bluuebunny/crossref_metadata_2025 huggingface dataset:
Aestheticism
Authors: Livesey Ruth
Published: June 2011

Aestheticism can be defined broadly as the elevation of taste and the pursuit of beauty as chief principles in art and in life. In the context of British literature there is considerable controversy about when and where aestheticism occurs; but a line can be traced from the art criticism of John Ruskin in the 1850s, through the artists and writers of the Pre-Raphaelite movement and the writings of Walter Pater, to the works of Oscar Wilde and the flowering of decadent poetry of the 1890s. The movement drew upon the formula of “l’art pour l’art”—art for art’s sake—articulated most memorably by the French novelist Théophile Gautier in his 1836 preface to Mademoiselle de Maupin. Gautier was one of a number of French writers and artists of the period who argued that art should be evaluated with reference to its own criteria. In aestheticism the subjective view of beauty becomes the primary means of judging value: when considering whether a poem or a painting is good, aestheticism merely asks if it is beautiful or meaningful as a work of art in itself. This forms a stark contrast to the long-standing custom of judging art and literature either on the basis of the moral lessons it might teach to readers or viewers (its social usefulness) or in terms of its correspondence to real life (its realism). It is this refusal to acknowledge the primacy of morality within art that made aestheticism such a controversial movement from the mid 19th century onward: its proponents were the subjects of vituperative attacks from mainstream writers and critics and were consistently satirized throughout this period. The category of aestheticism is a notoriously slippery one and can overlap with and encompass the categories of Pre-Raphaelitism, decadence, symbolism, and early modernism. The section Defining Aestheticism thus aims to orient readers in this controversy before moving on to examine the many spheres in which studies in aestheticism have expanded at the end of the 20th and beginning of the 21st centuries: from the improvement of life of the urban working classes to the literary modernism that so strenuously disavowed its debt to the aestheticism of the 1880s and 1890s.
Changes in Carbohydrate Metabolism in Plasmopara viticola-Infected Grapevine Leaves
Authors: Gamm Magdalena , Héloir Marie-Claire , Bligny Richard , Vaillant-Gaveau Nathalie , Trouvelot Sophie , Alcaraz Gérard , Frettinger Patrick , Clément Christophe , Pugin Alain , Wendehenne David , Adrian Marielle
Published: June 2011

The oomycete Plasmopara viticola is responsible for downy mildew, a severe grapevine disease. In infected grapevine leaves, we have observed an abnormal starch accumulation at the end of the dark period, suggesting modifications in starch metabolism. Therefore, several complementary approaches, including transcriptomic analyses, measurements of enzyme activities, and sugar quantification, were performed in order to investigate and to understand the effects of P. viticola infection on leaf starch and—to a larger extent—carbohydrate metabolism. Our results indicate that starch accumulation is associated with an increase in ADP-glucose pyrophosphorylase (AGPase) activity and modifications in the starch degradation pathway, especially an increased α-amylase activity. Together with these alterations in starch metabolism, we have observed an accumulation of hexoses, an increase in invertase activity, and a reduction of photosynthesis, indicating a source-to-sink transition in infected leaf tissue. Additionally, we have measured an accumulation of the disaccharide trehalose correlated to an increased trehalase gene expression and enzyme activity. Altogether, these results highlight a dramatic alteration of carbohydrate metabolism correlated with later stages of P. viticola development in leaves.
Separation of the gluconeogenic and mitochondrial functions of PGC-1α through S6 kinase
Authors: Lustig Yaniv , Ruas Jorge L. , Estall Jennifer L. , Lo James C. , Devarakonda Srikripa , Laznik Dina , Choi Jang Hyun , Ono Hiraku , Olsen Jesper V. , Spiegelman Bruce M.
Published: June 2011

PGC-1α is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1α controls mitochondrial biogenesis in most tissues but also initiates important tissue-specific functions, including fiber type switching in skeletal muscle and gluconeogenesis and fatty acid oxidation in the liver. We show here that S6 kinase, activated in the liver upon feeding, can phosphorylate PGC-1α directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1α to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1α as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1α to bind to HNF4α, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1α with ERRα and PPARα, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC-1α and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation.
Senescent cells develop a PARP-1 and nuclear factor-κB-associated secretome (PNAS)
Authors: Ohanna Mickaël , Giuliano Sandy , Bonet Caroline , Imbert Véronique , Hofman Véronique , Zangari Joséphine , Bille Karine , Robert Caroline , Bressac-de Paillerets Brigitte , Hofman Paul , Rocchi Stéphane , Peyron Jean-François , Lacour Jean-Philippe , Ballotti Robert , Bertolotto Corine
Published: June 2011

Melanoma cells can enter the process of senescence, but whether they express a secretory phenotype, as reported for other cells, is undetermined. This is of paramount importance, because this secretome can alter the tumor microenvironment and the response to chemotherapeutic drugs. More generally, the molecular events involved in formation of the senescent-associated secretome have yet to be determined. We reveal here that melanoma cells experiencing senescence in response to diverse stimuli, including anti-melanoma drugs, produce an inflammatory secretory profile, where the chemokine ligand-2 (CCL2) acts as a critical effector. Thus, we reveal how senescence induction might be involved in therapeutic failure in melanoma. We further provide a molecular relationship between senescence induction and secretome formation by revealing that the poly(ADP-ribose) polymerase-1 (PARP-1)/nuclear factor-κB (NF-κB) signaling cascade, activated during senescence, drives the formation of a secretome endowed with protumoral and prometastatic properties. Our findings also point to the existence of the PARP-1 and NF-κB-associated secretome, termed the PNAS, in nonmelanoma cells. Most importantly, inhibition of PARP-1 or NF-κB prevents the proinvasive properties of the secretome. Collectively, identification of the PARP-1/NF-κB axis in secretome formation opens new avenues for therapeutic intervention against cancers.
Genetic variability and individual assignment of Chinese indigenous sheep populations (Ovis aries) using microsatellites
Authors: Niu L. L. , Li H. B. , Ma Y. H. , Du L. X.
Published: June 2011

The purpose of this study was to assess the genetic characteristics of six breeds of Chinese local sheep using 19 microsatellite loci and to effectively validate statistical methods for individual assignment based on informative microsatellites. All the six breeds deviated from Hardy–Weinberg equilibrium expectations, while the majority of markers complied. The polymorphism information content (PIC) of overall loci for the six populations ranged from 0.283 (SRCRSP5) to 0.852 (OarVH72). Tibetan sheep were the most diverse population with the highest mean allelic richness (6.895), while Ujmuqin (UQ) harboured the lowest allelic richness (6.000). The F‐statistics for the six populations were FIS = −0.172, FIT = −0.082 and FST = 0.077, respectively. Furthermore, the pair‐wise FIS revealed a moderate genetic differentiation among populations (P < 0.01), indicating that all breeds can be considered genetically independent entities. The lowest genetic differentiation was between Tengchong (TC) and UQ (FST = 0.041), and the highest one was between TC and Fat‐tailed Han (FST = 0.111). In comparing the three statistical models, we note that the seven microsatellite loci (MAF65, OarJMP58, SRCRSP9, MCM140, OarAE129, BM8125 and SRCRSP5) commonly used for individual assignment will ensure a powerful detection of individual origin, with accuracy up to 91.87%, when the likelihood‐based method is used. Overall, these findings shed light onto the genetic characteristics of Chinese indigenous sheep and offer a set of microsatellite loci that is simple, economic and highly informative for individual assignment of Chinese sheep.
Association analyses of single nucleotide polymorphisms in bovine stearoyl‐CoA desaturase and fatty acid synthase genes with fatty acid composition in commercial cross‐bred beef steers
Authors: Li C. , Aldai N. , Vinsky M. , Dugan M. E. R. , McAllister T. A.
Published: June 2011

Two previously reported non‐synonymous coding single nucleotide polymorphisms (SNPs) of bovine stearoyl‐CoA desaturase (delta‐9‐desaturase) (SCD) (c.878C>T) and fatty acid synthase (FASN) (g:17924A>G) were assessed for their associations with 72 individual and 12 groups of fatty acids in brisket adipose tissue of 223 Canadian commercial cross‐bred beef steers. It was found that the ‘CC’ genotype of the SCD SNP was significantly associated with lower concentrations of saturated fatty acids (SFA) including 10:0, 14:0 and 20:0, higher concentrations of monounsaturated fatty acids including 9c‐14:1, 12c‐16:1 and 13c‐18:1, higher concentrations of polyunsaturated fatty acids (PUFA) including 9c,15c‐18:2, 10c,12c‐18:2, 11c,13t‐18:2 and 12c,14t‐18:2, but lower concentrations of other PUFA of 9c,13t/8t,12c and 20:2n‐6 (P < 0.05). The ‘AA’ genotype of the FASN SNP was significantly associated with higher concentrations of SFAs of 10:0, 12:0, 13:0, 14:0 and 15:0, lower concentrations of unsaturated fatty acids of 9c‐18:1 and 20:3n‐6, and higher concentrations of unsaturated fatty acids of 9c‐14:1 and 12c‐16:1 (P < 0.05). Significant epistatic effects between the SCD and FASN SNP genotypes were also found for several fatty acids including 10:0, 23:0, 6t/7t/8t‐18:1, 12t‐18:1, 13t/14t‐18:1, 16t‐18:1, total trans18:1 and 9c,13t/8t,12c‐18:2 (P < 0.05). These results further suggest that SCD and FASN are strong candidate genes influencing fatty acid composition in beef cattle.
Genome‐wide mapping for fatty acid composition and melting point of fat in a purebred Duroc pig population
Authors: Uemoto Y. , Soma Y. , Sato S. , Ishida M. , Shibata T. , Kadowaki H. , Kobayashi E. , Suzuki K.
Published: June 2011

The fatty acid composition and melting point of fatty tissue are among the most important economic traits in pig breeding because of their influence on the eating quality of meat. Identifying the quantitative trait locus (QTL) of these traits may help reveal the genetic structure of fatty acid composition and the melting point of fatty tissue and improve meat‐quality traits by marker‐assisted selection. We conducted whole‐genome QTL analysis for fatty acid composition and melting point of inner and outer subcutaneous fat and inter‐ and intramuscular fat in a purebred Duroc population. A total of 129 markers were genotyped and used for QTL analysis. For fatty acid compositions of inner and outer subcutaneous fat, three significant QTL and 17 suggestive QTL were detected on SSC2, 4, 6, 8, 9, 10, 11, 12, 14 and 18. For the melting point of inner and outer subcutaneous fat, two significant QTL were detected on the same region of SSC14. For fatty acid compositions of inter‐ and intramuscular fat, five significant QTL and 13 suggestive QTL were detected on SSC2, 4, 6, 8, 9, 10, 14 and 15. On SSC14, significant QTL for C18:0 and C18:1 of outer subcutaneous fat and intramuscular fat, and melting point of subcutaneous fat, which had high likelihood of odds (LOD) scores (2.67–5.78), were detected in the same region. This study determined QTL affecting fatty acid composition and melting point of different fat tissues in purebred Duroc pigs.
Mitochondrial lineages reveal intense gene flow between Iberian wild boars and South Iberian pig breeds
Authors: van Asch B. , Pereira F. , Santos L. S. , Carneiro J. , Santos N. , Amorim A.
Published: June 2011

The phylogeography of wild boars (WB) and domestic pigs (Sus scrofa) has contributed important insights into where and when domestication occurred. The geographic distribution of two core haplotypes (E1a and E1c) of the main European phylogenetic clade suggests that Central Europe was an early domestication centre, although the complexity of the pattern does not exclude the possibility that multiple domestication events occurred in different regions. To investigate the relationships among WB and domestic pig breeds in Iberia, a fragment of the mitochondrial DNA control region from a large sample (n = 409) of WB and local pig breeds was co‐analysed with published sequences from other European populations. The Iberian sample revealed a high frequency of a sub‐cluster (E1c) of the European haplogroup E1 in 77% of total Iberian samples, 96% of WB, 90% of Alentejano (Portugal) and 87% of Iberian breed pigs (Spain; Black Hairy, Black Hairless and Red varieties). Low genetic distance (F’ST = 0.105) was observed between Alentejano (Portugal) and Iberian breed pigs (Spain). Alentejano and Iberian breed pigs showed low genetic distances to both Iberian and Central European WB (average F’ST = 0.345 and 0.215, respectively). This pattern suggests that early pig husbandry in the Iberian Peninsula did not solely rely on imported Central European stock, but also included the recruitment of local WB.
Cold storage of Pacific oysters out of water: biometry, intervalval water and sensory assessment
Authors: Buzin Florence , Baudon Violaine , Cardinal Mireille , Barillé Laurent , Haure Joël
Published: June 2011

Due to the important economic activity of oyster production in France, microalgal toxic events represent a significant constraint for shellfish farmers who face closures of bivalve production‐sites. The frequency of closures of 3 weeks or less represents half of the total closures along the French coasts. Cold storage could be a simple and affordable solution for temporary and short‐term storage before commercialisation. A stock of marketable Pacific oyster Crassostrea gigas was therefore stored during 22 days in non‐immersed conditions at 3 °C with 100% humidity. At the end of the experiment, the oyster mortality rate remained at a low level of less than 3.5%. The sensory attributes, odour, appearance, texture and flavour, did not show significant variations. However, the oyster total weight and fresh flesh weight exhibited losses of 10.5% and a 16.6% after 15 days of storage. At the same time, intervalval water showed a decrease in quality with 20% of the samples characterized by an absence of intervalval water with a flesh more or less moist. These results suggested that the cold storage represents a partial solution to sustain the commercialisation of bivalves during closures of 15 days.
The impact of psychological capital on job embeddedness and job performance among nurses: a structural equation approach
Authors: Sun Tao , Zhao Xiao Wen , Yang Li Bin , Fan Li Hua
Published: June 2011

sun t., zhao x.w., yang l.b. & fan l.h. (2012) The impact of psychological capital on job embeddedness and job performance among nurses: a structural equation approach. Journal of Advanced Nursing68(1), 69–79.

Aims.  The objective of this study was to provide empirical evidence on the relationships between psychological capital, job embeddedness and performance. This paper also seeks to present the theoretical development of psychological capital and job embeddedness in nursing research and their application to nursing practices.

Background.  Psychological capital was recently identified as a core construct in the literature of positive psychology. However, there is considerably less evidence on its positive effects on job embeddedness and performance among nursing personnel.

Methods.  Questionnaires were distributed to approximately 1000 nurses employed in five university hospitals in Heilongjiang province in China. Data were collected in November 2009. The response rate was 73·3%. Structural equation modelling was employed to test the proposed relationships.

Findings.  The results support the hypothesized model. This research outlined a strong relationship between the self‐reported psychological capital, job embeddedness and performance of the nurses. The study findings suggest that improving the individual‐accumulated psychological state of nurses will have a positive impact on their retention intention and job performance.

Conclusions.  These findings suggest that higher psychological capital increases the self‐reported job embeddedness and performance of these nurses.
Qualitative studies using in‐depth interviews with older people from multiple language groups: methodological systematic review
Authors: Fryer Caroline , Mackintosh Shylie , Stanley Mandy , Crichton Jonathan
Published: June 2011

fryer c., mackintosh s., stanley m. & crichton j. (2012) Qualitative studies using in‐depth interviews with older people from multiple language groups: methodological systematic review.Journal of Advanced Nursing68(1), 22–35.

Aim. This paper is a report of a methodological review of language appropriate practice in qualitative research, when language groups were not determined prior to participant recruitment.

Background. When older people from multiple language groups participate in research using in‐depth interviews, additional challenges are posed for the trustworthiness of findings. This raises the question of how such challenges are addressed.

Data sources. The Cumulative Index to Nursing and Allied Health Literature, Scopus, Embase, Web of Science, Ageline, PsycINFO, Sociological abstracts, Google Scholar and Allied and Complementary Medicine databases were systematically searched for the period 1840 to September 2009. The combined search terms of ‘ethnic’, ‘cultural’, ‘aged’, ‘health’ and ‘qualitative’ were used.

Review methods. In this methodological review, studies were independently appraised by two authors using a quality appraisal tool developed for the review, based on a protocol from the McMaster University Occupational Therapy Evidence‐Based Practice Research Group.

Results. Nine studies were included. Consideration of language diversity within research process was poor for all studies. The role of language assistants was largely absent from study methods. Only one study reported using participants’ preferred languages for informed consent.

Conclusion. More examples are needed of how to conduct rigorous in‐depth interviews with older people from multiple language groups, when languages are not determined before recruitment. This will require both researchers and funding bodies to recognize the importance to contemporary healthcare of including linguistically diverse people in participant samples.
Fine‐scale population structure, inbreeding risk and avoidance in a wild insect population
Authors: BRETMAN AMANDA , RODRÍGUEZ‐MUÑOZ ROLANDO , WALLING CRAIG , SLATE JON , TREGENZA TOM
Published: June 2011

The ecological and evolutionary importance of fine‐scale genetic structure within populations is increasingly appreciated. However, available data are largely restricted to wild vertebrates and eusocial insects. In addition, there is the expectation that most insects tend to have such large‐ and high‐density populations and are so mobile that they are unlikely to face inbreeding risks through fine‐scale population structuring. This has made the growing body of evidence for inbreeding avoidance in insects and its implication in mating systems evolution somewhat enigmatic. We present a 4‐year study of a natural population of field crickets. Using detailed video monitoring combined with genotyping, we track the movement of all adults within the population and investigate genetic structure at a fine scale. We find some evidence for relatives being found in closer proximity, both across generations and within a single breeding season. Whilst incestuous matings are not avoided, population inbreeding is low, suggesting that mating is close to random and the limited fine‐scale structure does not create significant inbreeding risk. Hence, there is little evidence for selective pressures associated with the evolution of inbreeding avoidance mechanisms in a closely related species.
Frequent somatic mutations of mitochondrial DNA in traditional serrated adenomas but not in sessile serrated adenomas of the colorectum
Authors: Shimomura Takako , Hiyama Toru , Oka Shiro , Tanaka Shinji , Yoshihara Masaharu , Shimamoto Fumio , Chayama Kazuaki
Published: June 2011

Background and Aim:  Serrated adenomas (SAs), recently subdivided into traditional SAs (TSAs) and sessile SAs (SSAs), are recognized as a distinct form of neoplasia of the colorectum. One of the characteristics of SAs is hypermaturation of the gland epithelium due to the low extent of cell loss by apoptosis. Mutations of mitochondrial DNA (mtDNA) are closely associated with abnormality in apoptosis. We therefore examined mtDNA mutations in colorectal lesions including hyperplastic polyps (HPs), SSAs, TSAs, and carcinomas.

Methods:  Examined were 25 HPs, 32 SSAs, 19 TSAs, and 138 carcinomas. The D310 region of the mtDNAs was examined by microsatellite assay.

Results:  mtDNA mutations were detected in none of 25 (0%) HPs, one of 32 (3%) SSAs, six of 19 (32%) TSAs, and eleven of 133 (8%) carcinomas (five of the 138 carcinomas were not informative). The frequency of mtDNA mutations in the TSAs was significantly higher than that in the HPs, SSAs, and carcinomas (P = 0.004, P = 0.008, and P = 0.009, respectively). The frequency of mtDNA mutations in carcinomas was not significantly higher than that in HPs and SSAs (P = 0.14 and P = 0.28, respectively).

Conclusion:  Our data suggest that mtDNA mutations may play an important role in the development of TSAs and could be used as a genetic marker to aid in the diagnosis of colorectal lesions.
Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro
Authors: Whyte LS , Ford L , Ridge SA , Cameron GA , Rogers MJ , Ross RA
Published: June 2011

BACKGROUND AND PURPOSE Both CB1 and CB2 cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro.

EXPERIMENTAL APPROACH Quantitative RT‐PCR was used to determine expression of cannabinoid receptors and liquid chromatography‐electrospray ionization tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarization and resorption was determined by assessing the number of cells expressing αvβ3 or with F‐actin rings, or measurement of resorption area.

KEY RESULTS Human osteoclasts express both CB1 and CB2 receptors. CB2 expression was significantly higher in human monocytes compared to differentiated osteoclasts. Furthermore, the differentiation of human osteoclasts from monocytes was associated with a reduction in 2‐AG levels and an increase in anandamide (AEA) levels. Treatment of osteoclasts with LPS significantly increased levels of AEA. Nanomolar concentrations of AEA and the synthetic agonists CP 55 940 and JWH015 stimulated human osteoclast polarization and resorption; these effects were attenuated in the presence of CB1 and/or CB2 antagonists.

CONCLUSIONS AND IMPLICATIONS Low concentrations of cannabinoids activate human osteoclasts in vitro. There is a dynamic regulation of the expression of the CB2 receptor and the production of the endocannabinoids during the differentiation of human bone cells. These data suggest that small molecules modulating the endocannabinoid system could be important therapeutics in human bone disease.

LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Noncontact low‐frequency ultrasound therapy in the treatment of chronic wounds: A meta‐analysis
Authors: Driver Vickie R. , Yao Min , Miller Christopher J.
Published: June 2011

Our objective was to summarize and quantify the effects of a noncontact low‐frequency ultrasound (NLFU) therapy on healing of chronic wounds. We performed a meta‐analysis of eight published studies reporting effects of NLFU on wound size and healing rate of chronic wounds in 444 NLFU‐treated patients. A search of the PubMed database was conducted in January 2010 and updated in October 2010. We used random‐effects linear regression models to estimate the proportional reductions in wound area and volume and the proportion of wounds healed from baseline to last follow‐up. In four studies (N=188) reporting change in wound area from baseline, NLFU was associated with 85.2% area reduction (95% CI 64.7%–97.6%) over a mean 7 weeks. In four studies (N=278) reporting reduction in wound volume, NLFU was associated with 79.7% volume reduction (95% CI 46.1%–98.8%) over a mean 12 weeks. In seven studies (N=429) reporting proportion of wounds healing by study end (mean time to healing 8.2 weeks; median 6.8 weeks), meta‐analyzed healing rates over time suggest 32.7% of wounds healed on average by 6 weeks (95% CI 23.3%–42.1%) and 41.7% by 12 weeks. NLFU for treatment of chronic wounds was associated with consistent and substantial wound size reductions, as well as favorable rates of healing.
Spinal Manipulations for Cervicogenic Headaches: A Systematic Review of Randomized Clinical Trials
Authors: Posadzki Paul , Ernst Edzard
Published: June 2011

(Headache 2011;51:1132‐1139)

The objective of this systematic review was to assess the effectiveness of spinal manipulations as a treatment option for cervicogenic headaches. Seven databases were searched from their inception to February 2011. All randomized trials which investigated spinal manipulations performed by any type of healthcare professional for treating cervicogenic headaches in human subjects were considered. The selection of studies, data extraction, and validation were performed independently by 2 reviewers. Nine randomized clinical trials (RCTs) met the inclusion criteria. Their methodological quality was mostly poor. Six RCTs suggested that spinal manipulation is more effective than physical therapy, gentle massage, drug therapy, or no intervention. Three RCTs showed no differences in pain, duration, and frequency of headaches compared to placebo, manipulation, physical therapy, massage, or wait list controls. Adequate control for placebo effect was achieved in 1 RCT only, and this trial showed no benefit of spinal manipulations beyond a placebo effect. The majority of RCTs failed to provide details of adverse effects. There are few rigorous RCTs testing the effectiveness of spinal manipulations for treating cervicogenic headaches. The results are mixed and the only trial accounting for placebo effects fails to be positive. Therefore, the therapeutic value of this approach remains uncertain.
A Clinical Index to Stratify Hospitalized Older Adults According to Risk for New‐Onset Disability
Authors: Mehta Kala M. , Pierluissi Edgar , Boscardin W. John , Kirby Katharine A. , Walter Louise C. , Chren Mary‐Margaret , Palmer Robert M. , Counsell Steven R. , Landefeld C. Seth
Published: June 2011

BACKGROUND: Many older adults who are independent prior to hospitalization develop a new disability by hospital discharge. Early risk stratification for new‐onset disability may improve care. Thus, this study's objective was to develop and validate a clinical index to determine, at admission, risk for new‐onset disability among older, hospitalized adults at discharge.

DESIGN: Data analyses derived from two prospective studies.

SETTING: Two teaching hospitals in Ohio.

PARTICIPANTS: Eight hundred eighty‐five patients aged 70 years and older were discharged from a general medical service at a tertiary care hospital (mean age 78, 59% female) and 753 patients discharged from a separate community teaching hospital (mean age 79, 63% female). All participants reported being independent in five activities of daily living (ADLs: bathing, dressing, transferring, toileting, and eating) 2 weeks before admission.

MEASUREMENTS: New‐onset disability, defined as a new need for personal assistance in one or more ADLs at discharge in participants who were independent 2 weeks before hospital admission.

RESULTS: Seven independent risk factors known on admission were identified and weighted using logistic regression: age (80–89, 1 point; ≥90, 2 points); dependence in three or more instrumental ADLs at baseline (2 points); impaired mobility at baseline (unable to run, 1 point; unable to climb stairs, 2 points); dependence in ADLs at admission (2–3 ADLs, 1 point; 4–5 ADLs, 3 points); acute stroke or metastatic cancer (2 points); severe cognitive impairment (1 point); and albumin less than 3.0 g/dL (2 points). New‐onset disability occurred in 6%, 13%, 18%, 34%, 35%, 45%, 50%, and 87% of participants with 0, 1, 2, 3, 4, 5, 6, and 7 or more points, respectively, in the derivation cohort (area under the receiver operating characteristic curve (AUC)=0.784), and in 8%, 10%, 27%, 38%, 44%, 45%, 58%, and 83%, respectively, in the validation cohort (AUC=0.784). The risk score also predicted (P<.001) disability severity, nursing home placement, and long‐term survival.

CONCLUSION: This clinical index determines risk for new‐onset disability in hospitalized older adults and may inform clinical care.
Response of iron overload to deferasirox in rare transfusion‐dependent anaemias: equivalent effects on serum ferritin and labile plasma iron for haemolytic or production anaemias
Authors: Porter John B. , Lin Kai‐Hsin , Beris Photis , Forni Gian Luca , Taher Ali , Habr Dany , Domokos Gabor , Roubert Bernard , Thein Swee Lay ,   on behalf of the EPIC study investigators
Published: June 2011

Objectives:  It is widely assumed that, at matched transfusional iron‐loading rates, responses to chelation therapy are similar, irrespective of the underlying condition. However, data are limited for rare transfusion‐dependent anaemias, and it remains to be elucidated if response differs, depending on whether the anaemia has a primary haemolytic or production mechanism.

Methods:  The efficacy and safety of deferasirox (Exjade®) in rare transfusion‐dependent anaemias were evaluated over 1 yr, with change in serum ferritin as the primary efficacy endpoint. Initial deferasirox doses were 10–30 mg/kg/d, depending on transfusion requirements; 34 patients had production anaemias, and 23 had haemolytic anaemias.

Results:  Patients with production anaemias or haemolytic anaemias had comparable transfusional iron‐loading rates (0.31 vs. 0.30 mL red blood cells/kg/d), mean deferasirox dosing (19.3 vs. 19.0 mg/kg/d) and baseline median serum ferritin (2926 vs. 2682 ng/mL). Baseline labile plasma iron (LPI) levels correlated significantly with the transfusional iron‐loading rates and with serum ferritin levels in both cohorts. Reductions in median serum ferritin levels were initially faster in the production than the haemolytic anaemias, but at 1 yr, similar significant reductions of 940 and 617 ng/mL were attained, respectively (−26.0% overall). Mean LPI decreased significantly in patients with production (P < 0.0001) and haemolytic (P = 0.037) anaemias after the first dose and was maintained at normal mean levels (<0.4 μm) subsequently. The most common drug‐related, investigator‐assessed adverse events were diarrhoea (n = 16) and nausea (n = 12).

Conclusions:  At matched transfusional iron‐loading rates, the responses of rare transfusion‐dependent anaemias to deferasirox are similar at 1 yr, irrespective of the underlying pathogenic mechanism.
Anti‐Stroke Profile of Thiazolidin‐4‐One Derivatives in Focal Cerebral Ischemia Model in Rat
Authors: Raghubir Ram , Verma Rajkumar , Samuel Sheeba S. , Raza Saman , Haq Wajahul , Katti Seturam B.
Published: June 2011

Recently, some PPARγ agonists like pioglitazone, rosiglitazone, and other newer thiazolidine‐2, 4‐dione (TZD) derivatives have been shown to be neuroprotective in experimental model of cerebral ischemia/reperfusion (I/R) injury. Replacement of active pharmacophore viz: thiazolidine‐2,4‐dione of these PPARγ agonists with biologically privileged scaffold thiazolidin‐4‐one derivatives have been synthesized and bioevaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral ischemic damage. Of 20 synthesized molecules, three of the substituted compounds (2, 6 and 18) have shown significant (p < 0.001) neuroprotection even much better than rosiglitazone at same dose, when administered 1 h prior to 2/24hrI/R cerebral injury in rats, whereas compounds 10, 15, and 17 also showed significant but moderate effect on most of the parameters used in the study. Moreover, compound 2 and 6 also showed curative potential after 6 h post I/R treatment. The compound 2 has also shown significant effect on glutamate uptake by perhaps enhancing the GLT‐1 activity. Thus, the present study indicates that some of the synthesized thiazolidin‐4‐one substituted PPARγ agonists exhibit better neuroprotection and have potential to ameliorate the ischemic damage. Therefore, this novel class of compounds could be further suitably modified to obtain potent anti‐ischemic agents, warranting clinical exploitation.
The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in Acute Ischemic Stroke: A Randomized, Double-Blind, Placebo-Controlled, Multinational Pivotal Phase III Study
Authors: Rosenberg Gilad , Bornstein Natan , Diener Hans-Christoph , Gorelick Philip B. , Shuaib Ashfaq , Lees Kennedy ,   for the MACSI investigators
Published: June 2011

Rationale

Zinc is both a direct neurotoxin and a signaling mediator in multiple early and late detrimental processes following ischemia. DP-b99, a lipophilic moderate-affinity chelator of zinc, is a first-in-class multitargeted neuroprotective agent for ischemic stroke. DP-b99 has completed several Phase I studies and two double-blind placebo-controlled Phase II trials, which supported the safety of DP-b99 and were consistent with a beneficial effect on poststroke recuperation.

Aim:

Membrane-Activated Chelator Stroke Intervention is a Phase III study. The primary objective is to evaluate the safety and therapeutic effects of intravenous 1·0 mg/kg/day DP-b99, initiated within nine-hours of stroke onset in patients with moderately severe hemispheric acute ischemic stroke, through the analysis across the whole distribution of scores of the primary efficacy endpoint of the modified Rankin Scale, 90 days after the stroke.

Methods

The Membrane-Activated Chelator Stroke Intervention study is a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-arm trial comparing a placebo group to a group treated with intravenous DP-b99 for four consecutive days. Non-rtPA-treated acute ischemic stroke patients – with a baseline NIHSS score of 10–16 and a clinical syndrome that includes language dysfunction, visual field defect and/or neglect–will be stratified on a 1:1 basis to one of the two treatments. Half will be randomized within 0–4·5 h of stroke onset. Follow-up after the four treatment days will occur on days 12, 30 and 90. An interim futility analysis will be performed after primary endpoint data have been collected for 50% of 770 subjects planned to be enrolled. A data and safety monitoring board will assess safety data and will oversee the interim analysis.

Conclusion

This Phase III Membrane-Activated Chelator Stroke Intervention trial is based on promising data derived from previous Phase I and II DP-b99 trials and capitalizes on lessons learned from failures of past stroke studies in relation to neuroprotection, patient selection and data analysis.
Seizures and Epilepsy in Alzheimer's Disease
Authors: Friedman Daniel , Honig Lawrence S. , Scarmeas Nikolaos
Published: June 2011

Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD—with reported lifetime prevalence rates of 1.5–64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.
Controlling Power Retailer's Gray Activities Through Contract Design
Authors: Su Xuemei , Mukhopadhyay Samar K.
Published: June 2011

We develop a model that captures dynamic relationships of a supply chain populated by a dominant retailer and a number of fringe retailers. The two types of retailers are asymmetric in buying power, retailing cost, and the ability to service the manufacturer's product. The wholesale prices offered through a quantity discount (QD) schedule can coordinate such a supply chain, but invite channel flow diversion type of gray trading between the dominant retailer and the fringe retailers. Our analysis is focused on how such a channel can be coordinated and the gray market activities be prevented. We propose a dynamic QD contract or a revenue‐sharing contract that the manufacturer can use to fight the gray market activity. The performance of the supply chain and the manufacturer's profit under each of the two contract forms are compared and managerial guidelines are provided to help the manufacturer make a judicious choice.
Aesthetic appraisal of product designs: Independent effects of typicality and arousal
Authors: Blijlevens Janneke , Carbon Claus‐Christian , Mugge Ruth , Schoormans Jan P. L.
Published: June 2011

Theories differ on how typicality and arousal influence aesthetic appraisal and whether these processes together interact or have independent effects on aesthetic appraisal. This research investigates the simultaneous effects of typicality and arousal on aesthetic appraisal for product designs by manipulating both processes separately: typicality by prototype deviation and arousal by colour saturation levels. We demonstrate that typicality has a curvilinear relationship with aesthetic appraisal. Additionally, arousal has a positive linear relationship with aesthetic appraisal of product designs. Moreover, arousal can influence aesthetic appraisal independent from typicality.
Testing the social identity relative deprivation (SIRD) model of social change: The political rise of Scottish nationalism
Authors: Abrams Dominic , Grant Peter R.
Published: June 2011

We tested a social‐identity relative deprivation (SIRD) model predicting Scottish nationalist beliefs and intention to vote for the separatist Scottish Nationalist Party (SNP). Data were from a survey of a large and representative sample of Scottish teenagers administered in the late 1980s. The SIRD model distinguishes effects of group‐based and personal relative deprivation, which should be independent of one another. Importantly, social change beliefs should mediate the effects of both collective relative deprivation and group identification on protest intentions (in this case intention to vote for the SNP). Egoistic relative deprivation should be the strongest predictor of feelings of depression. Using structural equation modelling, the results strongly support this model and replicate in two different cohorts.
Two distinct vesicle pools for depolarization‐induced exocytosis in somata of dorsal root ganglion neurons
Authors: Liu Tao , Shang Shu‐Jiang , Liu Bin , Wang Chang‐He , Wang Ye‐Shi , Xiong Wei , Zheng Liang‐Hong , Zhang Claire Xi , Zhou Zhuan
Published: June 2011

Non‐technical summary  Ca2+‐regulated exocytosis is essential for neurotransmitter and hormone release. As well as this type of exocytosis, the somata of dorsal root ganglion (DRG) neurons also show Ca2+‐independent but voltage‐dependent exocytosis. It is unclear whether these two types of exocytosis use the same or different vesicle pools in DRG neurons. Here, we found that they were separable in response to the same stimulation in low external Ca2+ solution. Depletion of the Ca2+‐dependent vesicle pool did not affect the Ca2+‐independent but voltage‐dependent exocytosis. These results show that DRG neurons exhibit two distinct types of exocytosis that use different vesicle pools.
The Effects of Thermal Loading on the Mechanical Properties of Interfaces of Dissimilar Materials by Nanoindentation Simulations
Authors: Liao Ningbo , Yang Ping , Zhang Miao , Xue Wei
Published: June 2011

Heat transfer across the interfaces of dissimilar materials is a critical consideration in a wide variety of scientific and engineering applications. In this paper, molecular dynamics (MD) simulations are conducted to investigate the effects of thermal loading on mechanical properties of Al–Cu and Cr–Cu interfaces. The mechanical properties are investigated by MD simulations of nanoindentation. Both the results of MD simulations and experiments show the Young’s modulus decrease after thermal cycling, and the Cr–Cu interface is more sensitive to the thermal loading than the Al–Cu interface. The thermal loading and mechanical test models proposed here can be used to evaluate interfacial properties under the effects of heat transferring.
The Base Component of 3′-Azido-2′,3′-Dideoxynucleosides Influences Resistance Mutations Selected in HIV-1 Reverse Transcriptase
Authors: Meteer Jeffrey D. , Koontz Dianna , Asif Ghazia , Zhang Hong-wang , Detorio Mervi , Solomon Sarah , Coats Steven J. , Sluis-Cremer Nicolas , Schinazi Raymond F. , Mellors John W.
Published: June 2011

We recently reported that HIV-1 resistant to 3′-azido-3′-deoxythymidine (AZT) is not cross-resistant to 3′-azido-2′,3′-dideoxypurines. This finding suggested that the nucleoside base is a major determinant of HIV-1 resistance to nucleoside analogs. To further explore this hypothesis, we conducted
in vitro
selection experiments by serial passage of HIV-1
LAI
in MT-2 cells in increasing concentrations of 3′-azido-2′,3′-dideoxyguanosine (3′-azido-ddG), 3′-azido-2′,3′-dideoxycytidine (3′-azido-ddC), or 3′-azido-2′,3′-dideoxyadenosine (3′-azido-ddA). 3′-Azido-ddG selected for virus that was 5.3-fold resistant to 3′-azido-ddG compared to wild-type HIV-1
LAI
passaged in the absence of drug. Population sequencing of the entire reverse transcriptase (RT) gene identified L74V, F77L, and L214F mutations in the polymerase domain and K476N and V518I mutations in the RNase H domain. However, when introduced into HIV-1 by site-directed mutagenesis, these 5 mutations only conferred ∼2.0-fold resistance. Single-genome sequencing analyses of the selected virus revealed a complex population of mutants that all contained L74V and L214F linked to other mutations, including ones not identified during population sequencing. Recombinant HIV-1 clones containing RT derived from single sequences exhibited 3.2- to 4.0-fold 3′-azido-ddG resistance. In contrast to 3′-azido-ddG, 3′-azido-ddC selected for the V75I mutation in HIV-1 RT that conferred 5.9-fold resistance, compared to the wild-type virus. Interestingly, we were unable to select HIV-1 that was resistant to 3′-azido-ddA, even at concentrations of 3′-azido-ddA that yielded high intracellular levels of 3′-azido-ddA-5′-triphosphate. Taken together, these findings show that the nucleoside base is a major determinant of HIV-1 resistance mechanisms that can be exploited in the design of novel nucleoside RT inhibitors.
The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection
Authors: Romero Christopher D. , Varma Tushar K. , Hobbs Jason B. , Reyes Aimee , Driver Brandon , Sherwood Edward R.
Published: June 2011

Monophosphoryl lipid A (MPLA) is a Toll-like receptor 4 (TLR4) agonist that is currently used as a vaccine adjuvant in humans. In this study, we evaluated the effect of MPLA treatment on the innate immune response to systemic bacterial infections in mice. Mice treated with MPLA after burn injury showed improved survival and less local and systemic dissemination of bacteria in a model of
Pseudomonas aeruginosa
burn wound infection. Prophylactic treatment with MPLA significantly enhanced bacterial clearance at the site of infection and reduced systemic dissemination of bacteria despite causing attenuation of proinflammatory cytokine production during acute intra-abdominal infection caused by cecal ligation and puncture. Administration of MPLA at 1 h after CLP also improved bacterial clearance but did not alter cytokine production. MPLA treatment increased the numbers of granulocytes, double-positive myeloid cells, and macrophages at sites of infection and increased the percentage and total numbers of myeloid cells mediating phagocytosis of bacteria. Depletion of Ly6G
+
neutrophils, but not macrophages, eliminated the ability of MPLA treatment to improve bacterial clearance. The immunomodulatory effects of MPLA were absent in TLR4-deficient mice. In conclusion, these studies show that MPLA treatment significantly augments the innate immune response to bacterial infection by enhancing bacterial clearance despite the attenuation of proinflammatory cytokine production. The enhanced bacterial clearance is mediated, in part, by increased numbers of myeloid cells with effective phagocytic functions at sites of infection and is TLR4 dependent.