bluuebunny/crossref_metadata_2025 huggingface dataset:
Non‐Human Primate Models of Hormonal Contraception and HIV
Authors: McNicholl Janet M. , Henning Tara C. , Vishwanathan Sundaram A. , Kersh Ellen N.
Published: April 2014

Problem

Recent concerns that hormonal contraception (HC) may increase risk of HIV acquisition has led to keen interest in using non‐human primates (NHP) to understand the underlying mechanism and the magnitude of the risk. This is, in part, because some experiments which would be difficult or logistically impossible in women are more easily conducted in NHP.

Method of study

NHP models of HIV can inform HIV acquisition and pathogenesis research and identify and evaluate biomedical preventions and treatments for HIV/AIDS. Widely used species include rhesus, pigtail, and cynomolgous macaques.

Results

This paper reviews past, current and proposed NHP research around the intersection of HIV and HC.

Conclusion

NHP research may lead to the identification of hormonally regulated biomarkers that correlate with HIV‐acquisition risk, to a ranking of existing or next‐generation HC along an HIV‐acquisition risk profile, and inform research around new biomedical preventions for HIV.
Analysis of transthoracic echocardiographic data in major vascular surgery from a prospective randomised trial comparing sevoflurane and fentanyl with propofol and remifentanil anaesthesia
Authors: Lindholm E. E. , Aune E. , Frøland G. , Kirkebøen K. A. , Otterstad J. E.
Published: April 2014

The aim of this study was to define pre‐operative echocardiographic data and explore if postoperative indices of cardiac function after open abdominal aortic surgery were affected by the anaesthetic regimen. We hypothesised that volatile anaesthesia would improve indices of cardiac function compared with total intravenous anaesthesia. Transthoracic echocardiography was performed pre‐operatively in 78 patients randomly assigned to volatile anaesthesia and 76 to total intravenous anaesthesia, and compared with postoperative data. Pre‐operatively, 16 patients (10%) had left ventricular ejection fraction < 46%. In 138 patients with normal left ventricular ejection fraction, 5/8 (62%) with left ventricular dilatation and 41/130 (33%) without left ventricular dilatation had evidence of left ventricular diastolic dysfunction (p < 0.001). Compared with pre‐operative findings, significant increases in left ventricular end‐diastolic volume, left atrial maximal volume, cardiac output, velocity of early mitral flow and early myocardial relaxation occurred postoperatively (all p < 0.001). The ratio of the velocity of early mitral flow to early myocardial relaxation remained unchanged. There were no significant differences in postoperative echocardiographic findings between patients anaesthetised with volatile anaesthesia or total intravenous anaesthesia. Patients had an iatrogenic surplus of approximately 4.1 l of fluid volume by the first postoperative day. N‐terminal prohormone of brain natriuretic peptide increased on the first postoperative day (p < 0.001) and remained elevated after 30 days (p < 0.001) in both groups. Although postoperative echocardiographic alterations were most likely to be related to increased preload due to a substantial iatrogenic surplus of fluid, a component of peri‐operative myocardial ischaemia cannot be excluded. Our hypothesis that volatile anaesthesia improved indices of cardiac function compared with total intravenous anaesthesia could not be verified.
Peri‐operative warming devices: performance and clinical application
Authors: John M. , Ford J. , Harper M.
Published: April 2014

Since the adverse consequences of accidental peri‐operative hypothermia have been recognised, there has been a rapid expansion in the development of new warming equipment designed to prevent it. This is a review of peri‐operative warming devices and a critique of the evidence assessing their performance. Forced‐air warming is a common and extensively tested warming modality that outperforms passive insulation and water mattresses, and is at least as effective as resistive heating. More recently developed devices include circulating water garments, which have shown promising results due to their ability to cover large surface areas, and negative pressure devices aimed at improving subcutaneous perfusion for warming. We also discuss the challenge of fluid warming, looking particularly at how devices’ performance varies according to flow rate. Our ultimate aim is to provide a guide through the bewildering array of devices on the market so that clinicians can make informed and accurate choices for their particular hospital environment.
A comparison of the predictive performance of three pharmacokinetic models for propofol using measured values obtained during target‐controlled infusion
Authors: Glen J. B. , White M.
Published: April 2014

We compared the predictive performance of the existing Diprifusor and Schnider models, used for target‐controlled infusion of propofol, with a new modification of the Diprifusor model (White) incorporating age and sex covariates. The bias and inaccuracy (precision) of each model were determined using computer simulation to replicate the infusion profiles in an earlier study of 41 patients undergoing surgery with propofol administered by target‐controlled infusion and in which timed, measured blood propofol concentrations were available. Bias with the White model (5%) was significantly less (p < 0.0001) than with the Diprifusor (16%) or Schnider (15%) models. The White model showed a significant improvement in accuracy (inaccuracy 19%, p < 0.0001) relative to the Diprifusor (26%). Temporal changes were such that with all three models, bias differed at induction and recovery. None of the models accounted fully for the extent of inter‐individual variation in propofol clearance, but the improved performance with the White model suggests it has merit.
Why place matters: imaginative geography and international student mobility
Authors: Beech Suzanne E
Published: April 2014

This paper develops and extends the recent work on international student mobility by expanding beyond the traditional push–pull factors of migration to show that students are influenced by more than the economic in their decision of where to study. It uses original data collected through interviews and focus groups with 38 higher education international students at three UK universities located in Aberdeen, Belfast and Nottingham to show that when students choose to study overseas they are influenced by diverse perceptions of place that they have constructed over long periods of time. These imaginative geographies are the direct result of exposure to a range of different media, as well as stories relayed to them from members of their social networks. This paper demonstrates that students studying in Scotland and Northern Ireland appear to have highly developed imaginative geographies in relation to their chosen study sites. By contrast, international students studying in England tended to have little conception of their chosen place of study. In this case the powerful imaginative geographies that had been instilled within them focused on London, overshadowing their understanding of their chosen study site.
Meeting the societal need for new antibiotics: the challenges for the pharmaceutical industry
Authors: O'Brien Seamus
Published: April 2014

The rise of antibiotic resistance is leading to clinicians being increasingly faced with clinical failure due to the lack of effective and safe treatment options. New antibiotics are needed now for current multi‐drug resistant infections but also in preparation for emerging and anticipated threats. There are significant challenges for the pharmaceutical industry to discover and develop new antibiotics including a business model that balances reasonable reimbursement with appropriate use. This summary reviews the key challenges and collaborative interventions that may contribute to addressing a societal problem.
Bridging the gap: a review of dose investigations in paediatric investigation plans
Authors: Hampson Lisa V. , Herold Ralf , Posch Martin , Saperia Julia , Whitehead Anne
Published: April 2014

Aims

In the EU, development of new medicines for children should follow a prospectively agreed paediatric investigation plan (PIP). Finding the right dose for children is crucial but challenging due to the variability of pharmacokinetics across age groups and the limited sample sizes available. We examined strategies adopted in PIPs to support paediatric dosing recommendations to identify common assumptions underlying dose investigations and the attempts planned to verify them in children.

Methods

We extracted data from 73 PIP opinions recently adopted by the Paediatric Committee of the European Medicines Agency. These opinions represented 79 medicinal development programmes and comprised a total of 97 dose investigation studies. We identified the design of these dose investigation studies, recorded the analyses planned and determined the criteria used to define target doses.

Results

Most dose investigation studies are clinical trials (83 of 97) that evaluate a single dosing rule. Sample sizes used to investigate dose are highly variable across programmes, with smaller numbers used in younger children (< 2 years). Many studies (40 of 97) do not pre‐specify a target dose criterion. Of those that do, most (33 of 57 studies) guide decisions using pharmacokinetic data alone.

Conclusions

Common assumptions underlying dose investigation strategies include dose proportionality and similar exposure−response relationships in adults and children. Few development programmes pre‐specify steps to verify assumptions in children. There is scope for the use of Bayesian methods as a framework for synthesizing existing information to quantify prior uncertainty about assumptions. This process can inform the design of optimal drug development strategies.
Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data
Authors: Fiorentino Alessia , O'Brien Niamh Louise , Locke Devin Paul , McQuillin Andrew , Jarram Alexandra , Anjorin Adebayo , Kandaswamy Radhika , Curtis David , Blizard Robert Alan , Gurling Hugh Malcolm Douglas
Published: April 2014

Objectives

Genetic markers in the genes encoding ankyrin 3 (ANK3) and the α‐calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP‐associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.

Methods

In order to screen both coding and non‐coding regions to identify potential aetiological variants, we used whole‐genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls.

Results

We found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)‐defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP‐associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome‐wide association.

Conclusions

Sequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so‐called ‘missing heritability’ of BP.
Insights into the Infiltrative Behavior of Adamantinomatous Craniopharyngioma in a New Xenotransplant Mouse Model
Authors: Stache Christina , Hölsken Annett , Schlaffer Sven‐Martin , Hess Andreas , Metzler Markus , Frey Benjamin , Fahlbusch Rudolf , Flitsch Jörg , Buchfelder Michael , Buslei Rolf
Published: April 2014

Adamantinomatous craniopharyngiomas (adaCP) cause hypothalamic pituitary dysfunction. Elucidation of pathomechanisms underlying tumor progression is essential for the development of targeted chemotherapeutic treatment options. In order to study the mechanisms of tumor outgrowth, we implanted human primary adaCP tissue from three different surgical specimens stereotactically into the brain of immunodeficient mice (n = 20). Three months after tumor inoculation, magnetic resonance imaging and histology confirmed tumor engraftment in all 20 mice (100%) that obtained tissue transplants. The lesions invaded adjoining brain tissue with micro finger‐shaped protrusions. Immunohistochemical comparison of the primary tumor and xenotransplants revealed a similar amount of proliferation (Mib‐1) and cytokeratin expression pattern (KL‐1). Whole tumor reconstruction using serial sections confirmed whirl‐like cell clusters with nuclear β‐catenin accumulations at the tumor brain border. These whirls were surrounded by a belt of Claudin‐1 expressing cells, showed an activated epidermal growth factor receptor (EGFR) and distinct CD133 as well as p21WAF1/Cip1 positivity, indicating a tumor stem cell phenotype. Consistent with our previous in vitro studies, intracranial xenotransplants of adaCP confirmed cells with nuclear β‐catenin and activated EGFR being the driving force of tumor outgrowth. This model provides the possibility to study in vivo tumor cell migration and to test novel treatment regimens targeting this tumor stem cell niche.
Behavioural treatment recommendations in clinical practice guidelines for attention‐deficit/hyperactivity disorder: a scoping review
Authors: Vallerand Isabelle A. , Kalenchuk Anna L. , McLennan John D.
Published: April 2014

Background

The extent of behavioural treatment recommendations described in attention‐deficit/hyperactivity disorder (ADHD) practice guidelines has not been examined.

Method

A scoping review identified eight agency‐based ADHD practice guidelines. Key components of behavioural treatment recommendations were summarized.

Results

All guidelines mentioned behavioural treatment as a consideration for managing ADHD, however, the extent to which they were detailed varied. Most guidelines provided lists of behavioural techniques but with minimal specifics regarding treatment delivery.

Conclusions

There is far less detailing of behavioural approaches compared to pharmacological treatments for ADHD. Greater detailing of evidence‐based behavioural approaches may foster improved delivery of high‐quality behaviour treatment.
Familial isolated primary hyperparathyroidism/hyperparathyroidism‐jaw tumour syndrome caused by germline gross deletion or point mutations of CDC73 gene in Chinese
Authors: Kong Jing , Wang Ou , Nie Min , Shi Jie , Hu Yingying , Jiang Yan , Li Mei , Xia Weibo , Meng Xunwu , Xing Xiaoping
Published: April 2014

Objective

Hyperparathyroidism‐jaw tumour syndrome (HPT‐JT) and familial isolated primary hyperparathyroidism (FIHP) are two subtypes of familial primary hyperparathyroidism, which are rarely reported in Chinese population. Here, we reported three FIHP families and one HPT‐JT family with long‐term follow‐up and genetic analysis.

Design and methods

A total of 22 patients, from four FIHP/HPT‐JT families of Chinese descent, were recruited and genomic DNA was extracted from their peripheral blood lymphocytes. Direct sequencing for MEN1, CDC73, CASR gene was conducted. Reverse transcription PCR (RT–PCR) and quantitative real‐time PCR (qRT‐PCR) were used to study the effect of splice site mutations and gross deletion mutations. Immunohistochemistry was performed to analyse parafibromin expression in parathyroid tumours. Genotype–phenotype correlations were assessed through clinical characteristics and long‐term follow‐up data.

Results

Genetic analysis revealed four CDC73 germline mutations that were responsible for the four kindreds, including two novel point mutation (c.157 G>T and IVS3+1 G>A), one recurrent point mutation (c.664 C>T) and one deletion mutation (c.307+?_513‐?del exons 4, 5, 6). RT‐PCR confirmed that IVS3+1 G>A generated an aberrant transcript with exon3 deletion. Immunohistochemical analysis demonstrated reduced nuclear parafibromin expression in tumours supporting the pathogenic effects of these mutations.

Conclusions

This study supplies information on mutations and phenotypes of HPT‐JT/FIHP syndrome in Chinese. Screening for gross deletion and point mutations of the CDC73 gene is necessary in susceptible subjects.
Enclosures within Enclosures and Hurricane Reconstruction in Cancún, Mexico
Authors: AZCÁRATE MATILDE CÓRDOBA , BAPTISTA IDALINA , RUBIO FERNANDO DOMÍNGUEZ
Published: April 2014

This article focuses on the reconstruction processes undertaken in Cancún, Mexico after hurricanes Gilbert in 1988 and Wilma in 2005. The article argues that both hurricanes facilitated the creation of an evolving logic of “enclosures within enclosures,” whereby hotel and real estate investors, aided by government authorities, privatized and commoditized Cancún's public lands and resources for the exclusive use of the global tourism market. In practice, this meant a radical spatial, aesthetic, and economic reconfiguration of the Hotel Zone in Cancún from a low‐density luxury resort to a mass tourism, all‐inclusive resort destination after Gilbert, followed by the emergence of the contemporary timeshare high‐rise condominium model after Wilma. With each new business model, investors strategically used post‐hurricane reconstruction to redefine space, displace risk, and to reposition themselves and the city in global circuits of capital accumulation. The case of Cancún provides an empirically grounded example of how, in the aftermath of natural disasters, strategies of enclosure are deployed through approaches to governance, business models, and forms of architecture and surveillance all in the name of defending the public good, providing security, and enhancing economic growth.
Influence of placement depth on bone remodeling around tapered internal connection implants: a histologic study in dogs
Authors: Huang Baoxin , Meng Huanxin , Zhu Weidong , Witek Lukasz , Tovar Nick , Coelho Paulo G.
Published: April 2014

Objectives

To evaluate the influence of implant‐abutment interface (IAI) placement depth on bone remodeling around implants with two different types of tapered internal IAI: screwed‐in (SI) and tapped‐in (TI) connections in dogs.

Materials and methods

Eight weeks post mandibular tooth extraction in six beagle dogs, two SI implants (OsseoSpeed™, Astra Tech, DENTSPLY) and two TI implants (Integra‐CP™, Bicon LLC) were placed in one side of the mandible. The four experimental groups were as follows: (i) SI‐placed equicrestally (SIC); (ii) TI‐placed equicrestally (TIC); (iii) SI‐placed 1.5 mm subcrestally (SIS); and (iv) TI‐placed 1.5 mm subcrestally (TIS). Healing abutments were connected 12 weeks after implant placement. Sixteen weeks later, the dogs were sacrificed and histomorphometric analysis was performed. Histometrical outcomes were evaluated using a nonparametric Brunner–Langer model.

Results

Mean distance from the IAI to first bone‐implant contact (IAI‐fBIC) was 0.88 mm (median: 0.77; SD: 0.54) for SIC group, 1.23 mm (median: 1.22; SD: 0.66) for TIC group, 0.41 mm (median: 0.31; SD: 0.36) for SIS group, and 0.41 mm (median: 0.26; SD: 0.45) for TIS group. Subcrestal groups showed lower IAI‐fBIC compared with equicrestal groups (P < 0.001). Connective tissue presented similar measurements regardless of the IAI placement depth and IAI type (P > 0.05), but the epithelium length and peri‐implant soft tissue length in subcrestal groups were significant larger than that in the equicrestal groups (P < 0.001 and P = 0.004, respectively).

Conclusion

Subcrestal implant placement with tapered internal IAI is beneficial for bone contact with the implant neck, and concurrently, it may not increase the soft tissue inflammation around IAI.
Assessment of periodontal and opportunistic flora in patients with peri‐implantitis
Authors: Albertini Matteo , López‐Cerero Lorena , O'Sullivan Manuel G. , Chereguini Carlos F. , Ballesta Sofia , Ríos Vicente , Herrero‐Climent Mariano , Bullón Pedro
Published: April 2014

Aim

To assess the presence of periodontal and opportunistic organisms in patients with peri‐implantitis.

Material and methods

Thirty‐three partially edentulous subjects (22 women, 11 men), aged 32–90 years, who had one or more implants with peri‐implantitis were included. Peri‐implantitis was defined as: (i) the presence of bleeding on probing and/or suppuration and (ii) radiographic images showed marginal bone loss >1.8 mm after 1 year in function. Criteria for inclusion were: (i) partially edentulous patients having at least one implant diagnosed with peri‐implantitis; (ii) no antibiotic therapy for 6 months prior to clinical examination. Following this definition, a total of 48 implants were diagnosed with peri‐implantitis. Subgingival bacterial samples were obtained with sterile paper points from infected implants and selected teeth of each individual. Periodontopathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia and Treponema denticola) were detected by multiplex PCR targeting 16S rDNA. Samples were placed in reduced transport medium and cultured for opportunistic pathogens (Staphylococcus aureus, enteric bacteria, Pseudomonas and yeasts).

Results

Twenty‐two patients yielded positive results for P. gingivalis, 25 for T. forsythia, eight for P. intermedia and 13 for T. denticola. None of the patients yielded a positive result for A. actinomycetemcomitans. Non‐periodontal species were found in five patients (15% of total). P. aeruginosa was found in four (12%) patients, and C. albicans (3%) and S. aureus in one patient (3%) each. In two cases of peri‐implantitis, none of the periodontal or opportunistic microorganisms studied were detected in either implant or tooth samples. When results of the periodontopathic bacteria from the implant and tooth samples of the same patient were compared, 18 patients (54%) showed the same results for both samples and 15 (45%) patients different results.

Conclusions

The implant surface may be colonized with pathogens different from periodontal bacteria. Opportunistic pathogens such as P. aeruginosa, S. aureus and C. albicans may be associated with implant failure.
Retracted: Enhanced bone regeneration with a novel synthetic bone substitute in combination with a new natural cross‐linked collagen membrane: radiographic and histomorphometric study
Authors: Calvo‐Guirado José Luis , Ramírez‐Fernández Maria P. , Maté‐Sánchez Jose E. , Bruno Negri , Velasquez Pablo , de Aza Piedad N.
Published: April 2014

Objectives

4Bone is a fully synthetic bioactive bone substitute composed of 60% hydroxyapatite (HA) and 40% beta‐tricalcium phosphate (ß‐TCP). This study aimed to investigate the effect of resorbable collagen membranes (RCM) on critical size defects in rabbit tibiae filled with this novel biphasic calcium phosphate at 15, 30, 45, and 60 days by radiological and histomorphometric analysis.

Material and methods

Three critical size defects of 6 mm diameter were created in both tibiae of 20 New Zealand rabbits and divided into three groups according to the filling material: Group A (4Bone), Group B (4Bone plus RCM), and Group C (unfilled control group). At each of the four study periods, five rabbits were sacrificed. Anteroposterior and lateral radiographs were taken. Samples were processed for observation under light microscopy.

Results

At the end of treatment, radiological analysis found that cortical defect closure was greater in Group B than Group A, and radiopacity was clearly lower and more heterogeneous in Group A cortical defects than in Group B. There was no cortical defect closure in Group C. Histomorphometric evaluation showed significant differences in newly formed bone and cortical closure in Group B compared with Groups A and C, with the presence of higher density newly formed bone in cortical and medullar zones.

Conclusions

Biphasic calcium phosphate functioned well as a scaffolding material allowing bone ingrowth and mineralization. The addition of absorbable collagen membranes enhanced bone gain compared with non‐membrane‐treated sites. This rabbit study provides radiological and histological evidence confirming the suitability of this new material for guided tissue regeneration of critical defects.
Systematic Review of Clinical Trials Assessing Pharmacological Properties of Salvia Species on Memory, Cognitive Impairment and Alzheimer's Disease
Authors: Miroddi Marco , Navarra Michele , Quattropani Maria C. , Calapai Fabrizio , Gangemi Sebastiano , Calapai Gioacchino
Published: April 2014

Salvia officinalis L. and Salvia lavandulaefolia L. have a longstanding use as traditional herbal remedies that can enhance memory and improve cognitive functions. Pharmacological actions of S. officinalis and S. lavandulaefolia on healthy subjects and on patients suffering of cognitive decline have been investigated. Aim of this review was to summarize published clinical trials assessing effectiveness and safety of S. officinalis and S. lavandulaefolia in the enhancement of cognitive performance in healthy subjects and neurodegenerative illnesses. Furthermore, to purchase a more complete view on safety of S. officinalis and S. lavandulaefolia, we collected and discussed articles regarding toxicity and adverse reactions. Eight clinical studies investigating on acute effects of S. officinalis on healthy subjects were included in the review. Six studies investigated on the effects of S. officinalis and S. lavandaeluaefolia on cognitive performance in healthy subjects. The two remaining were carried out to study the effects of sage on Azheimer's disease. Our review shows that S. officinalis and S. lavandulaefolia exert beneficial effects by enhancing cognitive performance both in healthy subjects and patients with dementia or cognitive impairment and is safe for this indication. Unfortunately, promising beneficial effects are debased by methodological issues, use of different herbal preparations (extracts, essential oil, use of raw material), lack of details on herbal products used. We believe that sage promising effects need further higher methodological standard clinical trials.
Associations between host plant concentrations of selected biochemical nutrients and Mexican rice borer, Eoreuma loftini, infestation
Authors: Showler Allan T. , Moran Patrick J.
Published: April 2014

The Mexican rice borer, Eoreuma loftini (Dyar) (Lepidoptera: Crambidae), is an economic pest of sugarcane (Saccharum spp. hybrids) and other graminaceous host crops, and it attacks grassy weeds. Oviposition preference has been known to be for plants with leaves that form folds. This study is the first to associate the nutritional quality of crop and forage plant hosts with Mexican rice borer injury. Three experiments were conducted to determine the levels of selected biochemical nutrients, including free amino acids and sugars, in four grass weeds [barnyardgrass, Echinochloa crus‐galli (L.); broadleaf signalgrass, Urochloa platyphylla (Munro ex C. Wright); johnsongrass, Sorghum halepense (L.) Pers.; and Vasey's grass, Paspalum urvillei Steud.], a forage grass [sudangrass, Sorghum bicolor (L.) Moensch spp. drummondi (Nees ex Steud.) de Wet & Harlan], three crop species [maize, Zea mays L.; sorghum, Sorghum bicolor (L.) Moench; and sugarcane, Saccharum spp.], and a sorghum‐sudangrass forage hybrid (all Poaceae). Of 16 free amino acids detected among plants in the first two experiments, only high accumulations of free histidine in sudangrass and maize were associated with increased infestations by Mexican rice borer larvae. In all three experiments, high levels of fructose were associated with heightened Mexican rice borer infestation. Ramifications of these findings on the potential dispersal of this invasive pest in the USA and possible applications of fructose in baits are discussed.
Tonic current through GABAA receptors and hyperpolarization‐activated cyclic nucleotide‐gated channels modulate resonance properties of rat subicular pyramidal neurons
Authors: Sah Nirnath , Sikdar Sujit K.
Published: April 2014

The subiculum, considered to be the output structure of the hippocampus, modulates information flow from the hippocampus to various cortical and sub‐cortical areas such as the nucleus accumbens, lateral septal region, thalamus, nucleus gelatinosus, medial nucleus and mammillary nuclei. Tonic inhibitory current plays an important role in neuronal physiology and pathophysiology by modulating the electrophysiological properties of neurons. While the alterations of various electrical properties due to tonic inhibition have been studied in neurons from different regions, its influence on intrinsic subthreshold resonance in pyramidal excitatory neurons expressing hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels is not known. Using pharmacological agents, we show the involvement of α5βγ GABAA receptors in the picrotoxin‐sensitive tonic current in subicular pyramidal neurons. We further investigated the contribution of tonic conductance in regulating subthreshold electrophysiological properties using current clamp and dynamic clamp experiments. We demonstrate that tonic GABAergic inhibition can actively modulate subthreshold properties, including resonance due to HCN channels, which can potentially alter the response dynamics of subicular pyramidal neurons in an oscillating neuronal network.
The crystal structure of a crustacean prophenoloxidase provides a clue to understanding the functionality of the type 3 copper proteins
Authors: Masuda Taro , Momoji Kyosuke , Hirata Takashi , Mikami Bunzo
Published: April 2014

Phenoloxidase (PO), which is classified as a type 3 copper protein, catalyzes the hydroxylation of monophenol to o‐diphenol and subsequent oxidation to the corresponding o‐quinone. The geometry and coordination environment of the active site of the arthropod PO are very similar to those of the arthropod hemocyanin (Hc). However, unlike the POs, Hc is an oxygen carrier in crustaceans, and does not possess PO activity in general. Recently, we identified a new type of proPO from a crustacean and designated it proPOβ. This enzyme has many characteristics that are rather similar to those of Hc, such as its maturation, localization, and oligomeric state. Here, we determined the crystal structure of proPOβ prepared from the hemolymph of kuruma prawns (Marsupenaeus japonicus) at 1.8‐Å resolution. M. japonicus proPOβ forms a homohexamer rather similar to that of arthropod Hc. The geometry of the active copper site in proPOβ is nearly identical to that of arthropod Hc. Furthermore, the well‐characterized ‘place‐holder’ phenylalanine is present (Phe72). However, the accessibility to the active site differs in several ways. First, another phenylalanine, which shields the active site by interacting with a copper‐coordinated histidine in crustacean Hc, is replaced by valine in the proPOβ structure. Second, two tyrosines, Tyr208 and Tyr209, both of which are absent in Hc, show the alternative conformations and form a pathway providing access to the reaction center. Thus, the present crystal structure clarifies the similarities and differences in the activity of two closely related proteins, PO and Hc.

Database

Structural data are available in the RSCB protein data bank under the accession number 3WKY.

Structured digital abstract

proPObeta and proPObeta bind by x-ray crystallography (View interaction)
20‐hydroxyecdysone mediates non‐canonical regulation of mosquito vitellogenins through alternative splicing
Authors: Provost‐Javier K. N. , Rasgon J. L.
Published: April 2014

Vitellogenesis is one of the most well‐studied physiological processes in mosquitoes. Expression of mosquito vitellogenin genes is classically described as being restricted to female adult reproduction. We report premature vitellogenin transcript expression in three vector mosquitoes: Culex tarsalis, Aedes aegypti and Anopheles gambiae. Vitellogenins expressed during non‐reproductive stages are alternatively spliced to retain their first intron and encode premature termination codons. We show that intron retention results in transcript degradation by translation‐dependent nonsense‐mediated mRNA decay. This is probably an example of regulated unproductive splicing and translation (RUST), a mechanism known to regulate gene expression in numerous organisms but which has never been described in mosquitoes. We demonstrate that the hormone 20‐hydroxyecdysone (20E) is responsible for regulating post‐transcriptional splicing of vitellogenin. After exposure of previtellogenic fat bodies to 20E, vitellogenin expression switches from a non‐productive intron‐retaining transcript to a spliced protein‐coding transcript. This effect is independent of factors classically known to influence transcription, such as juvenile hormone‐mediated competence and amino acid signalling through the target of rapamycin pathway. Non‐canonical regulation of vitellogenesis through RUST is a novel role for the multifunctional hormone 20E, and may have important implications for general patterns of gene regulation in mosquitoes.
Structure of the yellow sac spider Cheiracanthium punctorium genes provides clues to evolution of insecticidal two‐domain knottin toxins
Authors: Sachkova M. Y. , Slavokhotova A. A. , Grishin E. V. , Vassilevski A. A.
Published: April 2014

Yellow sac spiders (Cheiracanthium punctorium, family Miturgidae) are unique in terms of venom composition, because, as we show here, two‐domain toxins have replaced the usual one‐domain peptides as the major constituents. We report the structure of the two‐domain Che. punctorium toxins (CpTx), along with the corresponding cDNA and genomic DNA sequences. At least three groups of insecticidal CpTx were identified, each consisting of several members. Unlike many cone snail and snake toxins, accelerated evolution is not typical of cptx genes, which instead appear to be under the pressure of purifying selection. Both CpTx modules present the inhibitor cystine knot (ICK), or knottin signature; however, the sequence similarity between the domains is low. Conversely, notable similarity was found between separate domains of CpTx and one‐domain toxins from spiders of the Lycosidae family. The observed chimerism is a landmark of exon shuffling events, but in contrast to many families of multidomain protein genes no introns were found in the cptx genes. Considering the possible scenarios, we suggest that an early transcription‐mediated fusion event between two related one‐domain toxin genes led to the emergence of a primordial cptx‐like sequence. We conclude that evolution of toxin variability in spiders appears to be quite different from other venomous animals.
Implementing practice change in chronic cancer pain management: clinician response to a phase III study of ketamine
Authors: Hardy J. R. , Spruyt O. , Quinn S. J. , Devilee L. R. , Currow D. C.
Published: April 2014

Background

An adequately powered, double‐blind, multisite, randomised controlled trial has shown no net clinical benefit for subcutaneous ketamine over placebo in the management of cancer pain refractory to combination opioid and co‐analgesic therapy. The results of the trial were disseminated widely both nationally and internationally.

Aim

To determine whether the trial had impacted on clinical practice in Australasia.

Methods

Members of the Australia and New Zealand Society of Palliative Medicine were sent an online ketamine utilisation survey.

Results

A total of 123/392 clinicians responded (31% response rate). The majority of respondents had practised for more than 10 years in a metropolitan hospital setting. Ketamine had been prescribed by 91% of respondents, and 92% were aware of the trial. As a result, 65% of respondents had changed practice (17% no longer prescribed ketamine, 46% used less and 2% more). Thirty‐five per cent had not changed practice. Reasons for change included belief in the results of the study, concerns over the toxicity reported or because there were alternatives for pain control. Of those who prescribed less, over 80% were more selective and would now only use the drug in certain clinical situations or pain types, or when all other medications had failed.

Conclusions

Although two‐thirds of respondents reported practice change as a result of the randomised controlled trial, a minority remained convinced of the benefit of the drug from their own observations and would require additional evidence.
Outcomes of an Australian testing programme for epidermal growth factor receptor mutations in non‐small cell lung cancer
Authors: Peters M. J. , Bowden J. J. , Carpenter P. , Lewis J. , Solomon B.
Published: April 2014

Background

Molecular characterisation of non‐squamous non‐small‐cell lung cancer (NSCLC) is required to direct optimal treatment. Treatment of NSCLC with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase (EGFR‐TKI) should be guided by the presence of activating mutations of the EGFR gene.

Aim

To gain insight into the rate of testing, the range of tissues samples, test utility and outcome when cost of testing as a barrier to access is removed in the Australian setting.

Methods

In October 2010, a sponsored programme was commenced to gather data on EGFR gene mutation testing in Australia. Partnering laboratories were funded for provision of de‐identified results. For participating patients, the programme supported the test charge. Mutation testing was performed using Sanger sequencing of exons 18–21 of the EGFR.

Results

Samples 2013 were submitted from 2012 patients. Full sequencing was achieved in 1717 (85%). Failure of full sequencing was more likely in samples derived from fine needle aspiration(FNA) biopsy than tissue biopsy or pleural/pericardial fluid cell blocks OR 3.1 (95% CI 1.9–5.2). There were 359 mutations seen in 337 patients. 14.5% of cases had a classical mutation conferring sensitivity to EGFR‐TKI. In addition there was a range of less common mutations – some predicting responses and others of uncertain significance. 1.4% of cases had mutations associated with non‐responsiveness to EGFR‐TKI.

Conclusions

EGFR gene mutation testing is feasible on local and interstate lung cancer samples. The rate of valid test outcomes is high, but FNA samples are associated with more frequent test failure.
Leg ulcer due to multiple arteriovenous malformations in the lower extremity of an elderly patient
Authors: Ueda Takashi , Tanabe Kenichi , Morita Miho , Nakahara Chihoko , Katsuoka Kensei
Published: April 2014

A 66‐year‐old woman with a history of deep vein thrombosis (DVT) presented with an irregularly shaped leg ulcer surrounded by pigmentation on the left lower limb. In addition, the circumference of her left thigh had gradually increased. The ulcer did not respond to topical treatment and enlarged, therefore, she visited our hospital. Arteriography of the left lower limb showed multiple arteriovenous malformations (AVMs), based on which we made a diagnosis of a leg ulcer due to multiple AVMs. Transcatheter arterial embolisation with a mixture of N‐butyl‐2‐cyanoacrylate and lipiodol was performed six times in the period of about a year for treating the AVMs. The ulcer was managed with bed rest, surgical debridement, continuous pressure support with elastic wrap and topical treatment. After 15 months, the ulcer healed, leaving pigmentation and scarring. It is quite rare for AVMs to progress in the elderly. We speculate that the DVT had caused occult AVMs to become symptomatic following an increase in size.
Factors that influence young people's mental health help‐seeking behaviour: a study based on the Health Belief Model
Authors: O'Connor Peter J. , Martin Brett , Weeks Clinton S. , Ong Luzian
Published: April 2014

Aim

To identify key predictors and moderators of mental health ‘help‐seeking behavior’ in adolescents.

Background

Mental illness is highly prevalent in adolescents and young adults; however, individuals in this demographic group are among the least likely to seek help for such illnesses. Very little quantitative research has examined predictors of help‐seeking behaviour in this demographic group.

Design

A cross‐sectional design was used.

Methods

A group of 180 volunteers between the ages of 17–25 completed a survey designed to measure hypothesized predictors and moderators of help‐seeking behaviour. Predictors included a range of health beliefs, personality traits and attitudes. Data were collected in August 2010 and were analysed using two standard and three hierarchical multiple regression analyses.

Findings

The standard multiple regression analyses revealed that extraversion, perceived benefits of seeking help, perceived barriers to seeking help and social support were direct predictors of help‐seeking behaviour. Tests of moderated relationships (using hierarchical multiple regression analyses) indicated that perceived benefits were more important than barriers in predicting help‐seeking behaviour. In addition, perceived susceptibility did not predict help‐seeking behaviour unless individuals were health conscious to begin with or they believed that they would benefit from help.

Conclusion

A range of personality traits, attitudes and health beliefs can predict help‐seeking behaviour for mental health problems in adolescents. The variable ‘Perceived Benefits’ is of particular importance as it is: (1) a strong and robust predictor of help‐seeking behaviour; and (2) a factor that can theoretically be modified based on health promotion programmes.
Genetically‐based behavioural morph affects stopover refuelling performance in white‐throated sparrows Zonotrichia albicollis
Authors: Brown J. Morgan , McCabe Brendan J. , Kennedy Lisa V. , Guglielmo Christopher G.
Published: April 2014

Intraspecific competition can influence refuelling at migration stopover sites. White‐throated sparrows Zonotrichia albicollis have genetically‐determined plumage morphs that differ in dominance behaviour and competitive abilities. This study examines the effects of plumage morph, sex and age, three likely indicators of competitive ability, on fall migration timing, body composition, and refuelling rates during stopover at Long Point, Ontario. We used quantitative magnetic resonance analysis and plasma metabolite profiling to determine body composition and refuelling rates, respectively. We determined sex and plumage morph genetically. Competitive ability did not influence migration timing. Controlling for structural size, males had larger lean mass than females, but we found no differences in body fat or lean mass between plumage morphs. Plasma metabolite concentrations indicated that the aggressive white‐stripe morph refuelled faster than the less aggressive tan‐stripe morph, though there were no differences among sex and age groups. We suggest that increased refuelling rates did not result in increased fat or lean mass because 1) individuals categorised as less competitive had longer stopover durations to compensate for slower refuelling rates; or 2) costs of behaving more competitively offset gains from faster refuelling rates.
Fair Value‐related Information in Analysts’ Decision Processes: Evidence from the Financial Crisis
Authors: Bischof Jannis , Daske Holger , Sextroh Christoph
Published: April 2014

We use a sample of conference calls and analyst research reports from international banks to examine how financial analysts request and communicate fair value‐related information in their valuation process. We find that analysts devote considerable attention to fair value‐related topics. Most of the conference call questions and references in research reports pertain to fair value reclassifications and fair value changes of liabilities resulting from banks’ own credit risk. The accounting impact of these one‐time effects during the financial crisis and a lack of corresponding firm disclosures help to explain the prevalence of these two topics. The content of the questions and references suggests that analysts have different motives for their interest in fair value‐related information. While some analysts adjust reported earnings for unrecognised fair value changes of reclassified assets, most of the observed analysts exclude banks’ own credit risk effects from reported earnings. Thus, the use of fair value‐related information varies substantially across analysts and across instruments.
Stromal–epithelial cell interactions and alteration of branching morphogenesis in macromastic mammary glands
Authors: Zhong Aimei , Wang Guohua , Yang Jie , Xu Qijun , Yuan Quan , Yang Yanqing , Xia Yun , Guo Ke , Horch Raymund E. , Sun Jiaming
Published: April 2014

True macromastia is a rare but disabling condition characterized by massive breast growth. The aetiology and pathogenic mechanisms for this disorder remain largely unexplored because of the lack ofin vivoorin vitromodels. Previous studies suggested that regulation of epithelial cell growth and development by oestrogen was dependent on paracrine growth factors from the stroma. In this study, a co‐culture model containing epithelial and stromal cells was used to investigate the interactions of these cells in macromastia. Epithelial cell proliferation and branching morphogenesis were measured to assess the effect of macromastic stromal cells on epithelial cells. We analysed the cytokines secreted by stromal cells and identified molecules that were critical for effects on epithelial cells. Our results indicated a significant increase in cell proliferation and branching morphogenesis of macromastic and non‐macromastic epithelial cells when co‐cultured with macromastic stromal cells or in conditioned medium from macromastic stromal cells. Hepatocyte growth factor (HGF) is a key factor in epithelial–stromal interactions of macromastia‐derived cell cultures. Blockade ofHGFwith neutralizing antibodies dramatically attenuated epithelial cell proliferation in conditioned medium from macromastic stromal cells. The epithelial–stromal cell co‐culture model demonstrated reliability for studying interactions of mammary stromal and epithelial cells in macromastia. In this model,HGFsecreted by macromastic stromal cells was found to play an important role in modifying the behaviour of co‐cultured epithelial cells. This model allows further studies to investigate basic cellular and molecular mechanisms in tissue from patients with true breast hypertrophy.