bluuebunny/crossref_metadata_2025 huggingface dataset:
Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flurbiprofen in patients with rheumatoid arthritis.
Authors: Tracy TS , Worster T. , Bradley JD , Greene PK , Brater DC
Published: July 2012

The effects of three non‐steroidal anti‐inflammatory drugs (NSAIDs) on the pharmacokinetics of methotrexate were studied in 10 patients with rheumatoid arthritis. Ketoprofen (3 mg kg‐1 day‐1), flurbiprofen (3 mg kg‐1 day‐1), piroxicam (20 mg day‐1), or a non‐NSAID control (paracetamol/acetaminophen) were administered to patients for at least 6 days (13 days in the case of piroxicam to establish steady state) in a randomized crossover design prior to receiving a weekly oral dose of methotrexate. In the non‐NSAID control portion of the study, MTX oral clearance (CLo) was 11.0 +/‐ 3.9 l h‐1, renal clearance (CLR) was 7.9 +/‐ 2.8 l h‐1, percent excreted unchanged was 72 +2‐ 19% and fraction unbound (fu) was 0.54 +/‐ 0.11. Values of oral clearance, renal clearance, fraction unbound and percentage excreted unchanged of methotrexate varied no more than 12.2% from non‐NSAID control during concomitant administration of ketoprofen, flurbiprofen or piroxicam and were not statistically different from non‐NSAID control. In contrast to other NSAIDs such as ibuprofen and salicylates, ketoprofen, flurbiprofen or piroxicam in clinically relevant doses do not appear to affect methotrexate disposition and may be used safely in combination with methotrexate.
Trilinolein improves erythrocyte deformability during cardiopulmonary bypass.
Authors: Tsai SK , Chan P. , Lee TY , Yung JM , Hong CY
Published: July 2012

The in vitro effect of trilinolein, a triglyceride with linoleic acid as the major fatty acid residue in the esterified positions of glycerol, on erythrocyte deformability was studied in blood samples collected from 12 patients before and after cardiopulmonary bypass (CPB). Erythrocyte deformability was measured with a filtration method and expressed as red cell filtration rate (RFR). RFR was reduced after CPB and the reduction was time dependent. Trilinolein at a concentration of 10(‐7) M significantly reversed the CPB‐induced reduction of RFR when it was mixed with blood samples collected 30, 60 and 90 min from the start of CPB. This study confirmed the effect of CPB on erythrocyte deformability and showed that this damage could be significantly improved by mixing blood with trilinolein.
Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors
Authors: Frymoyer Adam , Verotta Davide , Jacobson Pamala , Long‐Boyle Janel
Published: July 2012

Aim

To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients.

Methods

A population‐based pharmacokinetic (PK) model of unbound MPA was developed using non‐linear mixed‐effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used. In addition to clinical covariates, genetic polymorphisms in UGT1A8, UGT1A9, UGT2B7 and MRP2 were evaluated for their impact on unbound MPA PK.

Results

Unbound MPA concentration−time data were well described by a two compartment model with first order absorption and linear elimination. For the typical patient (52 years of age, creatinine clearance 86 ml min−1), the median estimated values [coefficient of variation, %, (CV)] of systemic clearance, intercompartmental clearance, central and peripheral volumes of MPA were 1610 l h−1 (37.4%), 541 l h−1 (75.6%), 1230 l (37.5%), and 6140 l (120%), respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). No genetic polymorphisms tested significantly explained the variability among individuals. Creatinine clearance was a small but significant predictor of unbound MPA CL. No other clinical covariates impacted unbound MPA PK.

Conclusions

In adult alloHCT recipients, variability in unbound MPA AUC was large and remained largely unexplained even with the inclusion of pharmacogenetic information. Targeting unbound MPA AUC in a patient will require therapeutic drug monitoring.
Omega‐3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?
Authors: Calder Philip C.
Published: July 2012

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n‐3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte‐endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n‐6 fatty acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti‐inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti‐inflammatory actions of n‐3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro‐inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti‐inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor γ) and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2 g day–1 seems to be required to elicit anti‐inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n‐3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta‐analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.
Platelet‐associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia
Authors: Cooper Nichola , Stasi Roberto , Cunningham‐Rundles Susanna , Cesarman Ethel , McFarland Janice G. , Bussel James B.
Published: July 2012

Rituximab is widely used in autoimmune diseases including immune thrombocytopenia (ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet‐associated antibodies (PA‐APAs), B and T cell counts and clonality (
IGHV
and
TRG@
gene rearrangements),
FCGR3A
(FcγRIIIa) and
FCGR2A
(FcγRIIa) polymorphisms and correlation to anti‐CD40 ligand (CD40L) response. PA‐APA levels fell more frequently in responders (6/8) than in non‐responders (2/10: P = 0·08–0·15). Two responders had no PA‐APAs. Two non‐responders with a fall in PA‐APAs had very high CD8 levels. One non‐responder had a B cell clone, one responder and one non‐responder had a T cell clone. 15/16 patients had the same responses to rituximab and antiCD40L. Patients with
FCGR3A V/V polymorphisms were more likely to respond to rituximab (P = 0·03). In summary, the fall in PA‐APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA‐APA fall indicates a role for T cell‐mediated platelet/megakaryocyte destruction. Concordance of response to anti‐CD40L suggests autoantibody‐producing cells are under T cell control. Finally, the effect of
FCGR
polymorphisms on response confirms the importance of FCGR‐mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion.
Elevated plasma levels and platelet‐associated expression of the pro‐thrombotic and pro‐inflammatory protein, TNFSF14 (LIGHT), in sickle cell disease
Authors: Garrido Vanessa T. , Proença‐Ferreira Renata , Dominical Venina M. , Traina Fabiola , Bezerra Marcos A. C. , de Mello Mariana R. B. , Colella Marina P. , Araújo Aderson S. , Saad Sara T. O. , Costa Fernando F. , Conran Nicola
Published: July 2012

Chronic vascular inflammation and endothelial activation may initiate vaso‐occlusion in sickle cell disease (SCD). TNFSF14 (CD258; LIGHT), a recently‐identified pro‐thrombotic and pro‐inflammatory tumour necrosis factor (TNF)‐superfamily cytokine, has a potent activating effect on endothelial cells. We evaluated whether TNFSF14 production is altered in SCD and whether platelets contribute to this production. TNFSF14 was measured in platelet‐free plasma from healthy‐control individuals (CON), steady‐state sickle cell anaemia (SCA), SCA on hydroxycarbamide therapy (SCAHC) and haemoglobin SC (HbSC) patients. Mean plasma TNFSF14 was significantly increased in SCA, SCAHC and HbSC, compared to CON individuals. In SCA/SCAHC patients, plasma TNFSF14, showed no correlation with haematological variables, but was significantly correlated with serum lactate dehydrogenase and inflammatory markers (CD40LG
,
IL8 and ICAM1). Platelet‐membrane TNFSF14 expression was significantly augmented on SCA platelets, and correlated with platelet activation; furthermore, measurement of platelet TNFSF14 release indicated that platelets may be a major source of circulating TNFSF14 in SCA. Interestingly, high plasma TNFSF14 was significantly associated with elevated tricuspid regurgitant velocity (≥2·5 m/s) in a population of SCA/SCAHC patients. The pro‐inflammatory and atherogenic cytokine, TNFSF14, could contribute to endothelial activation and inflammation in SCA; future investigations may confirm whether this protein contributes to major clinical complications of the disease, such as pulmonary hypertension, and represents a potential therapeutic target.
Elevated TRIB2 with NOTCH1 activation in paediatric/adult T‐ALL
Authors: Hannon Maura M. , Lohan Fiona , Erbilgin Yucel , Sayitoglu Muge , O'Hagan Kathleen , Mills Ken , Ozbek Ugur , Keeshan Karen
Published: July 2012

TRIB2 is a potent oncogene, elevated in a subset of human acute myeloid leukaemias (AML) with a mixed myeloid/lymphoid phenotype and NOTCH1 mutations. Although rare in AML, activating NOTCH1 mutations occur in 50% of all T cell acute lymphoblastic leukaemias (T‐ALL). TRIB2 is a NOTCH1 target gene that functions in the degradation of key proteins and modulation of MAPK signalling pathways, implicated in haematopoietic cell survival and proliferation. This study showed that TRIB2 expression level is highest in the lymphoid compartment of normal haematopoietic cells, specifically in T cells. Analysis of TRIB2 expression across 16 different subtypes of human leukaemia demonstrated that TRIB2 expression was higher in ALL phenotypes versus all other phenotypes including AML, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML). A T cell profile was distinguished by high TRIB2 expression in normal and malignant haematopoiesis. High TRIB2 expression was seen in T‐ALL with normal karyotype and correlated with NOTCH signalling pathways. High TRIB2 expression correlated with NOTCH1/FBXW7 mutations in a paediatric T‐ALL cohort, strongly linking NOTCH1 activation and high TRIB2 expression in paediatric T‐ALL. The relationship between TRIB2 and T cell signalling pathways uniquely identifies leukaemia subtypes and will be useful in the advancement of our understanding of T cell and ALL biology.
Plant natural compounds: targeting pathways of autophagy as anti‐cancer therapeutic agents
Authors: Zhang X. , Chen L.‐X. , Ouyang L. , Cheng Y. , Liu B.
Published: July 2012

Natural compounds derived from plant sources are well characterized as possessing a wide variety of remarkable anti‐tumour properties, for example modulating programmed cell death, primarily referring to apoptosis, and autophagy. Distinct from apoptosis, autophagy (an evolutionarily conserved, multi‐step lysosomal degradation process in which a cell destroys long‐lived proteins and damaged organelles) may play crucial regulatory roles in many pathological processes, most notably in cancer. In this review, we focus on highlighting several representative plant natural compounds such as curcumin, resveratrol, paclitaxel, oridonin, quercetin and plant lectin – that may lead to cancer cell death – for regulation of some core autophagic pathways, involved in Ras‐Raf signalling, Beclin‐1 interactome, BCR‐ABL, PI3KCI/Akt/mTOR, FOXO1 signalling and p53. Taken together, these findings would provide a new perspective for exploiting more plant natural compounds as potential novel anti‐tumour drugs, by targeting the pathways of autophagy, for future cancer therapeutics.
Breeding perennial ryegrass (Lolium perenne L.) for turf usage: an assessment of genetic improvements in cultivars released in Europe, 1974–2004
Authors: Sampoux J. P. , Baudouin P. , Bayle B. , Béguier V. , Bourdon P. , Chosson J. F. , de Bruijn K. , Deneufbourg F. , Galbrun C. , Ghesquière M. , Noël D. , Tharel B. , Viguié A.
Published: July 2012

An assessment of genetic improvement in turf‐type perennial ryegrass was performed at a network of six locations. A comparison was made of the turf performances of five natural populations, five forage‐type cultivars used for turf seeding until the 1980s and 31 turf‐type cultivars released from 1974 to 2004. Populations and cultivars were also compared in two spaced‐plant experiments and in two seed‐yield trials. Trait regressions on registration year of turf‐type cultivars showed that breeding had been highly successful in improving the turf aesthetic merit (from +8·8 to +12·5% per decade according to seasons), wear tolerance (+5·4% per decade) and crown‐rust resistance (+8·9% per decade) and in lessening the turf height increase rate (−0·43 mm day−1 per decade). Turf winter greenness had been marginally improved, whereas summer greenness and seed yield had not been significantly changed. A multivariate analysis provided evidence that turf density and fineness played a major role in the visual assessment of turf aesthetic merit and that wear tolerance was closely associated with turf density. Conflicting trait associations may have precluded improvements in turf ground‐cover 3 months after sowing, turf winter greenness and turf persistency.
Perceived HIV symptom manageability: synthesis of a new use for a known concept
Authors: Fierz Katharina , Nicca Dunja , Spirig Rebecca
Published: July 2012

Aim

To report the synthesis of the concept of perceived symptom manageability.

Background

Common symptom assessment parameters fail to address concerns about the impact of symptoms on everyday life, overall functioning, or threats to individuals living with the human immunodeficiency virus. We claim that the concept of ‘perceived symptom manageability’ integrates these important dimensions of the patients' experience of their symptoms.

Data sources

Online databases, thesauri, and dictionaries were accessed in January 2012. A free search was performed scanning the PubMed, CINAHL, and PsycINFO databases for entries from 2001–2011 using ‘manageability’ in the title or abstract as a search term.

Design

Text‐based analysis.

Review methods

We followed the steps delineated by Walker and Avant for concept synthesis. Uses of the concept ‘manageability’ were identified and listed, meaningful usage clusters were generated, and a preliminary working definition was created.

Results

Social resources and individual interpretation were relevant in view of managing a difficult situation, thus positioning ‘manageability’ in a social and interpretational context that exceeded objective control. We preliminarily defined perceived symptom manageability as ‘the extent of the perceived ability to bring social and personal resources into play to successfully deal with or control symptoms, despite difficulties’.

Conclusion

We believe that our working definition represents a promising start to understand and address the manageability problems that individual patients face regarding particular symptoms and may serve as a basis to identify not only symptoms but also areas of intervention that are of most concern to individual patients.
What works: a realist evaluation case study of intermediaries in infection control practice
Authors: Williams Lynne , Burton Christopher , Rycroft‐Malone Jo
Published: July 2012

Aim

To report a study of an intermediary programme in infection control practice in one hospital in the UK.

Background

Promoting best evidence in everyday practice is a constant problem in infection control. Intermediaries can influence the transfer and use of evidence in health care, but there remains a lack of evidence and theory about the specific actions and change processes, which can be successful in improving infection control practices.

Design

An in‐depth mixed methods case study.

Methods

The study was undertaken in 2011. Participants were recruited through purposive sampling and included frontline staff, managers and nurses in intermediary roles in infection control.

Results

For frontline staff, intermediary presence triggered a modification in behaviour. Different reactions were noted from the intermediaries' high level of physical presence in clinical areas, the facilitative approaches they used to give feedback and the specific teaching strategies they employed to meet frontline staff needs. The specific intermediary actions uncovered in this study were contingent on the prevailing systems for performance management, organisational commitment and efforts in clinical areas to foster a collegiate environment.

Conclusions

The study provides theoretical threads of how intermediaries can be successful in promoting evidence use under certain contextual conditions. Further testing of the specific intermediary mechanisms uncovered in this study will contribute to understanding different approaches that work in infection control in embedding evidence in practice.
Prolactin Signalling in the Mouse Hypothalamus is Primarily Mediated by Signal Transducer and Activator of Transcription Factor 5b but not 5a
Authors: Yip S. H. , Eguchi R. , Grattan D. R. , Bunn S. J.
Published: July 2012

Prolactin acts at multiple targets throughout the body, including the mammary gland, heart, liver, muscle and brain. Upon binding to its receptors, prolactin signals through the phosphorylation and thus activation of signal transducer and activator of transcription 5 (STAT5). There are two very similar STAT5 isoforms, termed STAT5a and STAT5b, which are selectively activated by prolactin in specific tissues. Various brain regions, including the hypothalamus, are prolactin responsive, although the STAT5 isoform involved in these actions is unknown. Immunohistochemical and western blot analysis were used to determine the expression and activation of STAT5a and STAT5b throughout the hypothalamus in adult wild‐type and STAT5b‐deficient mice. Both groups were pretreated with bromocriptine to suppress endogenous prolactin levels followed by the administration of ovine prolactin (10 mg/kg) for 45 min. STAT5a and STAT5b were expressed throughout the hypothalamus of wild‐type mice. As expected, only STAT5a was detected in STAT5b‐deficient mice, although, unexpectedly, there was a marked reduction in its expression compared to wild‐type mice. When stimulated with prolactin, phosphorylated STAT5 was observed in the hypothalamus of wild‐type but not STAT5b‐deficient mice. By contrast, phosphorylated STAT5 was detected in mammary gland epithelial cells and adipocytes of STAT5b‐deficient animals. Thus, although STAT5a was still expressed in the STAT5b‐deficient mice, it was not phosphorylated in the hypothalamus in response to prolactin. These observations indicate that STAT5b but not STAT5a is the primary mediator of the action of prolactin in the hypothalamus. Despite the similarity between the two STAT5 isoforms, STAT5a was unable to compensate for the absence of STAT5b, suggesting that each isoform exhibits a unique biological activity.
Migration distance rather than migration rate explains genetic diversity in human patrilocal groups
Authors: MARKS SARAH J. , LEVY HILA , MARTINEZ‐CADENAS CONRADO , MONTINARO FRANCESCO , CAPELLI CRISTIAN
Published: July 2012

In patrilocal groups, females preferentially move to join their mate’s paternal relatives. The gender‐biased gene flow generated by this cultural practice is expected to affect genetic diversity across human populations. Greater female than male migration is predicted to result in a larger decrease in between‐group differentiation for mitochondrial DNA (mtDNA) than for the non‐recombining part of the Y chromosome (NRY). We address the question of how patrilocality affects the distribution of genetic variation in human populations controlling for confounding factors such as ethno‐linguistic heterogeneity and geographic distance which possibly explain the contradictory results observed in previous studies. By combining genetic and bio‐demographic data from Lesotho and Spain, we show that preferential female migration over short distances appears to minimize the impact of a generally higher female migration rate in patrilocal communities, suggesting patrilocality might influence genetic variation only at short ranges.
Rapid genetic assimilation of native wall lizard populations (Podarcis muralis) through extensive hybridization with introduced lineages
Authors: SCHULTE ULRICH , VEITH MICHAEL , HOCHKIRCH AXEL
Published: July 2012

The Common Wall Lizard (Podarcis muralis) has established more than 150 non‐native populations in Central Europe, stemming from eight geographically distinct evolutionary lineages. While the majority of these introduced populations are found outside the native range, some of these populations also exist at the northern range margin in southwestern Germany. To (i) infer the level of hybridization in contact zones of alien and native lineages; and (ii) compare the genetic diversity among purebred introduced, native and hybrid populations, we used a combination of maternally inherited markers (mtDNA: cytb) and Mendelian markers (microsatellites). Our results suggest a rapid genetic assimilation of native populations by strong introgression from introduced lineages. Discordant patterns of mtDNA and nDNA variation within hybrid populations may be explained by directed mate choice of females towards males of alien lineages. In contrast to previous studies, we found a nonlinear relationship between genetic diversity and admixture level. The genetic diversity of hybrid populations was substantially higher than in introduced and native populations belonging to a single lineage, but rapidly reaching a plateau of high genetic diversity at an admixture level of two. However, even introduced populations with low founder sizes and from one source population retained moderate levels of genetic diversity and no evidence for a genetic bottleneck was found. The extent of introgression and the dominance of alien haplotypes in mixed populations indicate that introductions of non‐native lineages represent a serious threat to the genetic integrity of native populations due to the rapid creation of hybrid swarms.
Prevalence of, and predictors of, bile acid malabsorption in outpatients with chronic diarrhea
Authors: Gracie D. J. , Kane J. S. , Mumtaz S. , Scarsbrook A. F. , Chowdhury F. U. , Ford A. C.
Published: July 2012

Background  Many physicians do not consider the diagnosis of bile acid malabsorption in patients with chronic diarrhea, or do not have access to testing. We examined yield of 23‐seleno‐25‐homo‐tauro‐cholic acid (SeHCAT) scanning in chronic diarrhea patients, and attempted to identify predictors of a positive test.

Methods  Consecutive patients with chronic diarrhea undergoing SeHCAT scan over a 7‐year period were identified retrospectively. Bile acid malabsorption was defined as present at a retention of <15%. Medical records were reviewed to obtain information regarding proposed risk factors. Gastrointestinal symptoms were recorded, and patients were classified as having diarrhea‐predominant irritable bowel syndrome (IBS‐D) if they reported abdominal pain or discomfort. Independent risk factors were assessed using multivariate logistic regression, and odds ratios (ORs) with 99% confidence intervals (CIs) were calculated.

Key Results  Of 373 patients, 190 (50.9%) had bile acid malabsorption. Previous cholecystectomy (OR 2.51; 99% CI 1.10–5.77), terminal ileal resection or right hemicolectomy for Crohn’s disease (OR 12.4; 99% CI 2.42–63.8), and terminal ileal resection or right hemicolectomy for other reasons (OR 7.94; 99% CI 1.02–61.6) were associated with its presence. Seventy‐seven patients had IBS‐D, and 21 (27.3%) tested positive. There were 168 patients with no risk factors for a positive SeHCAT scan, other than chronic diarrhea, and 63 (37.5%) had bile acid malabsorption.

Conclusions & Inferences  Bile acid malabsorption was present in 50% of patients undergoing SeHCAT scanning. Almost 40% of those without risk factors had evidence of bile acid malabsorption, and in those meeting criteria for IBS‐D prevalence was almost 30%.
A molecular phylogeny for the pyraloid moths (Lepidoptera: Pyraloidea) and its implications for higher‐level classification
Authors: REGIER JEROME C. , MITTER CHARLES , SOLIS M. ALMA , HAYDEN JAMES E. , LANDRY BERNARD , NUSS MATTHIAS , SIMONSEN THOMAS J. , YEN SHEN‐HORN , ZWICK ANDREAS , CUMMINGS MICHAEL P.
Published: July 2012

Pyraloidea, one of the largest superfamilies of Lepidoptera, comprise more than 15 684 described species worldwide, including important pests, biological control agents and experimental models. Understanding of pyraloid phylogeny, the basis for a predictive classification, is currently provisional. We present the most detailed molecular estimate of relationships to date across the subfamilies of Pyraloidea, and assess its concordance with previous morphology‐based hypotheses. We sequenced up to five nuclear genes, totalling 6633 bp, in each of 42 pyraloids spanning both families and 18 of the 21 subfamilies, plus up to 14 additional genes, for a total of 14 826 bp, in 21 of those pyraloids plus all 24 outgroups. Maximum likelihood analyses yield trees that, within Pyraloidea, differ little among datasets and character treatments and are strongly supported at all levels of divergence (83% of nodes with bootstrap ≥80%). Subfamily relationships within Pyralidae, all very strongly supported (>90% bootstrap), differ only slightly from a previous morphological analysis, and can be summarized as Galleriinae + Chrysauginae (Phycitinae (Pyralinae + Epipaschiinae)). The main remaining uncertainty involves Chrysauginae, of which the poorly studied Australian genera may constitute the basal elements of Galleriinae + Chrysauginae or even of Pyralidae. In Crambidae the molecular phylogeny is also strongly supported, but conflicts with most previous hypotheses. Among the newly proposed groupings are a ‘wet‐habitat clade’ comprising Acentropinae + Schoenobiinae + Midilinae, and a provisional ‘mustard oil clade’ containing Glaphyriinae, Evergestinae and Noordinae, in which the majority of described larvae feed on Brassicales. Within this clade a previous synonymy of Dichogaminae with the Glaphyriinae is supported. Evergestinae syn. n. and Noordinae syn. n. are here newly synonymized with Glaphyriinae, which appear to be paraphyletic with respect to both. Pyraustinae and Spilomelinae as sampled here are each monophyletic but form a sister group pair. Wurthiinae n. syn., comprising the single genus Niphopyralis Hampson, which lives in ant nests, are closely related to, apparently subordinate within, and here newly synonymized with, Spilomelinae syn. n.
The Arabidopsis B‐type response regulator 18 homomerizes and positively regulates cytokinin responses
Authors: Veerabagu Manikandan , Elgass Kirstin , Kirchler Tobias , Huppenberger Peter , Harter Klaus , Chaban Christina , Mira‐Rodado Virtudes
Published: July 2012

In higher plants, the two‐component system (TCS) is a signaling mechanism based on a His‐to‐Asp phosphorelay. The Arabidopsis TCS involves three different types of proteins, namely the histidine kinases (AHKs), the histidine phosphotransfer proteins (AHPs) and the response regulators (ARRs). The ARRs comprise three different families, namely A, B and C types, according to their protein structure. While some members of the B‐type family of ARRs have been studied extensively and reported to act as DNA‐binding transcriptional regulators, very limited information is available for other B‐type ARRs such as ARR18. In this study, we characterize in detail the molecular and functional properties of ARR18. ARR18 acts as a transcriptional regulator in plant cells and forms homodimers in planta as shown by FRET–FLIM studies. As demonstrated by mutational analysis, the aspartate at position 70 (D70) in the receiver domain of ARR18 acts as crucial phosphorylation site. The modification of D70 affects the response regulator’s ability to homodimerize and to activate its target genes. Furthermore, physiological investigations of Arabidopsis lines ectopically expressing ARR18 introduce ARR18 as a new member within the cytokinin‐regulated response pathway regulating root elongation.
Chinese patients with Huntington's disease initially presenting with spinocerebellar ataxia
Authors: Dong Y , Sun Y‐M , Liu Z‐J , Ni W , Shi S‐S , Wu Z‐Y
Published: July 2012

Recent studies have described Huntington's disease (HD) patients with atypical onset of ataxia. Symptoms in these patients can overlap with those of spinocerebellar ataxia (SCA). We retrospectively examined clinical data for 82 HD probands and found 7 had initially been clinically diagnosed as SCA cases. Clinical features in these patients were further investigated and the number of CAG repeats in the huntingtin (HTT) gene was determined by direct sequencing. Genetic screenings for SCAs in the 7 patients were all negative. By contrast, HTT was heterozygous in each patient. The distribution of CAG number in the 7 patients was statistically the same as that in the other 75 patients. Each of 7 HD patients had presented with atypical onset of ataxia. The mean time from onset to HTT genetic testing was 5.6 ± 5.52 years. Three of the patients developed chorea, but the others did not. Our observations confirm the clinical heterogeneity of HD in Han Chinese. Based on these findings, testing for HTT expansions should be considered for clinically diagnosed SCA patients who test negatively in genetic screening of SCA genes.
Genetic heterogeneity in Pakistani microcephaly families
Authors: Sajid Hussain M , Marriam Bakhtiar S , Farooq M , Anjum I , Janzen E , Reza Toliat M , Eiberg H , Kjaer KW , Tommerup N , Noegel AA , Nürnberg P , Baig SM , Hansen L
Published: July 2012

Autosomal recessive primary microcephaly (MCPH) is caused by mutations in at least eight different genes involved either in cell division or DNA repair. Most mutations are identified in consanguine families from Pakistan, Iran and India. To further assess their genetic heterogeneity and mutational spectra, we have analyzed 57 consanguine Pakistani MCPH families. In 34 MCPH families, we detected linkage to five out of the eight well‐characterized disease loci and identified mutations in 27 families, leaving seven families without mutations in the coding exons of the presumably underlying MCPH genes. In the MCPH cohort 23 families could not be linked to any of the known loci, pointing to remarkable locus heterogeneity. The majority of mutations were found in ASPM followed by WDR62, CENPJ, CEP152 and MCPH1. One ASPM mutation (p.Trp1326*) was found in as many as eight families suggesting a Pakistani founder mutation. One third of the families were linked to ASPM followed by WDR62 confirming previous data. We identified three novel ASPM mutations, four novel WDR62 mutations, one novel MCPH1 mutation and two novel CEP152 mutations. CEP152 mutations have not been described before in the Pakistani population.
Effective control of Epstein–Barr virus infection following pediatric liver transplantation by monitoring of viral DNA load and lymphocyte surface markers
Authors: Imadome Ken‐Ichi , Fukuda Akinari , Kawano Fuyuko , Imai Yumi , Ichikawa Sayumi , Mochizuki Masashi , Shigeta Takanobu , Kakiuchi Toshihiko , Sakamoto Seisuke , Kasahara Mureo , Fujiwara Shigeyoshi
Published: July 2012

Imadome K‐I, Fukuda A, Kawano F, Imai Y, Ichikawa S, Mochizuki M, Shigeta T, Kakiuchi T, Sakamoto S, Kasahara M, Fujiwara S. Effective control of Epstein–Barr virus infection following pediatric liver transplantation by monitoring of viral DNA load and lymphocyte surface markers.

Abstract:  EBV‐associated PTLD is a serious complication of liver transplantation. We performed periodical molecular EBV monitoring in 140 consecutive pediatric patients who had living‐related liver transplantation in the National Center for Child Health and Development, Tokyo. Sixty‐three of the 140 patients showed elevation of EBV DNA level to >102 copies/μg DNA and were further examined immunologically by flow cytometry, and the dose of tacrolimus and/or cyclosporine A was adjusted according to the results. The decrease in CD4/CD8 ratio and the increase in the number of HLA‐DR+CD8+ cells were observed in parallel with the decrease in EBV DNA load and in the number of CD19+CD23+ cells following the reduction in immunosuppressive drugs. Analysis with HLA tetramers in a patient demonstrated a dramatic increase in the number of CD8+ T cells specific to the EBV latent protein LMP2 accompanying the decline of EBV DNA load, suggesting that T cells of this specificity were actually involved in the control of EBV infection. No clinically apparent PTLD has developed in the 140 recipients, suggesting that our program of EBV control by molecular EBV monitoring coupled with lymphocyte phenotype analyses is effective in controlling EBV infection in pediatric liver transplant recipients.
Complex patterns of local adaptation in heat tolerance  in Drosophila simulans from eastern Australia
Authors: van Heerwaarden B. , Lee R. F. H. , Wegener B. , Weeks A. R. , Sgró C. M.
Published: July 2012

Latitudinal clines are considered a powerful means of investigating evolutionary responses to climatic selection in nature. However, most clinal studies of climatic adaptation in Drosophila have involved species that contain cosmopolitan inversion polymorphisms that show clinal patterns themselves, making it difficult to determine whether the traits or inversions are under selection. Further, although climatic selection is unlikely to act on only one life stage in metamorphic organisms, a few studies have examined clinal patterns across life stages. Finally, clinal patterns of heat tolerance may also depend on the assay used. To unravel these potentially confounding effects on clinal patterns of thermal tolerance, we examined adult and larval heat tolerance traits in populations of Drosophila simulans from eastern Australia using static and dynamic (ramping 0.06 °C min−1) assays. We also used microsatellites markers to clarify whether demographic factors or selection are responsible for population differentiation along clines. Significant cubic clinal patterns were observed for adult static basal, hardened and dynamic heat knockdown time and static basal heat survival in larvae. In contrast, static, hardened larval heat survival increased linearly with latitude whereas no clinal association was found for larval ramping survival. Significant associations between adult and larval traits and climatic variables, and low population differentiation at microsatellite loci, suggest a role for climatic selection, rather than demographic processes, in generating these clinal patterns. Our results suggest that adaptation to thermal stress may be species and life‐stage specific, complicating our efforts to understand the evolutionary responses to selection for increasing thermotolerance.
The Role of Climatic Factors in the Expression of an Intrasexual Signal in the Paper Wasp Polistes dominulus
Authors: Green Jonathan P. , Rose Charles , Field Jeremy
Published: July 2012

Within a species, variation in the use of sexual signals is observed between different populations. For intersexual traits, differences in the environmental conditions experienced by populations can play an important role in driving variation in male ornaments and female preferences. However, little is known about the factors maintaining variation in intrasexual traits used in competition. In this study, we investigate the role of climatic conditions in maintaining variation in the expression of an intrasexual signal in the paper wasp Polistes dominulus. The results of an experiment in which pupae were housed under different temperature and humidity conditions revealed a strong effect of temperature during pupal development on the expression of the signal. Furthermore, a comparison of survival and body weight between wasps reared at different temperatures indicates that signal expression exhibits phenotypic plasticity in response to developmental temperature. The effect of temperature on signal expression is consistent with patterns of signal expression observed across populations in the wild and suggests that climatic conditions may act to constrain signal expression in some populations but not in others, driving variation in signal use within P. dominulus. Environmental conditions may therefore be important in defining the scope for intrasexual signalling in animal populations and, in doing so, may play a role in maintaining variation in intrasexual traits in the face of sexual selection.
Do Brooding Pythons Recognize their Clutches? Investigating External Cues for Offspring Recognition in the Children's Python, Antaresia childreni
Authors: Brashears Jake , DeNardo Dale F.
Published: July 2012

Parental care provides substantial benefits to offspring but exacts a high cost to parents, necessitating the evolution of offspring recognition systems when the risk of misdirected care is high. In species that nest, parents can use cues associated with the offspring (direct offspring recognition) or the nest (indirect offspring recognition) to reduce the risk of misdirected care. Pythons have complex parental care, but a low risk of misdirected care. Thus, we hypothesized that female Children's pythons (Antaresia childreni) use indirect cues to induce and maintain brooding behavior. To test this, we used a series of five clutch manipulations to test the importance of various external brooding cues. Contrary to our hypothesis, we found that female A. childreni are heavily internally motivated to brood, needing only minimal external cues to induce and maintain egg‐brooding behavior. Females were no more likely to brood their own clutch in the original nest as they were to brood a clutch from a conspecific, a pseudoclutch made from only the shells of a conspecific, or their clutch in a novel nest. The only scenario where brooding was reduced, but even then not eliminated, was when the natural clutch was replaced with similarly sized stones. These results suggest that egg recognition in pythons is similar to that of solitary‐nesting birds, which have similar nesting dynamics.
Persistence of the entomoparasitic nematode Heterorhabditis bacteriophora in maize fields
Authors: Pilz C. , Toepfer S. , Knuth P. , Strimitzer T. , Heimbach U. , Grabenweger G.
Published: July 2012

The entomoparasitic nematode (EPN) Heterorhabditis bacteriophora (Rhabditida: Heterorhabditidae) is a promising candidate for the biological control of larvae of the maize pest Western Corn Rootworm, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae). An easily applicable and economically feasible method is the inundative release of EPNs together with sowing of maize in spring. At that time, however, D. v. virgifera eggs are still diapausing and larval hatch will only start about four to 6 weeks after EPN application, depending on climatic conditions. Efficacy of the nematode application against the targeted pest species therefore depends on the ability of the biocontrol agent to persist in the pest's environment, at least until emergence of the first larvae. To address this key issue, 18 field trials were carried out at six locations in Germany, Austria and Hungary between 2010 and 2011. Fields differed in their soil type and in the presence or absence of a host. Nematodes were either applied as fluid stream (suspended in water) or as microgranules (without water) into the soil during the sowing process. Persistence of the nematodes was determined by examining soil samples, using larvae of Tenebrio molitor (Coleoptera: Tenebrionidae) as a bait. Results showed that EPNs, either applied as a suspension or as microgranules, were able to persist in the soil of all field sites. EPNs could be detected for at least 6 weeks in the soil. Persistence levels were higher in sandy soil types than in clay or silty soils. The applied EPN formulation had no effect on the persistence level of EPNs in the soil, and the presence or absence of the host insects had a minor effect. It can be concluded that EPNs applied with sowing of maize persist long enough to potentially control the later hatching larvae of the maize pest D. v. virgifera.
A PCR‐based method for discriminating between high molecular weight glutenin subunits Bx7 and Bx7* in Triticum aestivum L.
Authors: Espí Araceli , Giraldo Patricia , Rodriguez‐Quijano Marta , Carrillo José M.
Published: July 2012

With 1 figure and 1 table

The correct assignment of high molecular weight glutenin subunit variants is a key task in wheat breeding for quality. However, traditional analysis by protein electrophoresis is sometimes difficult and not very precise. This work describes a novel DNA marker for accurate discrimination between the Glu‐B1 locus subunits Bx7 and Bx7*. An analysis of 142 bread wheat varieties from different countries identified a considerable number of misclassified genotypes that could lead to incorrect conclusions in studies of the relationship between glutenin composition and wheat quality.
Fatigue during intermittent‐sprint exercise
Authors: Bishop David J
Published: July 2012

There is a reversible decline in force production by muscles when they are contracting at or near their maximum capacity. The task‐dependent nature of fatigue means that the mechanisms of fatigue may differ between different types of contractions. This paper examines how fatigue manifests during whole‐body, intermittent‐sprint exercise and discusses the potential muscular and neural mechanisms that underpin this fatigue.

Fatigue is defined as a reversible, exercise‐induced reduction in maximal power output (e.g. during cycling exercise) or speed (e.g. during running exercise), even though the task can be continued.

The small changes in surface electromyogram (EMG), along with a lack of change in voluntary muscle activation (estimated from both percutaneous motor nerve stimulations and trans‐cranial magnetic stimulation), indicate that there is little change in neural drive to the muscles following intermittent‐sprint exercise. This, along with the observation that the decrease in EMG is much less than that which would be predicted from the decrease in power output, suggests that peripheral mechanisms are the predominant cause of fatigue during intermittent‐sprint exercise.

At the muscle level, limitations in energy supply, including phosphocreatine hydrolysis and the degree of reliance on anaerobic glycolysis and oxidative metabolism, and the intramuscular accumulation of metabolic by‐products, such as hydrogen ions, emerge as key factors responsible for fatigue.
Hf–Nd isotope constraints on the origin of Dehshir Ophiolite, Central Iran
Authors: MOGHADAM HADI SHAFAII , STERN ROBERT J. , KIMURA JUN‐ICHI , HIRAHARA YUKA , SENDA RYOKO , MIYAZAKI TAKASHI
Published: July 2012

The peri‐Arabian ophiolite belt, from Cyprus in the west, eastward through Northwest Syria, Southeast Turkey, Northeast Iraq, Southwest Iran, and into Oman, marks a 3000 km‐long convergent margin that formed during a Late Cretaceous (ca 100 Ma) episode of subduction initiation on the north side of Neotethys. The Zagros ophiolites of Iran are part of this belt and are divided into Outer (OB) and Inner (IB) Ophiolitic Belts. We here report the first Nd–Hf isotopic study of this ophiolite belt, focusing on the Dehshir ophiolite (a part of IB). Our results confirm the Indian mid‐oceanic ridge basalt (MORB) mantle domain origin for the Dehshir mafic and felsic igneous rocks. All lavas have similar Hf isotopic compositions, but felsic dikes have significantly less‐radiogenic Nd isotopic compositions compared to mafic lavas. Elevated Th/Nb and Th/Yb in felsic samples accompany nonradiogenic Nd, suggesting the involvement of sediments or continental crust.
Uterus‐relaxing effect of β2‐agonists in combination with phosphodiesterase inhibitors: Studies on pregnant rat in vivo and on pregnant human myometrium in vitro
Authors: Verli Judit , Klukovits Anna , Kormányos Zsolt , Hajagos‐Tóth Judit , Ducza Eszter , Seres Adrienn B. , Falkay George , Gáspár Róbert
Published: July 2012

Aims:  Our aims were to examine the effects of a simultaneous stimulation of β2‐adrenergic receptors and inhibition of uterine phosphodiesterases (PDE), in the pregnant rat uterus in vivo and on human uterine tissue in vitro. We also set out to measure cAMP levels and detect the expressions of the isoenzymes PDE4B and PDE4D in human uterine tissue samples.

Material and Methods:  Preterm birth was induced in Sprague‐Dawley rats with bacterial lipopolysaccharide. The uterine effects of terbutaline alone or in combination with rolipram were tested in vivo. Human myometrial strips from cesarean sections at full‐term pregnancy and at preterm labor were stimulated with oxytocin, and the inhibitory effects of theophylline, rolipram and terbutaline were studied. The myometrial accumulation of cAMP in the presence of rolipram and terbutaline was determined by enzyme immunoassay. The expressions of PDE4B and PDE4D proteins were detected by Western blotting.

Results:  The selective PDE4 inhibitor rolipram was more effective than the non‐selective PDE inhibitor theophylline in inhibiting the oxytocin‐induced contractions in the human uterus. The uterus‐relaxing effects of low doses of terbutaline were markedly potentiated by rolipram, both in rats and in human tissues. The changes in uterine cAMP levels correlated with these results. At preterm labor, PDE4B was the predominant form of PDE4 expressed; at full term, PDE4D was expressed more strongly.

Conclusions:  A combination of selective PDE4 inhibitors and β2‐agonists should be considered for the treatment of preterm contractions.
Intra‐leiomyoma massive hemorrhage after delivery
Authors: Manopunya Manatsawee , Tongprasert Fuanglada , Sukpan Kornkanok , Tongsong Theera
Published: July 2012

Massive bleeding into a uterine leiomyoma is an extremely rare cause of hypovolemic shock. Only one case of this life‐threatening condition has been reported. Our patient was a 39‐year‐old woman who had a gradual growth of a subserous myoma throughout pregnancy and sudden rapid growth after cesarean section at 35 weeks of gestation. The rapid growth was due to intra‐tumor massive bleeding and was associated with hypovolemic shock without evidence of external or intra‐abdominal hemorrhage. We hypothesize that a rapid decrease in size of the uterus after delivery might have compressed the venous drainages, which were more vulnerable to occlusion than arterial blood flows, resulting in blood sequestration into the tumor leading to hypovolemia.