clinical and radiological dynamics and cessation of bacterial excretion by the end of the 24-week course of treatment were noted in all patients included in the study. In the course of 2-year follow-up, no exacerbation of the tuberculous process was observed in any case. All patients achieved clinical cure of tuberculosis.Conclusion. Regimen containing bedaquiline for children aged 5–17 years with multidrug-resistant tuberculosis is effective and safe.

This paper explores the possibility of recovering a tradition of Donatist readings of John’s Gospel, by highlighting five of the so-called Donatist ‘anonymous’ homilies of the Vienna Collection (Sermones Escorial. 16, 19, 20, 22 and 23; cf. Leroy 1994/1999; Bass 2014/2016; Dossey 2010; and Shaw 2011). After pointing out their relatively limited, threefold Johaninne interest – chapters 4 and 8, and the ‘farewell discourse’ of chapters 14-17 (Tilley 1997) – I then focus on Sermo Escorial. 16, presenting its exegetical and theological strategies in the light of Donatist ecclesiology and its North African context. Here, I argue that a particular use of John 4:23, in conjunction with a modified form of a well-known concept of Cyprian (nulla salus extra ecclesiam), stands in sharp opposition to any of Augustine’s interpretations of the same verse. Thus, I suggest, Augustine seems both to correct Donatist views of salvation and the church, as well as a Donatist reading of the verse in question. This thesis is to be linked up with other Johannine citations in future research.

Human minisatellite UPS29 localized in one of CENTB5 introns was studied in silico and using molecular genetic analysis. For the first time there were revealed seven UPS29 alleles which contained 6-24 repeated units. Allele consisting of 17 repeats was prevailed (91,5 %). Frequency of other alleles varied from 0,29 % to 4,39 %. UPS29 heterozygosity was 12,3 %. Minisatellite UPS29 was classified as low polymorphic and non hypervariable.

Aims This study reviews the use of a titanium mesh cage (TMC) as an adjunct to intramedullary nail or plate reconstruction of an extra-articular segmental long bone defect. Patients and Methods A total of 17 patients (aged 17 to 61 years) treated for a segmental long bone defect by nail or plate fixation and an adjunctive TMC were included. The bone defects treated were in the tibia (nine), femur (six), radius (one), and humerus (one). The mean length of the segmental bone defect was 8.4 cm (2.2 to 13); the mean length of the titanium mesh cage was 8.3 cm (2.6 to 13). The clinical and radiological records of the patients were analyzed retrospectively. Results The mean time to follow-up was 55 months (12 to 126). Overall, 16 (94%) of the patients achieved radiological filling of their bony defect and united to the native bone ends proximally and distally, resulting in a functioning limb. Complications included device failure in two patients (12%), infection in two (12%), and wound dehiscence in one (6%). Four patients (24%) required secondary surgery, four (24%) had a residual limb-length discrepancy, and one (6%) had a residual angular limb deformity. Conclusion A titanium mesh cage is a useful adjunct in the treatment of an extra-articular segmental defect in a long bone. Cite this article: Bone Joint J 2018;100-B:646–51.

Karnataka, a state in south India, reported its first case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on March 8, 2020, more than a month after the first case was reported in India. We used a combination of contact tracing and genomic epidemiology to trace the spread of SARS-CoV-2 in the state up until May 21, 2020 (1578 cases). We obtained 91 genomes of SARS-CoV-2 which clustered into seven lineages (Pangolin lineages—A, B, B.1, B.1.80, B.1.1, B.4, and B.6). The lineages in Karnataka were known to be circulating in China, Southeast Asia, Iran, Europe and other parts of India and are likely to have been imported into the state both by international and domestic travel. Our sequences grouped into 17 contact clusters and 24 cases with no known contacts. We found 14 of the 17 contact clusters had a single lineage of the virus, consistent with multiple introductions and most (12/17) were contained within a single district, reflecting local spread. In most of the 17 clusters, the index case (12/17) and spreaders (11/17) were symptomatic. Of the 91 sequences, 47 belonged to the B.6 lineage, including eleven of 24 cases with no known contact, indicating ongoing transmission of this lineage in the state. Genomic epidemiology of SARS-CoV-2 in Karnataka suggests multiple introductions of the virus followed by local transmission in parallel with ongoing viral evolution. This is the first study from India combining genomic data with epidemiological information emphasizing the need for an integrated approach to outbreak response.