bluuebunny/crossref_metadata_2025 huggingface dataset:
How adoption speed affects the abandonment of cultural tastes
Authors: Berger Jonah , Le Mens Gaël
Published: May 2009

Products, styles, and social movements often catch on and become popular, but little is known about why such identity-relevant cultural tastes and practices die out. We demonstrate that the velocity of adoption may affect abandonment: Analysis of over 100 years of data on first-name adoption in both France and the United States illustrates that cultural tastes that have been adopted quickly die faster (i.e., are less likely to persist). Mirroring this aggregate pattern, at the individual level, expecting parents are more hesitant to adopt names that recently experienced sharper increases in adoption. Further analysis indicate that these effects are driven by concerns about symbolic value: Fads are perceived negatively, so people avoid identity-relevant items with sharply increasing popularity because they believe that they will be short lived. Ancillary analyses also indicate that, in contrast to conventional wisdom, identity-relevant cultural products that are adopted quickly tend to be less successful overall (i.e., reduced cumulative adoption). These results suggest a potential alternate way to explain diffusion patterns that are traditionally seen as driven by saturation of a pool of potential adopters. They also shed light on one factor that may lead cultural tastes to die out.
Encapsulated-guest rotation in a self-assembled heterocapsule directed toward a supramolecular gyroscope
Authors: Kitagawa Hitomi , Kobori Yasuhiro , Yamanaka Masamichi , Yoza Kenji , Kobayashi Kenji
Published: May 2009

The self-assembled heterocapsule 1·2, which is formed by the hydrogen bonds of tetra(4-pyridyl)-cavitand 1 and tetrakis(4-hydroxyphenyl)-cavitand 2, encapsulates 1 molecule of guests such as 1,4-diacetoxybenzene 3a, 1,4-diacetoxy-2,5-dimethylbenzene 3b, 1,4-diacetoxy-2,5-dialkoxybenzenes (3c, OCH
3
; 3d, OC
2
H
5
; 3e, OC
3
H
7
; 3f, OC
4
H
9
; 3g, OC
5
H
11
; 3h, OC
6
H
13
; 3i, OC
8
H
17
), 1,4-diacetoxy-2,5-difluorobenzene 4a, and 1,4-diacetoxy-2,3-difluorobenzene 4b. The X-ray crystallographic analysis of 3c@(1·2) showed that the acetoxy groups at the 1,4-positions of 3c are oriented toward the 2 aromatic cavity ends of 1·2 and that 3c can rotate along the long axis of 1·2. Thus, the 1·2 (stator) with the encapsulation guest (rotator) behaves as a supramolecular gyroscope. A variable temperature (VT)
1
H NMR study in CDCl
3
showed that 3a, 3b, 4a, and 4b within 1·2 rotate rapidly even at 218 K, whereas guest rotation is almost inhibited for 3h and 3i even at 323 K. In this respect, 4b with a large dipole moment is a good candidate for the rotator of 1·2. For 3c–3g, the enthalpic (Δ
H
‡
) and entropic (Δ
S
‡
) contributions to the free energy of activation (Δ
G
‡
) for the guest-rotational steric barriers within 1·2 were obtained from Eyring plots based on line-shape analysis of the VT
1
H NMR spectra. The value of Δ
G
‡
increased in the order 3c < 3d < 3e < 3f < 3g. Thus, the elongation of the alkoxy chains at the 2,5-positions of 3 puts the brakes on guest rotation within 1·2.
The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity
Authors: Macomber Lee , Imlay James A.
Published: May 2009

Excess copper is poisonous to all forms of life, and copper overloading is responsible for several human pathologic processes. The primary mechanisms of toxicity are unknown. In this study, mutants of
Escherichia coli
that lack copper homeostatic systems (
copA cueO cus
) were used to identify intracellular targets and to test the hypothesis that toxicity involves the action of reactive oxygen species. Low micromolar levels of copper were sufficient to inhibit the growth of both WT and mutant strains. The addition of branched-chain amino acids restored growth, indicating that copper blocks their biosynthesis. Indeed, copper treatment rapidly inactivated isopropylmalate dehydratase, an iron-sulfur cluster enzyme in this pathway. Other enzymes in this iron-sulfur dehydratase family were similarly affected. Inactivation did not require oxygen, in vivo or with purified enzyme. Damage occurred concomitant with the displacement of iron atoms from the solvent-exposed cluster, suggesting that Cu(I) damages these proteins by liganding to the coordinating sulfur atoms. Copper efflux by dedicated export systems, chelation by glutathione, and cluster repair by assembly systems all enhance the resistance of cells to this metal.
Biomechanical assessment of evolutionary changes in the lepidosaurian skull
Authors: Moazen Mehran , Curtis Neil , O'Higgins Paul , Evans Susan E. , Fagan Michael J.
Published: May 2009

The lepidosaurian skull has long been of interest to functional morphologists and evolutionary biologists. Patterns of bone loss and gain, particularly in relation to bars and fenestrae, have led to a variety of hypotheses concerning skull use and kinesis. Of these, one of the most enduring relates to the absence of the lower temporal bar in squamates and the acquisition of streptostyly. We performed a series of computer modeling studies on the skull ofUromastyx hardwickii,an akinetic herbivorous lizard. Multibody dynamic analysis (MDA) was conducted to predict the forces acting on the skull, and the results were transferred to a finite element analysis (FEA) to estimate the pattern of stress distribution. In the FEA, we applied the MDA result to a series of models based on theUromastyxskull to represent different skull configurations within past and present members of the Lepidosauria. In this comparative study, we found that streptostyly can reduce the joint forces acting on the skull, but loss of the bony attachment between the quadrate and pterygoid decreases skull robusticity. Development of a lower temporal bar apparently provided additional support for an immobile quadrate that could become highly stressed during forceful biting.
Storage of molecular hydrogen in an ammonia borane compound at high pressure
Authors: Lin Yu , Mao Wendy L. , Mao Ho-kwang
Published: May 2009

We studied ammonia borane (AB), NH
3
BH
3
, in the presence of excess hydrogen (H
2
) pressure and discovered a solid phase, AB(H
2
)
x
, where
x
≈1.3–2. The new AB–H
2
compound can store an estimated 8–12 wt % molecular H
2
in addition to the chemically bonded H
2
in AB. This phase formed slowly at 6.2 GPa, but the reaction rate could be enhanced by crushing the AB sample to increase its contact area with H
2
. The compound has 2 Raman H
2
vibron peaks from the absorbed H
2
in this phase: one (ν
1
) at frequency 70 cm
−1
below the free H
2
vibron, and the other (ν
2
) at higher frequency overlapping with the free H
2
vibron at 6 GPa. The peaks shift linearly over the pressure interval of 6–16 GPa with average pressure coefficients of dν
1
/d
P
= 4 cm
−1
/GPa and dν
2
/d
P
= 6 cm
−1
/GPa. The formation of the compound is accompanied by changes in the N–H and B–H stretching Raman peaks resulting from the AB interactions with H
2
which indicate the structural complexity and low symmetry of this phase. Storage of significant amounts of additional molecular H
2
in AB increases the already high hydrogen content of AB, and may provide guidance for developing improved hydrogen storage materials.
Vernalization-induced flowering in cereals is associated with changes in histone methylation at the
VERNALIZATION1
gene
Authors: Oliver Sandra N. , Finnegan E. Jean , Dennis Elizabeth S. , Peacock W. James , Trevaskis Ben
Published: May 2009

Prolonged exposure to low temperatures (vernalization) accelerates the transition to reproductive growth in many plant species, including the model plant
Arabidopsis thaliana
and the economically important cereal crops, wheat and barley. Vernalization-induced flowering is an epigenetic phenomenon. In Arabidopsis, stable down-regulation of
FLOWERING LOCUS C
(
FLC
) by vernalization is associated with changes in histone modifications at
FLC
chromatin. In cereals, the vernalization response is mediated by stable induction of the floral promoter
VERNALIZATION1
(
VRN1
), which initiates reproductive development at the shoot apex. We show that in barley (
Hordeum vulgare
), repression of
HvVRN1
before vernalization is associated with high levels of histone 3 lysine 27 trimethylation (H3K27me3) at
HvVRN1
chromatin. Vernalization caused increased levels of histone 3 lysine 4 trimethylation (H3K4me3) and a loss of H3K27me3 at
HvVRN1
, suggesting that vernalization promotes an active chromatin state at
VRN1
. Levels of these histone modifications at 2 other flowering-time genes,
VERNALIZATION2
and
FLOWERING LOCUS T
, were not altered by vernalization. Our study suggests that maintenance of an active chromatin state at
VRN1
is likely to be the basis for epigenetic memory of vernalization in cereals. Thus, regulation of chromatin state is a feature of epigenetic memory of vernalization in Arabidopsis and the cereals; however, whereas vernalization-induced flowering in Arabidopsis is mediated by epigenetic regulation of the floral repressor
FLC
, this phenomenon in cereals is mediated by epigenetic regulation of the floral activator,
VRN1
.
Transcellular biosynthesis of cysteinyl leukotrienes in vivo during mouse peritoneal inflammation
Authors: Zarini Simona , Gijón Miguel A. , Ransome Aaron E. , Murphy Robert C. , Sala Angelo
Published: May 2009

Leukotrienes (LTs) are lipid mediators of inflammation formed by enzymatic oxidation of arachidonic acid. One intriguing aspect of LT production is transcellular biosynthesis: cells expressing 5-lipoxygenase (5LO) form LTA4and transfer it to cells expressing LTA4hydrolase (LTA4H) or LTC4synthase (LTC4S) to produce LTB4or LTC4. This process has been demonstrated in vivo for LTB4, but not for cysteinyl LTs (cysLTs). We examined transcellular cysLT synthesis during zymosan-induced peritonitis, using bone marrow transplants with transgenic mice deficient in key enzymes of LT synthesis and analyzing all eicosanoids by liquid chromatography/tandem mass spectrometry. WT mice time-dependently produced LTB4and cysLTs (LTC4, LTD4, and LTE4). 5LO−/−mice were incapable of producing LTs. WT bone marrow cells restored this biosynthetic ability, but 5LO−/−bone marrow did not rescue LT synthesis in irradiated WT mice, demonstrating that bone marrow-derived cells are the ultimate source of all LTs in this model. Total levels of 5LO-derived products were comparable in LTA4H−/−and WT mice, but were reduced in LTC4S−/−animals. No differences in prostaglandin production were observed between these transgenic or chimeric mice. Bone marrow cells from LTA4H−/−or LTC4S−/−mice injected into 5LO−/−mice restored the ability to synthesize LTB4and cysLTs, providing unequivocal evidence of efficient transcellular biosynthesis of cysLTs. These results highlight the potential relevance of transcellular exchange of LTA4for the synthesis of LTs mediating biological activities during inflammatory events in vivo.
The nucleoporins Nup170p and Nup157p are essential for nuclear pore complex assembly
Authors: Makio Tadashi , Stanton Leslie H. , Lin Cheng-Chao , Goldfarb David S. , Weis Karsten , Wozniak Richard W.
Published: May 2009

We have established that two homologous nucleoporins, Nup170p and Nup157p, play an essential role in the formation of nuclear pore complexes (NPCs) in Saccharomyces cerevisiae. By regulating their synthesis, we showed that the loss of these nucleoporins triggers a decrease in NPCs caused by a halt in new NPC assembly. Preexisting NPCs are ultimately lost by dilution as cells grow, causing the inhibition of nuclear transport and the loss of viability. Significantly, the loss of Nup170p/Nup157p had distinct effects on the assembly of different architectural components of the NPC. Nucleoporins (nups) positioned on the cytoplasmic face of the NPC rapidly accumulated in cytoplasmic foci. These nup complexes could be recruited into new NPCs after reinitiation of Nup170p synthesis, and may represent a physiological intermediate. Loss of Nup170p/Nup157p also caused core and nucleoplasmically positioned nups to accumulate in NPC-like structures adjacent to the inner nuclear membrane, which suggests that these nucleoporins are required for formation of the pore membrane and the incorporation of cytoplasmic nups into forming NPCs.
OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis
Authors: Hirschhorn-Cymerman Daniel , Rizzuto Gabrielle A. , Merghoub Taha , Cohen Adam D. , Avogadri Francesca , Lesokhin Alexander M. , Weinberg Andrew D. , Wolchok Jedd D. , Houghton Alan N.
Published: May 2009

Expansion and recruitment of CD4+ Foxp3+ regulatory T (T reg) cells are mechanisms used by growing tumors to evade immune elimination. In addition to expansion of effector T cells, successful therapeutic interventions may require reduction of T reg cells within the tumor microenvironment. We report that the combined use of the alkylating agent cyclophosphamide (CTX) and an agonist antibody targeting the co-stimulatory receptor OX40 (OX86) provides potent antitumor immunity capable of regressing established, poorly immunogenic B16 melanoma tumors. CTX administration resulted in tumor antigen release, which after OX86 treatment significantly enhanced the antitumor T cell response. We demonstrated that T reg cells are an important cellular target of the combination therapy. Paradoxically, the combination therapy led to an expansion of T reg cells in the periphery. In the tumor, however, the combination therapy induced a profound T reg cell depletion that was accompanied by an influx of effector CD8+ T cells leading to a favorable T effector/T reg cell ratio. Closer examination revealed that diminished intratumoral T reg cell levels resulted from hyperactivation and T reg cell–specific apoptosis. Thus, we propose that CTX and OX40 engagement represents a novel and rational chemoimmunotherapy.
Kallikrein 5 induces atopic dermatitis–like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome
Authors: Briot Anaïs , Deraison Céline , Lacroix Matthieu , Bonnart Chrystelle , Robin Aurélie , Besson Céline , Dubus Pierre , Hovnanian Alain
Published: May 2009

Netherton syndrome (NS) is a severe genetic skin disease with constant atopic manifestations that is caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lymphoepithelial Kazal-type–related inhibitor (LEKTI). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopy in NS. We show for the first time that the pro-Th2 cytokine thymic stromal lymphopoietin (TSLP), the thymus and activation-regulated chemokine, and the macrophage-derived chemokine are overexpressed in LEKTI-deficient epidermis. This is part of an original biological cascade in which unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor κB–mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor α, and IL8. This proinflammatory and proallergic pathway is independent of the primary epithelial failure and is activated under basal conditions in NS keratinocytes. This cell-autonomous process is already established in the epidermis of Spink5−/− embryos, and the resulting proinflammatory microenvironment leads to eosinophilic and mast cell infiltration in a skin graft model in nude mice. Collectively, these data establish that uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)–like lesions, independently of the environment and the adaptive immune system. They illustrate the crucial role of protease signaling in skin inflammation and point to new therapeutic targets for NS as well as candidate genes for AD and atopy.
Validation of a Modified Version of the National Nosocomial Infections Surveillance System Risk Index for Health Services Research
Authors: Daneman Nick , Simor Andrew E. , Redelmeier Donald A.
Published: May 2009

Objective.

To validate the National Nosocomial Infections Surveillance system risk index through administrative data to predict surgical site infections.

Design.

Retrospective cohort study.

Setting.

Population-based analysis in Ontario, Canada.

Patients.

All elderly patients who underwent elective surgery from April 1, 1992, through March 31, 2006 (n = 469,349).

Methods.

Data on procedural and patient outcomes were gathered from linked population-wide hospital discharge records and physician claims. The 75th percentile of surgical duration was estimated through anesthesiologist billing fees recorded in 15-minute increments; the American Society of Anesthesiology score of at least 3 out of 5 was estimated by diagnostic codes for severe systemic illness; and all surgeries were classified as clean or clean-contaminated because of their elective nature (thus, the maximum score on the modified index was 2).

Results.

A total of 147,216 surgeries (31%) had a score of 0;246,592 (53%) had a score of 1; and 75,541 (16%) had a score of 2 on the modified index. The 30-day risk of surgical site infection increased with each increment in the modified index (score of 0, 5.4%; score of 1, 8.0%; score of 2, 14.3%; P < .001). The association was evident for surgical site infection diagnosed during the index admission (score of 0, 2.0%; score of 1, 3.7%; score of 2, 8.9%; P < .001), as well as that associated with reoperation or death (score of 0, 0.04%; score of 1, 0.23%; score of 2, 0.73%; P < .001). The modified index predicted increases in surgical site infection risk within each of 11 surgical subgroups. In accord with past research, the modified index had modest discrimination (C statistic, 0.59), and the majority of surgical site infections (72%) occurred within lower risk strata.

Conclusions.

The modified index predicts surgical site infection in population-based analyses and is associated with incremental increases in risk.
Feasibility of Routinely Using Hydrogen Peroxide Vapor to Decontaminate Rooms in a Busy United States Hospital
Authors: Otter Jonathan A. , Puchowicz Matthew , Ryan David , Salkeld James A. G. , Cooper Timothea A. , Havill Nancy L. , Tuozzo Kathy , Boyce John M.
Published: May 2009

During a 22-month period at a 500-bed teaching hospital, 1,565 rooms that had housed patients infected with multidrug-resistant pathogens were decontaminated using hydrogen peroxide vapor. Hydrogen peroxide vapor decontamination required a mean time of 2 hours and 20 minutes, compared with 32 minutes for conventional cleaning. Despite the greater time required for decontamination, hydrogen peroxide vapor decontamination of selected patient rooms is feasible in a busy hospital with a mean occupancy rate of 94%.
Rate of Latent Tuberculosis Infection Detected by Occupational Health Screening of Nurses New to a London Teaching Hospital
Authors: Khanna Priya , Nikolayevskyy Vladyslav , Warburton Fiona , Dobson Elek , Drobniewski Francis
Published: May 2009

The prevalence of latent tuberculosis infection in a cohort of nurses new to a London hospital was 7.6% (13 of 171), using an interferon-γ(IFN-γ) release assay, and 16.2% (24 of 148), using the tuberculin skin test. On multivariate analysis, birth in a country with tuberculosis prevalence of more than 40 cases per 100,000 population was associated with positive results of both the IFN-γ release assay and the tuberculin skin test.
Patient and informal caregivers’ knowledge of heart failure: necessary but insufficient for effective self‐care
Authors: Clark Alexander M. , Freydberg C. Nicole , McAlister Finlay A. , Tsuyuki Ross T. , Armstrong Paul W. , Strain Laurel A.
Published: May 2009

Aims

Self‐care of heart failure (HF) is a process that is important, complex, and challenging. Little is understood of the contextual factors influencing self‐care. We aimed to examine the individual and contextual factors perceived by patients and their informal caregivers’ to influence their willingness and capacity to undertake effective HF self‐care.

Methods and results

This was a qualitative study using semi‐structured interviews with 42 patients with HF (NYHA Class II and III, mean age: 76 years, 64% males) and 30 nominated caregivers (63% spouses). All patients experienced severe and intrusive HF symptoms; a large proportion of patients practiced some of the range of recommended self‐care activities. However, links between knowledge of HF and self‐care were weak and long delays in seeking professional care were frequent. Factors consistently reported to influence self‐care were faith in health professionals, beliefs about the local health system, and values linked to work associated with place, history, and culture.

Conclusion

Knowledge of HF and its management is a necessary though not sufficient determinant of HF self‐care. Individual and contextual factors influence willingness and capacity to undertake effective HF self‐care.
A computational model for emergent dynamics in the kidney
Authors: Moss Robert , Kazmierczak Ed , Kirley Michael , Harris Peter
Published: May 2009

In this paper, concepts from network automata are adapted and extended to model complex biological systems. Specifically, systems ofnephrons, the operational units of the kidney, are modelled and thedynamicsof such systems are explored. Nephron behaviour can fluctuate widely and, under certain conditions, become chaotic. However, the behaviour of the whole kidney remains remarkably stable and blood solute levels are maintained under a wide range of conditions even when many nephrons are damaged or lost. A network model is used to investigate the stability of systems of nephrons and interactions between nephrons. More sophisticated dynamics are explored including the observed oscillations in single nephron filtration rates and the development of stable ionic and osmotic gradients in the inner medulla which contribute to the countercurrent exchange mechanism. We have used the model to explore the effects of changes in input parameters including hydrostatic and osmotic pressures and concentrations of ions, such as sodium and chloride. The intrinsic nephron control, tubuloglomerular feedback, is included and the effects of coupling between nephrons are explored in two-, eight- and 72-nephron models.
Rapid contemporary evolution and clonal food web dynamics
Authors: Jones Laura E. , Becks Lutz , Ellner Stephen P. , Hairston Nelson G. , Yoshida Takehito , Fussmann Gregor F.
Published: May 2009

Character evolution that affects ecological community interactions often occurs contemporaneously with temporal changes in population size, potentially altering the very nature of those dynamics. Such eco-evolutionary processes may be most readily explored in systems with short generations and simple genetics. Asexual and cyclically parthenogenetic organisms such as microalgae, cladocerans and rotifers, which frequently dominate freshwater plankton communities, meet these requirements. Multiple clonal lines can coexist within each species over extended periods, until either fixation occurs or a sexual phase reshuffles the genetic material. When clones differ in traits affecting interspecific interactions, within-species clonal dynamics can have major effects on the population dynamics. We first consider a simple predator–prey system with two prey genotypes, parametrized with data from a well-studied experimental system, and explore how the extent of differences in defence against predation within the prey population determine dynamic stability versus instability of the system. We then explore how increased potential for evolution affects the community dynamics in a more general community model with multiple predator and multiple prey genotypes. These examples illustrate how microevolutionary ‘details’ that enhance or limit the potential for heritable phenotypic change can have significant effects on contemporaneous community-level dynamics and the persistence and coexistence of species.
Bacterial intermediate filaments: in vivo assembly, organization, and dynamics of crescentin
Authors: Charbon Godefroid , Cabeen Matthew T. , Jacobs-Wagner Christine
Published: May 2009

Crescentin, which is the founding member of a rapidly growing family of bacterial cytoskeletal proteins, was previously proposed to resemble eukaryotic intermediate filament (IF) proteins based on structural prediction and in vitro polymerization properties. Here, we demonstrate that crescentin also shares in vivo properties of assembly and dynamics with IF proteins by forming stable filamentous structures that continuously incorporate subunits along their length and that grow in a nonpolar fashion. De novo assembly of crescentin is biphasic and involves a cell size-dependent mechanism that controls the length of the structure by favoring lateral insertion of crescentin subunits over bipolar longitudinal extension when the structure ends reach the cell poles. The crescentin structure is stably anchored to the cell envelope, and this cellular organization requires MreB function, identifying a new function for MreB and providing a parallel to the role of actin in IF assembly and organization in metazoan cells. Additionally, analysis of an MreB localization mutant suggests that cell wall insertion during cell elongation normally occurs along two helices of opposite handedness, each counterbalancing the other's torque.
The Role of Personality in Task and Relationship Conflict
Authors: Bono Joyce E. , Boles Terry L. , Judge Timothy A. , Lauver Kristy J.
Published: May 2009

ABSTRACT Two studies explored the extent to which dispositions influence the attributions individuals make about the type of conflict they experience. Traits from the Five‐Factor Model of personality (FFM) were linked to the tendency to experience task‐and relationship‐oriented conflict. Results provide some support for the idea that individuals have stable tendencies in the attributions they make about their conflict experiences across time, partners, and situations. Agreeableness and openness were related to reports of relationship conflict at the individual level. However, the strongest effects of personality on conflict attributions were found in the analysis of dyads. This analysis revealed that partner levels of extraversion and conscientiousness were associated with individuals' tendencies to report relationship conflict. Moreover, mean levels of extraversion and conscientiousness in a pair were associated with reports of relationship conflict. Differences between partners in extraversion were associated with more frequent conflict and a greater likelihood of reporting task‐related conflict. Implications of these findings with respect to the role of personality in interpersonal relationships are discussed. Finally, these studies provide confirmatory evidence that conflict attributions have a meaningful impact on relationship satisfaction.
Goal Construction, Reconstruction and Depressive Symptoms in a Life‐Span Context: The Transition From School to Work
Authors: Nurmi Jari‐Erik , Salmela‐Aro Katariina
Published: May 2009

ABSTRACT This study focused on investigating the kinds of personal goals young adults have when they are faced with the transition from school to work; the extent to which they reconstruct these goals as a consequence of their success in dealing with this transition; and how their goals influence their depressive symptoms. In order to investigate these research questions, 250 young adults who were facing a transition from school to work were studied at three points of the transition process: while they were still at school; 8 months after their graduation; and 1.5 years after it. At each measurement point, they were asked to complete the Personal Project Analysis, a revised form of Beck's Depression Inventory, and the Work Status Questionnaire. The results revealed that the outcomes of young adults' efforts to deal with the transition from school to work had consequences for the ways in which they reconstructed their goals: Those who were successful in this transition showed a decline in the number of personal goals that did not relate to the next stages of this particular developmental trajectory, whereas those who had problems turned to goals that concerned other life domains, as an alternative, compensatory control strategy. The results also revealed that the impact of personal goals on depressive symptomatology was moderated by individuals' life situations following the transition: Work‐related goals reduced individuals' depressive symptoms only among those who had been able to find a job, whereas self‐related goals decreased it in a moratorium‐type of life situation.
Roles of Nox1 and other Nox isoforms in cancer development
Authors: Kamata Tohru
Published: May 2009

The NADPH oxidase (Nox) family of enzymes generates reactive oxygen species (ROS). At low ROS concentration, intracellular signaling is initiated, whereas at high ROS concentration, oxidative stress is induced. The extensive studies over the years have shed light on the mediating roles of the Nox enzymes in a variety of normal physiological processes ranging from bactericidal activity to remodeling of the extracellular matrix. Consequently, imbalance of Nox activities could be the potential cause of acute or chronic diseases. With regard to functional relationships between Nox isoforms and pathogenesis, it is of particular interest to study whether they are involved in carcinogenesis, because overproduction of ROS has long been implicated as a risk factor in cancer development. We see one remarkable example of the causal relationship between Nox1 and cancer in Ras oncogene‐induced cell transformation. Other studies also indicate that the Nox family of genes appears to be required for survival and growth of a subset of human cancer cells. Thus, the Nox family will be a focus of attention in cancer biology and etiology over the next couple years. (Cancer Sci 2009)
Quantitative trait loci for live animal and carcass composition traits in Jersey and Limousin back‐cross cattle finished on pasture or feedlot
Authors: Morris C. A. , Pitchford W. S. , Cullen N. G. , Esmailizadeh A. K. , Hickey S. M. , Hyndman D. , Dodds K. G. , Afolayan R. A. , Crawford A. M. , Bottema C. D. K.
Published: May 2009

A quantitative trait locus (QTL) study was carried out in two countries, recording live animal and carcass composition traits. Back‐cross calves (385 heifers and 398 steers) were generated, with Jersey and Limousin breed backgrounds. The New Zealand cattle were reared on pasture to carcass weights averaging 229 kg, whilst the Australian cattle were reared on grass and finished on grain (for at least 180 days) to carcass weights averaging 335 kg. From 11 live animal traits and 31 carcass composition traits respectively, 5 and 22 QTL were detected in combined‐sire analyses, which were significant (P < 0.05) on a genome‐wise basis. Fourteen significant traits for carcass composition QTL were on chromosome 2 and these were traits associated with muscling and fatness. This chromosome carried a variant myostatin allele (F94L), segregating from the Limousin ancestry. Despite very different cattle management systems between the two countries, the two populations had a large number of QTL in common. Of the 18 traits which were common to both countries, and which had significant QTL at the genome‐wise level, eight were significant in both countries.
A whole genome association analysis identifies loci associated with Mycobacterium avium subsp. paratuberculosis infection status in US holstein cattle
Authors: Settles M. , Zanella R. , McKay S. D. , Schnabel R. D. , Taylor J. F. , Whitlock R. , Schukken Y. , Van Kessel J. S. , Smith J. M. , Neibergs H.
Published: May 2009

The purpose of this study was to identify loci associated with Mycobacterium avium subspecies paratuberculosis (Map) infection status in US Holsteins using the Illumina BovineSNP50 BeadChip whole genome single nucleotide polymorphism (SNP) assay. Two hundred forty‐five cows from dairies in New York, Pennsylvania and Vermont enrolled in longitudinal herd studies between January 1999 and November 2007 were assessed for the presence of Map in both faecal and tissue samples. An animal was considered tissue infected if any sample contained at least one colony forming unit of Map per gram of tissue (CFU/g) and the same definition was employed for faecal samples. Each animal was genotyped with the Illumina BovineSNP50 BeadChip and after quality assurance filtering, 218 animals and 45 683 SNPs remained. We sought to identify loci associated with four different case/control classifications: presence of Map in the tissue, presence of Map in faeces, presence of Map in both tissue and faeces and presence of Map in tissue but not faeces. A case–control genome wide association study was conducted to test the four different classifications of Map infection status (cases) when compared with a Map‐negative control group (control). Regions on chromosomes 1, 5, 7, 8, 16, 21 and 23 were identified with moderate significance (P < 5 × 10−5). Two regions, one on chromosome 3 (near EDN2) and another on chromosome 9 (no positional gene candidates), were identified with a high level of association to the presence of Map in tissue and both tissue and faeces respectively (P < 5 × 10−7, genome‐wide Bonferonni P < 0.05).
Analysis of the oviductal glycoprotein 1 polymorphisms and their effects on components of litter size in rabbits
Authors: Merchán M. , Peiró R. , Argente M. J. , Santacreu M. A. , García M. L. , Blasco A. , Folch J. M.
Published: May 2009

The objective of this work was to study the effect of the oviductal glycoprotein 1 (OVGP1) genotype and mRNA expression on litter size and other fertility measures, as OVGP1 has positive effects on fertilization and early embryo development. We have analysed an F2 cross of two lines of rabbits divergently selected for uterine capacity. The OVGP1 mRNA expression was analysed in both lines, but no differences were observed between them. The promoter region and mRNA were sequenced in the F0 generation, and 17 polymorphic sites were found to co‐segregate in three haplotypes (A, B and C). An association study was performed between several reproductive traits and a triallelic microsatellite identified in the promoter region as well as a non‐synonymous SNP located in exon 11 [g.12944C>G (p.Arg468Gly)]. The alleles g.12944G and g.325(GT)14T(G)5 of the B haplotype have a positive effect on the total number of kits born, number born alive, number of implanted embryos and foetal and prenatal embryo survival.
Pharmacokinetic interaction between nevirapine and darunavir with low‐dose ritonavir in HIV‐1‐infected patients
Authors: Sekar Vanitha , Lefebvre Eric , Mariën Kris , De Pauw Martine , Vangeneugden Tony , Pozniak Anton , Hoetelmans Richard M. W.
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The protease inhibitor (PI) darunavir with low‐dose ritonavir (DRV/r) and the non‐nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) are used in combination with other antiretroviral agents and they may be co‐administered for the treatment of HIV‐1 infection.

• There is the potential for a pharmacokinetic interaction between NVP and DRV/r, since these drugs use similar metabolic pathways.

WHAT THIS STUDY ADDS

• This study assesses for the first time the extent of the drug–drug interaction between NVP and DRV/r in the relevant population of HIV‐1‐infected patients.

AIM

To investigate the pharmacokinetic interaction between darunavir/ritonavir (DRV/r) and nevirapine (NVP) in 19 HIV‐infected patients.

METHODS

An open‐label, randomized, crossover study. Patients received Treatment A [NVP 200 mg b.i.d. plus ≥2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)] and Treatment B [A plus DRV/r 300/100 mg b.i.d. (DRV oral solution)] or Treatment B2 [A plus DRV/r 400/100 mg b.i.d. (DRV tablet)] in two 14‐day sessions.

RESULTS

Mean NVP AUC12hincreased by 27% [least square means ratio 1.27 (95% confidence interval 1.02, 1.58)]. Mean DRV and ritonavir exposures were similar to historical data. Co‐administration was well tolerated.

CONCLUSIONS

DRV/r and NVP have no clinically relevant interaction. No dose adjustments are required.
Effects ofCYP2D6genotypes on age‐related change of flecainide metabolism: involvement of CYP1A2‐mediated metabolism
Authors: Doki Kosuke , Homma Masato , Kuga Keisuke , Aonuma Kazutaka , Kohda Yukinao
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• CYP2D6 is a main enzyme for flecainide metabolism in terms of the conversion of flecainide tom‐O‐dealkylated flecainide (MODF).

• Age‐related reduction of flecainide metabolism cannot be explained by CYP2D6 alone, the activity of which is known to be practically unchanged by ageing.

• Flecainide metabolites including MODF have been found in plasma obtained from CYP2D6 poor metabolizers, suggesting that other CYPs may be involved in flecainide metabolism.

WHAT THIS STUDY ADDS

• Age‐related reduction in metabolic clearance of flecainide was remarkable in patients carryingCYP2D6mutant alleles.

• Anin vitrostudy using human liver microsomes revealed that CYP1A2 was involved in MODF formation in addition to CYP2D6.

• It is suggested that CYP1A2 plays an important role in flecainide metabolism in patients with poor CYP2D6‐mediated metabolism.

AIMS

The aim of this study was to clarify the effects ofCYP2D6genotype on age‐related change in flecainide metabolism in patients with supraventricular tachyarrhythmias. Anin vitrostudy using microsomes was performed to identify other CYPs responsible for age‐related change in flecainide metabolism.

METHODS

The study population comprised 111 genotyped patients: CYP2D6‐homozygous extensive metabolizers (hom‐EMs,n= 34), heterozygous EMs (het‐EMs,n= 56), and intermediate and poor metabolizers (IMs/PMs,n= 21). Serum concentrations of flecainide and its metabolites [m‐O‐dealkylated flecainide (MODF) andm‐O‐dealkylated lactam of flecainide] were determined by use of a high‐performance liquid chromatography. Metabolic ratio (MR) was expressed as serum concentrations of flecainide to its metabolites.In vitroformation of MODF was examined in human liver microsomes and cDNA‐expressed CYP isoforms.

RESULTS

MR was higher in elderly patients (≥70 years) than in middle‐aged patients (<70 years). The increase of MR in elderly patients differed amongCYP2D6genotypes: 1.6‐fold in het‐EMs [4.3, 95% confidence interval (CI) 2.8, 5.7vs.2.7, 95% CI 2.3, 3.1,P< 0.05], 1.5‐fold in IMs/PMs (6.0, 95% CI 4.5, 7.6vs.4.1, 95% CI 2.9, 5.4,P< 0.05), and no change in hom‐EMs. Thein vitrostudy using microsomes revealed that both CYP2D6 and CYP1A2 were involved in the formation of MODF. MODF formation in CYP2D6 PM microsomes increased as CYP1A2 activity increased.

CONCLUSIONS

The results suggest that patients with poor CYP2D6‐mediated metabolism (het‐EMs and IMs/PMs) showed age‐related reduction in flecainide metabolism because metabolism was taken over by CYP1A2, whose activity decreases with age.
Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population
Authors: Lakhan Ram , Kumari Ritu , Misra Usha K. , Kalita Jayanti , Pradhan Sunil , Mittal Balraj
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The SCN1A and SCN2A genes encode α subunits of the neuronal voltage‐gated sodium channel, which are targets for various antiepileptic drugs such as carbamazepine, phenytoin, valproate and others.

• Recent studies have demonstrated that various genetic variants of these channel genes play important role in the pathogenesis and therapy of epilepsy.

WHAT THIS STUDY ADDS

• This study demonstrates a significant association between the SCN1A c.3184 A→G; AG genotype and epilepsy.

• However SCN2A c.56 G→A; allele ‘A’ was significantly associated with multiple drug resistance in epilepsy in north Indian population.

AIMS

To evaluate sodium channel genes as candidates for epilepsy susceptibility and their role in therapeutic efficacy, we screened coding single‐nucleotide polymorphism of SCN1A p. Thr 1067 Ala or c.3184 A→G (rs2298771) and SCN2A p.Arg19Lys or c.56 G→A (rs17183814) in north Indian epilepsy patients.

METHODS

The genotyping was performed in 160 control subjects and 336 patients with epilepsy, of whom 117 were drug resistant and 219 were drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital and valproate was also performed in 20% of the patients to confirm compliance.

RESULTS

AG genotype of SCN1A 3184 A→G polymorphism was significantly higher and associated in epilepsy patients [P= 0.005; odds ratio (OR) 1.76, 95% confidence interval (CI) 1.19, 2.61], whereas A variant of SCN2A c.56 G→A was associated with multiple drug resistance in north Indian patients with epilepsy (P= 0.03; OR 1.62, 95% CI 1.03, 2.56).

CONCLUSIONS

Overall, results indicate a differential role of genetic polymorphisms of sodium channels SCN1A and SCN2A in epilepsy susceptibility and drug response.
No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin
Authors: Keskitalo Jenni E. , Kurkinen Kaisa J. , Neuvonen Mikko , Backman Janne T. , Neuvonen Pertti J. , Niemi Mikko
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• ABCB1 genotype affects the pharmacokinetics and cholesterol‐lowering effects of simvastatin and atorvastatin.

• The cholesterol‐lowering effect of fluvastatin has been associated with ABCB1 genotype, and pravastatin, lovastatin, lovastatin acid, and rosuvastatin are substrates of ABCB1.

• However, it is not known whether ABCB1 genotype affects the pharmacokinetics of fluvastatin, pravastatin, lovastatin, or rosuvastatin.

WHAT THIS STUDY ADDS

• ABCB1 c.1236C‐c.2677G‐c.3435C and c.1236T‐c.2677T‐c.3435T haplotypes have no significant effects on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, or rosuvastatin.

AIMS

This study aimed to investigate possible effects of ABCB1 genotype on fluvastatin, pravastatin, lovastatin, and rosuvastatin pharmacokinetics.

METHODS

In a fixed‐order crossover study, 10 healthy volunteers with the ABCB1 c.1236C/C‐c.2677G/G‐c.3435C/C (CGC/CGC) genotype and 10 with the c.1236T/T‐c.2677T/T‐c.3435T/T (TTT/TTT) genotype ingested a single 20‐mg dose of fluvastatin, pravastatin, lovastatin, and rosuvastatin. Plasma fluvastatin, pravastatin, and lovastatin concentrations were measured up to 12 h and plasma and urine rosuvastatin concentrations up to 48 and 24 h, respectively.

RESULTS

The ABCB1 genotype had no significant effect on the pharmacokinetics of any of the investigated statins. The geometric mean ratio (95% confidence interval) of the area under the plasma concentration–time curve from 0 h to infinity (AUC0–∞) in participants with the TTT/TTT genotype to that in those with the CGC/CGC genotype was 0.96 (0.77, 1.20; P= 0.737) for fluvastatin, 0.92 (0.53, 1.62; P= 0.772) for pravastatin, 0.83 (0.36, 1.90; P= 0.644) for lovastatin, 1.25 (0.72, 2.17; P= 0.400) for lovastatin acid, and 1.10 (0.73, 1.65; P= 0.626) for rosuvastatin. The AUC0–∞ of lovastatin acid correlated significantly with that of rosuvastatin (r= 0.570, P= 0.009), but none of the other AUC0–∞ pairs showed a significant correlation.

CONCLUSIONS

These data suggest that the ABCB1 c.1236C‐c.2677G‐c.3435C and c.1236T‐c.2677T‐c.3435T haplotypes play no significant role in the interindividual variability in the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.
Randomized placebo‐controlled trial of granulocyte colony stimulating factor (G‐CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom Medical Research Council Adult Leukaemia Working Party
Authors: Wheatley Keith , Goldstone Anthony H. , Littlewood Tim , Hunter Anne , Burnett Alan K.
Published: May 2009

The role of granulocyte colony stimulating factor (G‐CSF) as supportive therapy following intensive induction chemotherapy for acute myeloid leukaemia (AML) in adults was investigated in a randomized trial. G‐CSF (Lenograstim, 263 μg/d) or placebo was administered from day 8 after the end of chemotherapy until neutrophil recovery to 0·5 × 109/l (or for up to 10 d). Eight hundred and three patients were entered. Neutrophil recovery was quicker with G‐CSF (P < 0·0001), but this did not lead to differences in the number, severity or duration of infections. There were no substantial supportive care savings, although G‐CSF patients spent 2 d less in hospital (P = 0·01). Complete remission (CR) rates were similar between arms (73% G‐CSF, 75% placebo, P = 0·5), as were reasons for failure (induction death: P = 0·7; resistant disease: P = 0·5) and, for remitters, 5‐year disease‐free survival (34% vs. 38%, P = 0·3). Overall survival at 5 years was 29% with G‐CSF vs. 36% with placebo (P = 0·10). Both CR rate (P = 0·006) and overall survival (P = 0·006) were worse with G‐CSF in patients aged <40 years, but this may be a chance effect. There is some evidence from this trial of an adverse effect of G‐CSF but these data need to be viewed in the context of the evidence from the other trials.
Prescribing of psychotropic medication to the intellectually disabled by community paediatricians – a survey
Authors: Elliott S. J. , Haider B. B.
Published: May 2009

Background  Children with intellectual disability are often managed by community paediatricians and have a high prevalence of mental disorder. We do not know whether community paediatricians feel adequately trained to treat this group although we know that paediatricians contribute significantly to psychotropic prescribing for children.

Methods  Psychotropic medication prescribing by community paediatricians to the intellectually disabled in the north‐west and northern regions, community paediatricians' perceived training needs in this area and the availability of specialized psychiatric services were surveyed. Postal questionnaires were sent to all members of the British Association of Community Child Health in the north and north western regions (n= 155), between summer 2004 and autumn 2005.

Results  A total of 70.1% (n= 110) of questionnaires were returned of which 66 were completed. The most common reason for non‐completion was that the respondent did not look after the intellectually disabled. A total of 54.5% of respondents did not have access to specialist psychiatry services for children and adolescents with an intellectual disability. Community paediatricians were most likely to prescribe for sleep disorders and attention deficit hyperactivity disorder (ADHD). There was a significant relationship between perceived adequacy of training and paediatrics prescribing for ADHD, but there was no such relationship for sleep disorders. The vast majority of community paediatricians did not feel adequately trained to prescribe for challenging behaviour or depression, although a small minority did prescribe.

Conclusions  Community paediatricians play a substantial role in prescribing psychotropic medications for this group. A substantial minority of community paediatricians do not feel that they have enough training to prescribe for ADHD and sleep disorders, and perceived competency is more likely to inform prescribing for ADHD than for sleep disorders. This may have implications for training. Although these children pose complex difficulties, access to specialist mental health services for children and adolescents with intellectual disability remains patchy, especially in the north‐west, and further development of these services is needed.