bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Summary1. 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.
Opportunistic hibernation by a free‐ranging marsupial
Authors: Turner J. M. , Warnecke L. , Körtner G. , Geiser F. 
Published: December 2011

AbstractKnowledge 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

AbstractThe 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

AbstractMutator 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

Abstract 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

AbstractAimTo examine changes in levels of gingival crevicular fluid (GCF) cytokines, after periodontal therapy of generalized aggressive periodontitis (GAgP).Materials and MethodsTwenty‐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.ResultsSignificant 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.ConclusionsPeriodontal 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

Abstractβ‐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.
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.xEnhancing the quality of life in elderly women through a programme to improve the condition of salivary hypofunctionObjective:  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

ABSTRACTBackground: 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