bluuebunny/crossref_metadata_2025 huggingface dataset:
A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABAA receptor modulator – an in vitro and in vivo comparison
Authors: Zhou Diansong , Sunzel Maria , Ribadeneira Maria D. , Smith Mark A. , Desai Dhaval , Lin Jianrong , Grimm Scott W.
Published: November 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• AZD7325 is an orally administered, potent, selective gamma‐amino‐butyric acid (GABAA) α2,3 receptor modulator intended for the treatment of anxiety.

• The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied.

WHAT THIS STUDY ADDS

• The in vitro studies showed that AZD7325 was a moderate CYP1A2 inducer and potent CYP3A4 inducer.

• The follow‐up clinical studies in healthy volunteers demonstrated that the expected efficacious daily dose of AZD7325 only weakly induced the pharmacokinetics of the CYP3A4 sensitive substrate, midazolam, and had no effect on the pharmacokinetics of the CYP1A2 substrate, caffeine. There was no apparent change in AZD7325 exposure following co‐administration of midazolam or caffeine compared with AZD7325 alone.

• The study demonstrated that clinical exposure of the inducer plays a critical role in the determination of cytochrome P450 induction risk of a drug candidate.

AIM(S) To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities.

METHODS Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects.

RESULTS The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 µm of AZD7325, in the range of 17.9%–54.9% and 76.9%–85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma Cmax of 0.2 µm after 10 mg daily dosing to steady‐state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81‐fold, 90% CI 0.77, 0.87), but had no effect on midazolam Cmax (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h−1 (midazolam alone) to 76 l h−1 when co‐administered with AZD7325. The AUC and Cmax of caffeine were not changed after co‐administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively.

CONCLUSIONS While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.
Impact of geographical isolation on genetic differentiation in insular and mainland populations of Weigela coraeensis (Caprifoliaceae) on Honshu and the Izu Islands
Authors: Yamada Takayuki , Maki Masayuki
Published: November 2011

Aim  To provide insights into genetic differentiation between insular endemic Weigela coraeensis var. fragrans and its progenitor variety W. coraeensis var. coraeensis, the population genetic structure of both varieties was examined, and factors promoting genetic differentiation between the two taxa were explored.

Location  The natural range of W. coraeensis (sensu lato) throughout mainland Japan (Honshu) and the Izu Islands.

Methods  The analysis included 349 and 504 individuals across the mainland (Honshu) and the Izu Islands, respectively, using 10 allozyme and 10 microsatellite loci. The population genetic structure of W. coraeensis was assessed by analysing genetic diversity indices for each population, genetic differentiation among populations, model‐based Bayesian clustering or distance‐based clustering, and bottleneck tests.

Results  The level of genetic diversity in each of the populations on the Izu Islands was negatively correlated with geographical distance between each island and the mainland. The populations on the mainland and on the Izu Islands were genetically differentiated to a certain extent; however, the microsatellite analyses suggested that gene flow also occurred between the mainland and the islands, and among individual islands. These microsatellite analyses also suggested recent bottlenecks in several populations in both areas.

Main conclusions  The decrease in genetic diversity throughout the Izu Islands, which correlated with distance to the mainland, Honshu, may be the result of a repeated founder effect occurring at a series of inter‐island colonizations from north to south. The stepping stone‐like configuration of the islands may have played a role in the dispersal of the species. Geographical isolation by sea would effectively result in genetic differentiation of W. coraeensis between mainland Honshu and the Izu Islands, although some gene flow may still occur between Honshu and the northern Izu Islands. The differentiation process of the endemic plants on the Izu Islands is anagenetic but not completed, and the study of these plants will provide insightful knowledge concerning the evolution of insular endemics.
The evolution of cardenolide‐resistant forms of Na+,K+‐ATPase in Danainae butterflies
Authors: AARDEMA MATTHEW L. , ZHEN YING , ANDOLFATTO PETER
Published: December 2011

Cardenolides are a class of plant secondary compounds that inhibit the proper functioning of the Na+, K+‐ATPase enzyme in susceptible animals. Nonetheless, many insect species are able to sequester cardenolides for their own defence. These include butterflies in the subfamily Danainae (Family: Nymphalidae) such as the monarch (Danaus plexippus). Previous studies demonstrated that monarchs harbour an asparagine (N) to histidine (H) substitution (N122H) in the α subunit of Na+, K+‐ATPase (ATPα) that reduces this enzyme’s sensitivity to cardenolides. More recently, it has been suggested that at ATPα position 111, monarchs may also harbour a leucine (L)/glutamine (Q) polymorphism. This later amino acid could also contribute to cardenolide insensitivity. However, here we find that incorrect annotation of the initially reported DNA sequence for ATPα has led to several erroneous conclusions. Using a population genetic and phylogenetic analysis of monarchs and their close relatives, we show that an ancient Q111L substitution occurred prior to the radiation of all Danainae, followed by a second substitution at the same site to valine (V), which arose before the diversification of the Danaus genus. In contrast, N122H appears to be a recent substitution specific to monarchs. Surprisingly, examination of a broader insect phylogeny reveals that the same progression of amino acid substitutions (Q111L → L111V + N122H) has also occurred in Chyrsochus beetles (Family: Chrysomelidae, Subfamily: Eumolpinae) that feed on cardenolide‐containing host plants. The parallel pattern of amino acid substitution in these two distantly related lineages is consistent with an adaptive role for these substitutions in reducing cardenolide sensitivity and suggests that their temporal order may be limited by epistatic interactions.
Multi locus analysis of Pristionchus pacificus on La Réunion Island reveals an evolutionary history shaped by multiple introductions, constrained dispersal events and rare out‐crossing
Authors: MORGAN KATY , McGAUGHRAN ANGELA , VILLATE LAURE , HERRMANN MATTHIAS , WITTE HANH , BARTELMES GABI , ROCHAT JACQUES , SOMMER RALF J.
Published: December 2011

Pristionchus pacificus, recently established as a model organism in evolutionary biology, is a cosmopolitan nematode that has a necromenic association with scarab beetles. The diverse array of host beetle species and habitat types occupied by P. pacificus make it a good model for investigating local adaptation to novel environments. Presence of P. pacificus on La Réunion Island, a young volcanic island with a dynamic geological history and a wide variety of ecozones, facilitates such investigation in an island biogeographic setting. Microsatellite data from 20 markers and 223 strains and mitochondrial sequence data from 272 strains reveal rich genetic diversity among La Réunion P. pacificus isolates, shaped by differentially timed introductions from diverse sources and in association with different beetle species. Distinctions between volcanic zones and between arid western and wet eastern climatic zones have likely limited westward dispersal of recently colonized lineages and maintained a genetic distinction between eastern and western clades. The highly selfing lifestyle of P. pacificus contributes to the strong fine‐scale population structure detected, with each beetle host harbouring strongly differentiated assemblages of strains. Periodic out‐crossing generates admixture between genetically diverse lineages, creating a diverse array of allelic combinations likely to increase the evolutionary potential of the species and facilitate adaptation to local environments and beetle hosts.
Mast cells trigger epithelial barrier dysfunction, bacterial translocation and postoperative ileus in a mouse model
Authors: Snoek S. A. , Dhawan S. , van Bree S. H. , Cailotto C. , van Diest S. A. , Duarte J. M. , Stanisor O. I. , Hilbers F. W. , Nijhuis L. , Koeman A. , van den Wijngaard R. M. , Zuurbier C. J. , Boeckxstaens G. E. , de Jonge W. J.
Published: November 2011

Background  Abdominal surgery involving bowel manipulation commonly results in inflammation of the bowel wall, which leads to impaired intestinal motility and postoperative ileus (POI). Mast cells have shown to play a key role in the pathogenesis of POI in mouse models and human studies. We studied whether mast cells contribute to the pathogenesis of POI by eliciting intestinal barrier dysfunction.

Methods  C57BL/6 mice, and two mast cell‐deficient mutant mice KitW/W‐v, and KitW‐sh/W‐sh underwent laparotomy (L) or manipulation of the small bowel (IM). Postoperative inflammatory infiltrates and cytokine production were assessed. Epithelial barrier function was determined in Ussing chambers, by measuring transport of luminal particles to the vena mesenterica, and by assessing bacterial translocation.

Key Results  In WT mice, IM resulted in pro‐inflammatory cytokine and chemokine production, and neutrophil extravasation to the manipulated bowel wall. This response to IM was reduced in mast cell‐deficient mice. IM caused epithelial barrier dysfunction in WT mice, but not in the two mast cell‐deficient strains. IM resulted in a decrease in mean arterial pressure in both WT and mast cell‐deficient mice, indicating that impaired barrier function was not explained by tissue hypoperfusion, but involved mast cell mediators.

Conclusions & Inferences  Mast cell activation during abdominal surgery causes epithelial barrier dysfunction and inflammation of the muscularis externa of the bowel. The impairment of the epithelial barrier likely contributes to the pathogenesis of POI. Our data further underscore that mast cells are bona fide cellular targets to ameliorate POI.
Sedimentological and ichnological signatures of changes in wave, river and tidal influence along a Neogene tropical deltaic shoreline
Authors: BUATOIS LUIS A. , SANTIAGO NUBIA , HERRERA MEYLIN , PLINK‐BJÖRKLUND PIRET , STEEL RON , ESPIN MARÍA , PARRA KAOLU
Published: December 2011

Analysis of Neogene cores from the Eastern Venezuela Basin along 65 km of a west–east trending shoreline allows characterization of the sedimentological and ichnological signatures of wave, river and tidal processes. The area displays deltas prograding northward from the Guyana Shield. Twenty‐three facies are defined and grouped into four categories (wave‐influenced, river‐influenced, tide‐influenced and basinal). Wave‐dominated deltaic deposits occur mostly in the Tácata Field. The delta plain was characterized by tide‐influenced distributary channels separated by interdistributary bays. Fluvial discharge in the delta front and prodelta was repeatedly interrupted by storm‐wave reworking and suspended sediment fallout. Delta‐front and prodelta deposits contain some ichnotaxa that typically do not occur in brackish water (for example, Chondrites and Phycosiphon). Amalgamated storm deposits are unburrowed or contain vertical Ophiomorpha. Lateral (especially on the updrift side) to the river mouths, waves caused nearly continuous accretion of the associated strandplains. These deposits are the most intensely bioturbated, and are dominated by the estenohaline echinoid‐generated ichnogenus Scolicia. River‐dominated deltaic deposits are present in the Santa Bárbara, Mulata, Carito and El Furrial Fields. Low‐sinuosity rivers characterized the alluvial plain, whereas the subaerial delta plain was occupied by higher‐sinuosity rivers. The subaqueous delta plain includes distributary channels and tide‐influenced interdistributary bays. Further seaward, successions are characterized by terminal distributary‐channel and distributary mouth‐bar deposits, as well as by delta‐front and prodelta deposits showing evidence of sediment gravity‐flow and fluid‐mud emplacement. Delta‐front and prodelta deposits are unbioturbated to sparsely bioturbated, suggesting extreme stress, mostly as a result of high fluvial discharge and generation of sediment gravity flows. Tidal influence is restricted to interdistributary bays, lagoons and some distributary channels. From an ichnological perspective, and in order of decreasing stress levels, four main depositional settings are identified: river‐dominated deltas, tide‐influenced delta plains, wave‐dominated deltas and wave‐dominated strandplain–offshore complexes.
Decrease in interleukin‐21 in children suffering with severe atopic dermatitis
Authors: Lin Sheng‐Chieh , Chuang Ya‐Hui , Yang Yao‐Hsu , Chiang Bor‐Luen
Published: November 2011

To cite this article: Lin S‐C, Chuang Y‐H, Yang Y‐H, Chiang B‐L. Decrease in interleukin‐21 in children suffering with severe atopic dermatitis. Pediatr Allergy Immunol 2011: 22: 869–875.

Background:  Atopic dermatitis (AD) is a kind of eczema with an inflammatory, relapsing, non‐contagious, and pruritic skin disorder. It is associated with the local infiltration of T helper type 2 (Th2) cells that secrete interleukin (IL)‐4 and IL‐5. IL‐21 is a member of IL‐2 family cytokine mainly expressed by activated CD4+ T lymphocytes. Until now, there is no clinical research in the expression of IL‐21 in patients with AD.

Methods:  We analyzed serum levels of total immunoglobulin E (IgE), allergen‐specific IgE, and cytokines IL‐4, IL‐5, IFN‐γ, IL‐17, and IL‐21 in AD cases and controls. In addition, cytokine levels in the culture supernatants of peripheral blood mononuclear cells stimulated with anti‐CD3 and anti‐CD28 Abs, phytohemagglutin (PHA), or pokeweed mitogen (PWM) were measured. We also assessed clinical skin severity by Scoring of Atopic Dermatitis (SCORAD) index.

Results:  Our results showed that serum total IgE in the case group was significantly higher than that of control group (365.449 ± 52.945 and 39.243 ± 7.605 IU/ml, respectively). Logistic regression analysis system reveals serum levels of IL‐21 and IFN‐γ are significantly correlated. However, IL‐21 and IL‐4, IL‐21 and IL‐5, as well as IL‐21 and IL‐17 showed no correlation.

Conclusion:  A significantly decreased level of IL‐21 was observed in children suffering with severe AD compared with controls, suggesting that IL‐21 may play a role in AD.
Allospecific CD154 + T‐cytotoxic memory cells as potential surrogate for rejection risk in pediatric intestine transplantation
Authors: Sindhi Rakesh , Ashokkumar Chethan , Higgs Brandon W. , Gilbert P. B. , Sun Qing , Ranganathan Sarangarajan , Jaffe Ron , Snyder Sara , Ningappa Mylarappa , Soltys Kyle A. , Bond Geoffrey J. , Mazariegos George V. , Abu‐Elmagd Kareem , Zeevi Adriana
Published: November 2011

Sindhi R, Ashokkumar C, Higgs BW, Gilbert PB, Sun Q, Ranganathan S, Jaffe R, Snyder S, Ningappa M, Soltys KA, Bond GJ, Mazariegos GV, Abu‐Elmagd K, Zeevi A. Allospecific CD154 + T‐cytotoxic memory cells as potential surrogate for rejection risk in pediatric intestine transplantation.  Pediatr Transplantation 2012: 16: 83–91. © 2011 John Wiley & Sons A/S.

Abstract:  Clinical end‐points dictate large trial enrollments and exclude children with the rare intestine transplant procedure (ITx), who experience higher drug‐related morbidity. We evaluate the novel rejection‐risk parameter, allo‐(antigen)‐specific CD154 + TcMs (i) as surrogates for ACR using Prentice’s criteria, (ii) for association with immunosuppression targets to determine Fleming’s surrogate end‐point designation, and (iii) as time‐to‐event end‐point in a simulated comparison of alemtuzumab (NCT#01208337, n = 14) and rabbit anti‐human thymocyte globulin (rATG, n = 16) among 30 children with ITx. CD154 + TcM were measured in MLR before, and at 1–60 and 61–200 days after ITx (NCT#01163578). CD154 + TcM correlate significantly with rejection severity (Spearman r = 0.685, p = 2.03E−5) and associate with biopsy‐proven ITx rejection with sensitivity/specificity of 90%/84% independent of immunosuppressant. The rejection‐risk threshold of CD154 + TcM resolves rapidly in 200‐day follow‐up (46 ± 20 vs. 158 ± 59 days, p = 0.009, K–M) with alemtuzumab, which demonstrates lower 90‐day ACR incidence (50% vs. 69%, p=NS, Fisher’s exact), and is associated with accelerated prednisone minimization to ≤2.5 mg/day, compared with rATG (120 ± 28 vs. 180 ± 30 days, p = 0.027, K–M). As a surrogate end‐point, time‐to‐rejection‐risk resolution measured with CD154 + TcM portends 50% reduction in sample sizes in a simulated trial of alemtuzumab vs. rATG. Rejection‐risk assessment with CD154 + TcM may enable informed immunosuppression minimization, and preliminary efficacy comparisons in pediatric ITx.
Comparison of candidate vCJD in vitro diagnostic assays using identical sample sets
Authors: Cooper J. K. , Ladhani K. , Minor P.
Published: December 2011

Background and Objectives  With four transfusion related transmissions of variant Creutzfeldt–Jakob Disease (vCJD), three of which developed clinical disease and the other died of other causes but was positive for markers of infection, there is an increased urgency to identify and implement a test for blood donor screening. With limited amounts of blood samples from vCJD cases available test evaluation is challenging. Alternative approaches are therefore needed. Control and vCJD tissues homogenates, where levels of markers of infectivity are known, were sequentially diluted in pooled human plasma. Identical sets of samples were provided blind to research groups developing diagnostic tests for vCJD; identical sample sets allows for direct comparisons of sensitivity to be made.

Materials and Methods  Control and vCJD tissue homogenates were sequentially diluted in pooled human plasma (detergent solvent treated or cryo‐depleted) supplied by commercial fractionators. Dilutions of vCJD tissues were within and beyond the limits of detection previously determined by the conformation‐dependent immunoassay (Cooper et al.: Vox Sang 2007;92:302–310; Bellon et al.: J Gen Virol 2003;84: 1921–1925). A number of methods were used for the analysis of the blinded panels; with background signal from the normal prion protein (PrP) being removed by digestion with proteinase, epitope protection or selective capture of PrPtse.

Results  Assay sensitivities were directly compared using identical sample sets. This approach identified several transmissible spongiform encephalopathies (TSE) diagnostic tests, based on different principles, high in analytical sensitivity that reproducibly detected markers of vCJD infectivity in tissue homogenates.

Conclusion  The approach outlined has successfully compared in vitro diagnostics assays for their sensitivity and reproducibility and is a first step toward the evaluation of an assay suitable for blood donor screening/diagnosis of vCJD.
Targeting metabolic inflammation in Parkinson’s disease: Implications for prospective therapeutic strategies
Authors: Lu Ming , Hu Gang
Published: December 2011

1. Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the aetiology of PD has not been clarified as yet, it is believed that ageing, diet, diabetes and adiposity are associated with PD.

2. Type 2 diabetes and lipid abnormalities share multiple common pathophysiological mechanisms with PD. In particular, inflammation plays a critical role in the destruction of both pancreatic islet β‐cells and dopaminergic neurons in the substantia nigra. Emerging evidence indicates that dysfunctions of energy metabolism evoke metabolic inflammation, which differs to the narrow concept of inflammation, participating in systemic pathological processes such as neurodegenerative disease and diabetes.

3. The brain is considered an immunologically privileged organ, free from immune reactions, because it is protected by the blood–brain barrier (BBB). However, studies have shown that there is gradual impairment of neurovascular function with ageing and in neurodegenerative disorders, resulting in abnormal states, including increased BBB permeability. Consequently, harmful elements that would not normally be able to cross the BBB, such as pro‐inflammatory factors, reactive oxygen species and neurotoxins, infiltrate into the brain, triggering neural injury.

4. Currently, the drugs available for the treatment of PD only ameliorate the symptoms of the disease. Therapeutic strategies aimed at stopping or modifying disease progression are still being sought. Most recent studies suggest that both central and peripheral inflammation may be dysregulated in PD. Therefore, therapeutic strategies aimed at modulating systemic inflammatory reactions or energy metabolism may represent a goal in neuroprotection in PD.
Parentification and mental health symptoms: mediator effects of perceived unfairness and differentiation of self
Authors: Jankowski Peter J. , Hooper Lisa M. , Sandage Steven J. , Hannah Natalie J.
Published: December 2011

Existing research indicates that parentification can result in positive and negative outcomes for individuals; however, little is known about the mechanisms that account for the variability. This study tested a theoretical model of the relation between parentification tasks and mental health symptoms, with perceived unfairness and differentiation of self (DoS) as mediators. The results supported the proposed model in a sample of 783 college students. A significant total indirect effect existed between the latent construct of parentification and that of mental health symptoms. Significant specific indirect effects were observed between parentification and mental health symptoms with perceived unfairness as a mediator; between parentification and DoS with perceived unfairness as a mediator and between perceived unfairness and mental health symptoms mediated by DoS. Implications for clinical work with adult clients who have experienced parentification in their family of origin are addressed.
Opportunistic hibernation by a free‐ranging marsupial
Authors: Turner J. M. , Warnecke L. , Körtner G. , Geiser F.
Published: December 2011

Knowledge about the thermal biology of heterothermic marsupials in their native habitats is scarce. We aimed to examine torpor patterns in the free‐ranging western pygmy‐possum (Cercartetus concinnus), a small marsupial found in cool temperate and semi‐arid habitat in southern Australia and known to express aseasonal hibernation in captivity. Temperature telemetry revealed that during two consecutive winters four out of seven animals in a habitat with Mediterranean climate used both short (<24 h in duration) and prolonged (>24 h) torpor bouts (duration 6.4 ± 5.4 h and 89.7 ± 45.9 h, respectively). Torpor patterns were highly flexible among individuals, but low ambient temperatures facilitated torpor. Maximum torpor bout duration was 186.0 h and the minimum body temperature measured was 4.1°C. Individuals using short bouts entered torpor before sunrise at the end of the active phase, whereas those using prolonged torpor entered in the early evening after sunset. Rewarming from torpor usually occurred shortly after midday, when daily ambient temperature increased. We present the first quantitative data on a marsupial species expressing opportunistic hibernation during winter in the wild, and show that torpor use in C. concinnus is strongly influenced by small‐scale microclimatic conditions.
Allosteric modulators can restore function in an amino acid neurotransmitter receptor by slightly altering intra‐molecular communication pathways
Authors: Nussinov Ruth
Published: November 2011

Mutations, even if not directly in the ligand binding sites of proteins, can lead to disease. In cell surface receptors, this can happen if they uncouple conformational changes that take place upon agonist (or antagonist) binding to the extracellular domain and the intracellular response. Uncoupling can take place by disrupting a major allosteric propagation pathway between the extra‐ and intracellular domains. Here I provide a mechanistic explanation: I first describe how propagation takes place; second, what can happen in the presence of a disease‐related mutation which is distant from the binding site; and finally, how drugs may overcome this disruption and rescue function. The mutations in the glycine receptor α1 subunit (α1R271Q/L) which cause the neuromotor disorder hyperekplexia are on example of such allosteric mutations. In this issue of the BJP, Shan et al. show that normal function was restored to these mutant receptors by substitution of the segment which contained the mutated position, by a homologous one. An allosteric drug could mimic the effects of such substitution. Within this framework, I highlight the advantages of allosteric drugs and the challenges in their design.

LINKED ARTICLE This article is a commentary on Shan et al., pp. 2113–2123 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01701.x
A‐kinase anchoring proteins as potential drug targets
Authors: Tröger Jessica , Moutty Marie C , Skroblin Philipp , Klussmann Enno
Published: November 2011

A‐kinase anchoring proteins (AKAPs) crucially contribute to the spatial and temporal control of cellular signalling. They directly interact with a variety of protein binding partners and cellular constituents, thereby directing pools of signalling components to defined locales. In particular, AKAPs mediate compartmentalization of cAMP signalling. Alterations in AKAP expression and their interactions are associated with or cause diseases including chronic heart failure, various cancers and disorders of the immune system such as HIV. A number of cellular dysfunctions result from mutations of specific AKAPs. The link between malfunctions of single AKAP complexes and a disease makes AKAPs and their interactions interesting targets for the development of novel drugs.

LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue‐2
Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction
Authors: Jiao Kun‐Li , Li Yi‐Gang , Zhang Peng‐Pai , Chen Ren‐Hua , Yu Yi
Published: December 2011

The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty‐nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES‐induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non‐infarct zone (NIZ) were determined by real‐time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down‐regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up‐regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES‐induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression.
Lack of microsatellite instability in squamous cell vulvar carcinoma
Authors: BUJKO MATEUSZ , KOWALEWSKA MAGDALENA , ZUB RENATA , RADZISZEWSKI JAKUB , BIDZINSKI MARIUSZ , SIEDLECKI JANUSZ A.
Published: November 2011

Mutator phenotypes with microsatellite instability (MSI) are observed in a subset of solid tumors. The objective of our study was to investigate the occurrence of MSI in vulvar squamous cell carcinoma (VSCC) and a possible relation between MSI and the presence of human papilloma virus (HPV). DNA samples from 44 tissue specimens of the primary VSCC as well as from six metastatic lymph node samples were analysed and compared with matched reference DNA from blood samples. The MSI status was examined by polymerase chain reaction (PCR) using the Bethesda panel of five microsatellite markers. PCR products were analysed by fluorescent capillary electrophoresis. No microsatellite instability was detected in tumor samples or in metastatic lymph nodes from any of the VSCC patients examined. Microsatellite instability seems not to play a major role in the carcinogenesis of VSCC and is probably not associated with the HPV‐related genetic background of this neoplasm.
Mortality in infants of obese mothers: is risk modified by mode of delivery?
Authors: NOHR ELLEN A. , VILLAMOR EDUARDO , VAETH MICHAEL , OLSEN JORN , CNATTINGIUS SVEN
Published: November 2011

Objective. To examine the association between maternal obesity and infant mortality, while including information about mode of delivery and interpregnancy weight change. Design. Register‐based cohort study. Setting and population. A total of 1 199 183 singletons, including 3481 infant deaths, from the Swedish Birth Register 1992–2006. Methods. Maternal body mass index (BMI) was obtained from self‐reports in early pregnancy and categorized as underweight (<18.5 kg/m2), normal‐weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), obese (30–34.9 kg/m2) and extremely obese (≥35 kg/m2). Cox regression was used to estimate hazard ratios (95% confidence intervals). Infants of normal‐weight women were the referent. Main outcome measures. Neonatal and infant mortality. Results. Infant mortality increased with increasing maternal fatness [adjusted hazard ratios 1.2 (1.1–1.3), 1.4 (1.2–1.6) and 2.1 (1.8–2.5) for overweight, obesity and extreme obesity, respectively]. When accounting for mode of delivery, neonatal mortality was increased in infants of obese and extremely obese mothers after spontaneous births [adjusted hazard ratios 1.8 (1.4–2.4) and 2.6 (1.8–4.0), respectively, after term births, and 1.4 (1.1–1.9) and 2.2 (1.5–3.3), respectively, after preterm births]. No excess risk was present for infants of obese mothers after induced term and preterm births (p‐values for interaction <0.05). For post‐neonatal mortality, no interaction between mode of delivery and maternal obesity was observed. In women with two subsequent pregnancies, high interpregnancy weight change >1 BMI unit (1 kg/m2) seemed to involve a modest increase in neonatal mortality in the second infant, but only after spontaneous births [adjusted odds ratio 1.3 (0.9–1.7)]. Conclusions. Maternal obesity, especially at levels that may involve cardiometabolic morbidity, was associated with increased mortality in the offspring.
Effects of periodontal therapy on GCF cytokines in generalized aggressive periodontitis subjects
Authors: de Lima Oliveira Ana Paula , de Faveri Marcelo , Gursky Lauren Christine , Mestnik Maria Josefa , Feres Magda , Haffajee Anne D. , Socransky Sigmund S. , Teles Ricardo Palmier
Published: December 2011

Aim

To examine changes in levels of gingival crevicular fluid (GCF) cytokines, after periodontal therapy of generalized aggressive periodontitis (GAgP).

Materials and Methods

Twenty‐five periodontally healthy and 24 GAgP subjects had periodontal clinical parameters measured and gingival crevicular fluid (GCF) samples collected from up to 14 sites/subject. GCF samples were analysed using multiplex bead immunoassay for: GM‐CSF, IFN‐γ, IL‐10, IL‐1β, IL‐2, IL‐6 and TNF‐α. Aggressive periodontitis subjects were randomly assigned to either scaling and root planing (SRP) alone or SRP plus systemic amoxicillin (500 mg) and metronidazole (400 mg) 3 times a day for 14 days. Clinical parameters and GCF cytokines were re‐measured 6 months after treatment. Differences over time were analysed using the Wilcoxon test and between groups using the Mann‐Whitney test.

Results

Significant reductions in GCF GM‐CSF, IL‐1β and the ratio IL‐1β/IL‐10 and increases in GCF IL‐6 were detected after therapy. The mean change in GCF cytokines did not differ significantly between groups.

Conclusions

Periodontal therapy improved GCF cytokine profiles by lowering IL‐1β and increasing IL‐10 levels. The reduction in GCF GM‐CSF after therapy implicates this cytokine in the pathogenesis of GAgP. There was no difference between therapies in changes of GCF cytokines.
Y654 of β‐catenin is essential for FLT3/ITD‐related tyrosine phosphorylation and nuclear localization of β‐catenin
Authors: Kajiguchi Tomohiro , Katsumi Akira , Tanizaki Ryohei , Kiyoi Hitoshi , Naoe Tomoki
Published: December 2011

β‐Catenin plays a dual role as a key effecter in the regulation of adherens junctions as well as a transcriptional co‐activator. Tyrosine phosphorylation of β‐catenin affects the cell adhesion, migration, and gene transcription in many types of human cancer cells, including acute myeloid leukemia cells with FLT3 internal tandem duplication (FLT3/ITD‐AML). Here, we investigated the relationship between three tyrosine residues (Y86, Y142, and Y654) in β‐catenin and oncogenic FLT3/ITD kinase. In the experiments using COS‐7 cells expressing FLT3/ITD and Wt or mutant β‐catenin, FLT3/ITD phosphorylated Y654, and this residue was essential for β‐catenin’s nuclear localization by FLT3/ITD. Promoter‐reporter assays demonstrated that Y654 phosphorylation of β‐catenin was closely related to TCF transcriptional activity. In vitro kinase assays, using recombinant FLT3 and biotinylated β‐catenin peptide including Y654 showed that FLT3 directly phosphorylated Y654 of β‐catenin. These results explain how FLT3/ITD affects the tyrosine phosphorylation, nuclear localization, and transcriptional activity of β‐catenin. Targeting Y654 phosphorylation may lead to the development of novel approaches to therapy for FLT3/ITD‐AML.
Differentiation in developmental rate across geographic regions: a photoperiod driven latitude compensating mechanism?
Authors: Śniegula Szymon , Johansson Frank , Nilsson‐Örtman Viktor
Published: December 2011

Genetic differentiation and phenotypic plasticity in growth rates along latitudinal gradients may benefit our understanding of latitudinal compensating mechanisms in life history patterns. Here we explore latitudinal compensatory growth mechanisms with respect to photoperiod in northern and southern populations of two damselfly species, Coenagrion puella and C. pulchellum. In addition we compared size of field‐collected adults from southern and northern populations. Eggs from females in copulating tandems were collected at two or three localities for each species in each geographic region. Eggs were transported to the laboratory and the experiment started when the eggs hatched. The role of photoperiod on the expression of larval growth rate was evaluated under controlled laboratory conditions. Both species had lower growth rate when reared in the northern photoperiod, which is counter to expectations if species use photoperiodic cues to trigger compensatory growth. Instead, both species displayed countergradient variation in growth rates, which probably enable northern populations to compensate for the shorter growth season in the north. The smaller size of field‐collected adults from northern populations also supports the view that these species compensate for the shorter growth season by investing in growth and development but accomplish this at the expense of decreased final size.
Enhancing the quality of life in elderly women through a programme to improve the condition of salivary hypofunction
Authors: Cho Eun‐Pyol , Hwang Soo‐Jeong , Clovis Joanne. B. , Lee Tae‐Yong , Paik Dai‐Il , Hwang Yoon‐Sook
Published: December 2011

doi: 10.1111/j.1741‐2358.2011.00594.x

Enhancing the quality of life in elderly women through a programme to improve the condition of salivary hypofunction

Objective:  The purposes of this study were to examine the effects of oral exercise intended to improve the function of the oral cavity in the elderly and their quality of life to pave the way for the development of oral‐health promotion programmes geared towards the elderly.

Methods:  The subjects were 78 female Koreans who resided in Seoul and were aged 65 years and older. During a 3‐month period, an oral function promotion programme was conducted twice a week, between 10.00 am and 12.00 pm, applying oral exercise suggested by a Japanese public health centre. A survey was conducted by interviewing the selected women to determine the state of their subjective dry mouth, quality of life related to oral health and jaw functional limitation. Their opening, unstimulated whole saliva and pronunciation speed were measured before and after the oral function exercise programme.

Results:  The subjects showed a significant improvement in subjective dry mouth symptoms, relevant behaviour, the level of discomfort caused by dry mouth and subjective jaw functional limitation during mastication and swallowing and emotional expression after receiving the oral exercise. After the oral exercise, there was a significant increase in mouth opening, unstimulated whole saliva and speaking speed (‘patakala’ pronunciation) after oral exercise. There was also significant progress in their quality of life related to oral health. Overall improvement in subjective dry mouth symptoms and relevant behaviour over time after oral exercise had a positive correlation with the level of improvement in discomfort triggered by dry mouth and mastication. The level of improvement in OHIP‐14 had a positive correlation with the level of overall improvement in dry mouth symptoms and behaviour, the level of improvement in discomfort by dry mouth and that in mastication and swallowing.

Conclusion:  This study showed the effects of the oral function promotion programme and correlation of oral condition and oral health‐related quality of life. It is suggested that this oral function promotion programme has positive effects on both objective and subjective oral conditions. It is strongly recommended that this programme, along with other oral health promotion programmes, be implemented to improve oral function and oral health‐related quality of life for the elderly.
Factors Influencing Advanced Practice Nurses’ Ability to Promote Evidence‐Based Practice among Frontline Nurses
Authors: Gerrish Kate , Nolan Mike , McDonnell Ann , Tod Angela , Kirshbaum Marilyn , Guillaume Louise
Published: December 2011

Background: Advanced practice nurses (APNs) have an important role in promoting evidence‐based practice (EBP) among frontline nurses (FLNs). Factors influencing FLNs’ engagement with EBP are well documented but little is known about factors that affect APNs’ ability to facilitate evidence in practice.

Aims: To identify factors that influence APNs’ ability to promote EBP among FLNs.

Methods: A multiple case study of 23 APNs from hospital and primary care settings across seven English health authorities was undertaken. Data collection comprised interviews and observation of APNs and interviews with FLNs and other healthcare professionals. Data were analysed using the Framework approach.

Findings: Four groups of influencing factors were identified: (1) Personal attributes of APNs included knowledge and skills in EBP, clinical credibility with frontline staff and leadership style. (2) Relationships with stakeholders included APNs’ interactions with FLNs and the level of support from managers and medical colleagues. (3) Aspects of the APN role included their sphere of responsibility and workload. (4) Organisational context included the organisational culture, FLNs’ workload, professional networks and available resources.

Implications: Educational preparation for APNs should enable them to develop expertise in EBP plus interpersonal and leadership skills to manage relational dynamics in clinical settings. APN role specifications should provide the opportunity to promote EBP. The organisational culture should be conducive to enabling EBP with managers supportive of this aspect of the APNs’ role.

Conclusions: APNs need to be supported to address the individual, interpersonal and organisational factors, which influence their ability to promote EBP. Organisational commitment at the highest level is key to APNs’ ability to fulfil this aspect of their role.
Structure and activity of exo‐1,3/1,4‐β‐glucanase from marine bacterium Pseudoalteromonas sp. BB1 showing a novel C‐terminal domain
Authors: Nakatani Yoshio , Cutfield Susan M. , Cowieson Nathan P. , Cutfield John F.
Published: December 2011

Following the discovery of an exo‐1,3/1,4‐β‐glucanase (glycoside hydrolase family 3) from a seaweed‐associated bacterium Pseudoalteromonas sp. BB1, the recombinant three‐domain protein (ExoP) was crystallized and its structure solved to 2.3 Å resolution. The first two domains of ExoP, both of which contribute to the architecture of the active site, are similar to those of the two‐domain barley homologue β‐d‐glucan exohydrolase (ExoI) with a distinctive Trp–Trp clamp at the +1 subsite, although ExoI displays broader specificity towards β‐glycosidic linkages. Notably, excision of the third domain of ExoP results in an inactive enzyme. Domain 3 has a β‐sandwich structure and was shown by CD to be more temperature stable than the native enzyme. It makes relatively few contacts to domain 1 and none at all to domain 2. Two of the domain 3 residues involved at the interface, Q683 (forming one hydrogen bond) and Q676 (forming two hydrogen bonds) were mutated to alanine. Variant Q676A retained about half the activity of native ExoP, but the Q683A variant was severely attenuated. The crystal structure of Q683A–ExoP indicated that domain 3 was highly mobile and that Q683 is critical to the stabilization of ExoP by domain 3. Small‐angle X‐ray scattering data lent support to this proposal. Domain 3 does not appear to be an obvious carbohydrate‐binding domain and is related neither in sequence nor structure to the additional domains characterized in other glycoside hydrolase 3 subgroups. Its major role appears to be for protein stability but it may also help orient substrate.

Database
 Structural data are available in the Protein Data Bank under the accession numbers 3UT0, 3USZ, 3F95 and 3RRX
Discovery of a Be/X-ray pulsar binary and associated supernova remnant in the Wing of the Small Magellanic Cloud
Authors: Hénault-Brunet V. , Oskinova L. M. , Guerrero M. A. , Sun W. , Chu Y.-H. , Evans C. J. , Gallagher J. S. , Gruendl R. A. , Reyes-Iturbide J.
Published: December 2011

We report on a new Be/X-ray pulsar binary located in the Wing of the Small Magellanic Cloud (SMC). The strong pulsed X-ray source was discovered with the Chandra and XMM—Newton X-ray observatories. The X-ray pulse period of 1062 s is consistently determined from both Chandra and XMM—Newton observations, revealing one of the slowest rotating X-ray pulsars known in the SMC. The optical counterpart of the X-ray source is the emission-line star 2dFS 3831. Its B0-0.5(III)e+ spectral type is determined from VLT-FLAMES and 2dF optical spectroscopy, establishing the system as a Be/X-ray binary (Be-XRB). The hard X-ray spectrum is well fitted by a power law with additional thermal and blackbody components, the latter reminiscent of persistent Be-XRBs. This system is the first evidence of a recent supernova in the low-density surroundings of NGC 602. We detect a shell nebula around 2dFS 3831 in Hα and [O iii] images and conclude that it is most likely a supernova remnant. If it is linked to the supernova explosion that created this new X-ray pulsar, its kinematic age of (2–4) × 104 yr provides a constraint on the age of the pulsar.
Relationship between “purulent bronchitis” in military populations in Europe prior to 1918 and the 1918–1919 influenza pandemic
Authors: Dennis Shanks G. , MacKenzie Alison , Waller Michael , Brundage John F.
Published: November 2011

Please cite this paper as: Shanks et al. Relationship between “purulent bronchitis” in military populations in Europe prior to 1918 and the 1918–1919 influenza pandemic. Influenza and Other Respiratory Viruses 6(4), 235–239.

Purulent bronchitis was a distinctive and apparently new lethal respiratory infection in British and American soldiers during the First World War. Mortality records suggest that purulent bronchitis caused localized outbreaks in the midst of a broad epidemic wave of lethal respiratory illness in 1916–1917. Probable purulent bronchitis deaths in the Australian Army showed an epidemic wave that moved from France to England. Purulent bronchitis may have been the clinical expression of infection with a novel influenza virus which also could have been a direct precursor of the 1918 pandemic strain.
In Vitro Fungicidal Photodynamic Effect of Hypericin on Candida Species†
Authors: Rezusta Antonio , López‐Chicón Patricia , Paz‐Cristobal Manuel P. , Alemany‐Ribes Mireia , Royo‐Díez David , Agut Montserrat , Semino Carlos , Nonell Santi , Revillo Mª Jose , Aspiroz Carmen , Gilaberte Yolanda
Published: December 2011

Hypericin is a natural photosensitizer considered for the new generation of photodynamic therapy (PDT) drugs. The aim of this study was to evaluate the in vitro fungicidal effect of hypericin PDT on various Candida spp., assessing its photocytotoxicity to keratinocytes (HaCaT) and dermal fibroblasts (hNDF) to determine possible side effects. A 3 log fungicidal effect was observed at 0.5 McFarland for two Candida albicans strains, Candida parapsilosis and Candida krusei with hypericin concentrations of 0.625, 1.25, 2.5 and 40 μm, respectively, at a fluence of 18 J cm−2 (LED lamp emitting at 602 ± 10 nm). To obtain a 6 log reduction, significantly higher hypericin concentrations and light doses were needed (C. albicans 5 μm, C. parapsilosis 320 μM and C. krusei 320 μM; light dose 37 J cm−2). Keratinocytes and fibroblasts can be preserved by keeping the hypericin concentration below 1 μm and the light dose below 37 J cm−2. C. albicans appears to be suitable for treatment with hypericin PDT without significant damage to cutaneous cells.