bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical analysis of background noise in seismic prospecting
Authors: Zhong Tie , Li Yue , Wu Ning , Nie Pengfei , Yang Baojun
Published: March 2015

From a conventional viewpoint, seismic‐prospecting background noise is usually regarded as the product of a stationary and Gaussian stochastic process. In this paper, we use statistical methods to investigate the properties of the land‐seismic‐prospecting background noise on stationarity, Gaussianity, power spectral density, and spatial correlation. We use and analyse the passive noise records collected by receiver arrays at different typical geological environments (desert, steppe, and mountainous regions). Differences exist in the statistical properties of the background noise from different geological environments, but we still find some common characteristics. It is shown that the background noise is not strictly stationary and has different stationary properties over different timescales. Most of the noise records appear to be a Gaussian process when examined over a period of about 20 s but are found to be non‐Gaussian when examined over shorter periods of about 1 s. The background noise is a kind of colored noise, and its energy mainly concentrates in the low‐frequency bands. We also find that the spatial correlation of the background noise is weak. The results of this paper provide a scientific understanding about the properties of seismic‐prospecting background noise.
The Bertrand Paradox, the Useless Auctioneer and the Launhardt Model
Authors: Lambertini Luca , Mosca Manuela
Published: March 2015

We revisit the Cournot–Bertrand debate in the light of Cournot, Edgeworth and Launhardt, tracing back to Launhardt the origin of price competition in duopoly models with constant returns to scale. Then, we discuss the formalisation of consumer utility function for differentiated products, first appearing in Launhardt and then in Bowley. This allows us to point out that assuming that firms know the demand function(s) is equivalent to assuming that they know the structure of consumer preferences. Therefore, we argue that there is no role for the auctioneer, either in Cournot or in Walras.
Unity and Distinctiveness in UK Coalition Government: Lessons for Junior Partners
Authors: McEnhill Libby
Published: March 2015

Parties in coalition governments must address the ‘unity/distinctiveness’ dilemma: how to maintain governing cohesion, while sustaining individual identities. Within the Cameron–Clegg government this is a challenge for both parties, but it is more so for the Liberal Democrats as the junior partner. This paper considers how the Liberal Democrats negotiated this dilemma in relation to ministerial portfolio allocations. While the Liberal Democrat strategy of placing ministers in almost all departments has served the Coalition well in terms of governing unity, it has limited the extent to which they have been able to assert their distinctive contribution to Coalition policy‐making. This is demonstrated through an examination of the Liberal Democrats' influence on Coalition welfare policy. A lack of clear policy contributions is potentially highly damaging to the Liberal Democrats electorally, as it suggests that they have made little substantive contribution to the Coalition beyond propping up their Conservative partners. Accordingly, the paper reflects on lessons for junior partners in future UK coalition governments, suggesting that concentrating ministers within one or two departments may provide a more viable means of carving out a distinctive governing legacy.
The Burgeoning Fissures of Dissent: Allen Dulles and the Selling of the CIA in the Aftermath of the Bay of Pigs
Authors: Willmetts Simon
Published: March 2015

This article documents the efforts of Allen Dulles, upon his forced retirement from the Central Intelligence Agency in the aftermath of the Bay of Pigs, to promote his former agency in the face of mounting public criticism of its activities. It argues that the first wave of critical press regarding the CIA in the early 1960s was an early indication of the breakdown of the Cold War consensus – a phenomenon usually identified as occurring later in the decade in response to the escalation of the Vietnam War. Dulles, who as head of the CIA for most of the 1950s relied upon a compliant media to maintain the CIA's anonymity in public life, was confronted by an increasingly recalcitrant American media in the following decade that were beginning to question the logics of government secrecy, CIA covert action and US foreign policy more generally. In this respect the Bay of Pigs and the media scrutiny of the CIA and US foreign policy that it inspired can be regarded as an early precursor to the later emergence of adversarial journalism and a post‐consensus American culture that contested the Vietnam War and America's conduct in the Cold War more generally.
Through a Glass, Darkly: TheCIAand Oral History
Authors: Hammond Andrew
Published: March 2015

This article broaches the thorny issue of how we may study the history of theCIAby utilizing oral history interviews. This article argues that while oral history interviews impose particular demands upon the researcher, they are particularly pronounced in relation to studying the history of intelligence services. This article, nevertheless, also argues that while intelligence history and oral history each harbour their own epistemological perils and biases, pitfalls which may in fact be pronounced when they are conjoined, the relationship between them may nevertheless be a productive one. Indeed, each field may enrich the other provided we have thought carefully about the linkages between them: this article's point of departure. The first part of this article outlines some of the problems encountered in studying theCIAby relating them to the author's own work. This involved researching theCIA's role inUSforeign policy towards Afghanistan since a landmark year in the history of the lateColdWar, 1979 (i.e. the year theSovietUnion invaded that country). The second part of this article then considers some of the issues historians must confront when applying oral history to the study of theCIA. To bring this within the sphere of cognition of the reader the author recounts some of his own experiences interviewingCIAofficers in and aroundWashingtonDC. The third part then looks at some of the contributions oral history in particular can make towards a better understanding of the history of intelligence services and theCIA.
Turning Against theCIA: Whistleblowers During the ‘Time of Troubles’
Authors: Moran Christopher
Published: March 2015

Edward Snowden is not the first – nor will he be the last – disgruntledUSintelligence officer to spill the beans. Using newly declassified materials, private papers and interviews, this article explores how theCentralIntelligenceAgency (CIA) dealt with whistleblowers and disillusioned staff in the 1970s, a period often described as theAgency's ‘Time of Troubles’. It will be argued that ugly revelations by former employees caused more distress to theCIAthan disclosures that emerged in the press and onCapitolHill. At Langley, there was genuine shock that supposedly trusted insiders would write tell‐it‐all books and betray theAgency's code of ‘never celebrate successes, never explain failures’. Focusing on theCIA's attempts to manage three intelligence apostates –VictorMarchetti,PhillipAgee andFrankSnepp – it will be shown that the Agency invariably made a rod for its own back. As well as ham‐fisted efforts to spy on them and steal manuscripts, theCIAconstitutionally frogmarched certain whistleblowers off to court, provoking widespread criticism that it was an enemy of free speech. By looking at how theCIAresponded to the challenge of leaks in the 1970s, this article places into long‐term perspective the contemporary struggle between intelligence agencies and rebellious insiders who use electronic media to promote transparency.
American Journalism and the Landscape of Secrecy:TadSzulc, theCIAandCuba
Authors: Aldrich Richard J.
Published: March 2015

The relationship between secret services and the press is an enduring one. Although theCIAdid not seek the kind of salient media profile enjoyed by theFBI, it nevertheless maintained an informal press office from its foundation in 1947. Directors of theCIAand their senior staff devoted significant time to the public profile of theAgency. Their efforts to engage with the world of newspapers divided journalists. Some saw it as their patriotic duty to assist theAgency, even reporting for it overseas, while other saw it as their constitutional role to oppose theAgency. This was especially true during theVietnam War and Watergate. Thereafter, a more nuanced relationship developed in which the press saw themselves as an informal wing of new accountability processes that provided the intelligence community with oversight. This was ambiguous terrain and its complexities are explored here by focusing on the example of the prominentNewYorkTimesjournalistTadSzulc, whose complex relationship with theCIAspanned several decades and connected closely with the vexed issue ofKennedy andCuba.Szulc played a number of roles including outrider, renegade and overseer, but there was confusion about who was servant and who was master.
Development and Evaluation of Food Safety Modules for K‐12 Science Education
Authors: Chapin Travis K. , Pfuntner Rachel C. , Stasiewicz Matthew J. , Wiedmann Martin , Orta‐Ramirez Alicia
Published: March 2015

Career and educational opportunities in food science and food safety are underrecognized by K‐12 students and educators. Additionally, misperceptions regarding nature of science understanding persist in K‐12 students despite being emphasized as an important component of science education for over 100 y. In an effort to increase awareness concerning career and educational opportunities in food science and food safety and to improve the nature of science understanding among K‐12 students, a series of problem‐based learning modules was developed and pilot tested with a total of 61 K‐12 students. Results of pre‐ and postevaluations and assessments indicated that (1) interest in science, food science, and food safety increased and (2) content knowledge related to the nature of science, food science, and food safety was improved. We further suggest that these modules provide opportunities for educators in traditional as well as extracurricular settings to demonstrate important concepts contained in the newly released Next Generation Science Standards.
Impact of clinical pharmacists in the emergency department of an Australian public hospital: A before and after study
Authors: Proper John S , Wong Annie , Plath Alice E , Grant Kirsty A , Just Derek W , Dulhunty Joel M
Published: March 2015

Objective

To evaluate the impact of an ED pharmacy service on ED clinical staff and hospital pharmacist activity.

Methods

A prospective study measuring pharmacist activities and surveying ED staff attitudes and experience before and after commencement of an ED pharmacy service.

Results

There were 2275 and 2072 hospital‐wide pharmacist occasions of service recorded over a 1 month period before and after implementation of the ED pharmacy service, respectively; 339 (16.4%) of these occurred in the ED post‐implementation. ED pharmacists most commonly were involved in obtaining medication histories (74% of ED occasions of service); 43% of all pharmacist‐performed medication histories occurred in the ED. Post‐implementation of the service, 26% of medication interventions occurred in the ED with the number of medication errors identified by ward pharmacists decreasing by 11%; 59% of ED pharmacist medication interventions were clinically significant. ED clinicians perceived the greatest impact of the service to be on patient education and medication safety. Qualitative feedback was overwhelmingly positive.

Conclusions

Pharmacy staff can rapidly become a vital component of clinical service provision in the ED, contributing to medication safety from the point of patient entry into the hospital and impacting ED clinicians and whole of hospital activity for pharmacists.
Training match and mismatch as a driver of key employee behaviours
Authors: Lee Gregory John
Published: March 2015

Training is widely believed to have the potential to improve key workplace outcomes such as the in‐role behaviours and organisational citizenship of employees. However, this article argues that match of actual training provision to requirements leads to the greatest possible improvement in key behaviours, an assertion that lacks prior validation. Undertraining relative to requirements would typically be associated with lower behavioural gain, or even negative behaviours. Overtraining may have both positive and negative implications; however, this article argues that on aggregate excess training will be associated with worse outcomes compared with match. An analysis of 699 matched employee–manager dyads supports the assertion that match is associated with the best relative levels of key workplace behaviours, and associates either undertraining or overtraining with degradation in outcomes. This research highlights the importance of training needs analysis and encourages active management of trained workers to match work to skills.
Hunting tourism and animal conservation
Authors: Buckley R. , Mossaz A.
Published: March 2015

Read the Feature Paper: Does trophy hunting matter to long‐term population trends in African herbivores of different dietary guilds?; other Commentaries on this paper: Monitoring required for effective sustainable use of wildlife and the Response from the authors: The assessment of the role of trophy hunting in wildlife conservation
Autogenous bone and a bovine bone substitute for ridge preservation: preliminary clinical and histologic findings
Authors: Schulz MC , Kallweit MB , Kallweit S , Koch R , Lauer G , Mai R , Hoffmann T
Published: March 2015

Background

Tooth extractions lead to morphological changes of the alveolar ridge. For oral rehabilitation sufficient bone volume of the alveolar ridge is required. This clinical study compared the ability of Bio‐Oss® Collagen to autogenous bone to preserve bone volume after tooth extraction.

Methods

A total of 17 patients with 20 extraction sites were examined. After extraction, 10 sockets were each filled with either autogenous bone or Bio‐Oss® Collagen and covered with a resorbable membrane. The width of the alveolar ridge was measured postoperatively, and after 4 and 6 months respectively. Prior to implant insertion, a bone biopsy was taken from the grafted sites and evaluated histologically.

Results

The width of the alveolar ridge in the Bio‐Oss® Collagen group decreased about 5.33 ± 6.62% after 4 months and 9.45 ± 10.51% after 6 months. The reduction in the group augmented with autogenous bone was 14.31 ± 21.41% after 4 months and 19.17 ± 8.38% after 6 months. No statistically significant differences were observed. The histological examination showed comparable area fractions of total bone in both groups (Bio‐Oss® Collagen: 59.99 ± 24.23%; autogenous bone: 61.55 ± 25.13%; p = 1.0).

Conclusions

The present study demonstrated that autogenous bone and Bio‐Oss® Collagen are suitable for ridge preservation. However, both techniques could not entirely prevent tissue volume loss.
Ecological niche breadth and microhabitat guild structure in temperate Australian reptiles: Implications for natural resource management in endangered grassy woodland ecosystems
Authors: Michael Damian R. , Kay Geoffrey M. , Crane Mason , Florance Daniel , MacGregor Christopher , Okada Sachiko , McBurney Lachlan , Blair David , Lindenmayer David B.
Published: March 2015

Ecological theory predicts that species with narrow niche requirements (habitat specialists) are more vulnerable to anthropocentric disturbances than those with broad niche requirements (habitat generalists). Hence, understanding a species ecological niche and guild membership would serve as a valuable management tool for providing a priori assessments of a species extinction risk. It also would help to forecast a species capacity to respond to land use change, as what might be expected to occur under financial incentive schemes to improve threatened ecological vegetation communities. However, basic natural history information is lacking for many terrestrial species, particularly reptiles in temperate regions of the world. To overcome this limitation, we collated 3527 reptile observations from 52 species across an endangered woodland ecoregion in south‐eastern Australia and examined ecological niche breadth and microhabitat guild structure. We found 30% of species had low ecological niche values and were classified as habitat specialists associated with large eucalypt trees, woody debris, surface rock or rocky outcrops. Cluster analysis separated species into six broad guilds based on microhabitat similarity. Approximately 80% of species belonged to guilds associated with old growth vegetation attributes or non‐renewable litho‐resources such as surface rock or rocky outcrops. Our results suggest that agri‐environment schemes that focus purely on grazing management are unlikely to provide immediate benefits to broad suites of reptiles associated with old growth vegetation and litho‐resources. Our classification scheme will be useful for identifying reptile species that are potentially vulnerable to anthropocentric disturbances and may require alternative strategies for improving habitat suitability and reptile conservation outcomes in grassy woodland ecosystems.
Neotropical dragonflies (Insecta: Odonata) as indicators of ecological condition of small streams in the eastern Amazon
Authors: de Oliveira‐Junior José Max Barbosa , Shimano Yulie , Gardner Toby Alan , Hughes Robert M. , de Marco Júnior Paulo , Juen Leandro
Published: March 2015

Sensitive and cost‐effective indicators of aquatic ecosystem condition in Amazon streams are necessary to assess the effects of anthropogenic disturbances on those systems in a viable and ecologically meaningful manner. We conducted the present study in the municipality of Paragominas, state of Pará, northern Brazil, where we sampled adult dragonflies in 50 100‐m‐long wadeable stream sites in 2011. We collected 1769 specimens represented by 11 families, 41 genera and 97 species. The suborder Zygoptera contributed 961 individuals and Anisoptera 808. Among the 97 recorded species, nine were classified as useful indicators of ecological condition, with four species being associated with more degraded streams (three Anisoptera, one Zygoptera) and five with more preserved streams (all were Zygoptera). Anisoptera (dragonflies) tend to provide more useful indicators of more degraded environments because they have more efficient homeostatic mechanisms and are more mobile, enabling them to tolerate a wider range of environmental conditions. By contrast, Zygoptera (damselflies) tend to provide a more useful role as indicators of more preserved environments and high levels of environmental heterogeneity because of their smaller body sizes and home ranges and greater ecophysiological restrictions. We conclude from our assessment of this low‐order Amazonian stream system that (i) the occurrence of specific odonate species is strongly associated with the configuration of riparian vegetation, (ii) agricultural activities appear to be the main factor determining changes in the composition of odonate assemblages and (iii) these insects can act as useful indicators of the ecological consequences of riparian habitat loss and disturbance. Because generalist species invade moderately degraded areas, those areas may have high species richness but host few species of Zygoptera. Therefore, preserving dense riparian vegetation is necessary to maintain aquatic ecological condition, and that condition can be rehabilitated by planting new trees. Both require enforcing existing environmental regulations, various types of incentives and educating local communities.
Prevalence of Regulatory T‐Cell Subtypes in Preeclampsia
Authors: Toldi Gergely , Vásárhelyi Zsófia Eszter , Rigó János , Orbán Csaba , Tamássy Zita , Bajnok Anna , Shima Tomoko , Saito Shigeru , Molvarec Attila
Published: March 2015

Problem

The prevalence of regulatory T cells (Tregs) is lower in preeclampsia (PE) compared with healthy pregnancy (HP). However, the proportion of recently described Treg subtypes has not been investigated.

Method

Peripheral blood samples of 19 PE and 21 HP women in the third trimester were evaluated using flow cytometry for the prevalence of activated T cells and naive, effector, thymic, extrathymic, and exhausted Tregs.

Results

The prevalence of activated T cells and exhausted Tregs was higher in PE than in HP. The prevalence of the functionally most active effector Tregs is decreased, while naive Tregs appear to be unaffected in PE compared with HP. No difference was detected between Tregs according to their origin (thymic or extrathymic).

Conclusion

The combination of lower effector Treg and higher exhausted Treg prevalence may account for the decrease in the functionality of Tregs in PE.
Evaluation of prognostic indicators for canine primary immune‐mediated haemolytic anaemia and application of a scoring system for the determination of prognosis
Authors: Ke SS , Anderson GA , Connolly SL
Published: March 2015

Objective

Apply a previously described scoring system retrospectively to cases of canine primary immune‐mediated haemolytic anaemia (pIMHA) to determine its accuracy and reliability for the determination of prognosis inVictoria,Australia.

Methods

Retrospective cohort study of 41 dogs diagnosed withpIMHAat theUniversity ofMelbourneVeterinaryHospital (UMVH) betweenAugust 2006 toDecember 2012.

Results

Of the 41 dogs included, 70.7% were female while 29.3% were male. The overall mortality in this study was 43.9%. The previously described prognostic scoring system when applied to cases ofpIMHAinVictoria,Australia, was not found to show statistical significance for prognostification. None of the five prognostic factors were found to be independently significant for prognostification.

Conclusion

Application of the previously described prognostic scoring system indicated that it may not be reliable for predicting prognoses of dogs withpIMHAinVictoria,Australia.
Agreement among three different equine venipuncture sites with regard to measurement of packed cell volume and total solids
Authors: Dahan R , Sutton GA , Oreff GL , Kelmer G
Published: March 2015

The primary objective of this study was to determine the agreement between the packed cell volume (PCV) and total solids (TS) values in blood collected from the jugular vein (JV) in comparison with the cephalic vein (CV) and the transverse facial venous sinus (TFVS) in healthy adult horses. A total of 72 samples were taken from 24 horses. We found high agreement that reflects no clinically relevant differences between the PCV and TS values obtained from the CV or the TFVS in comparison with the JV in standing healthy adult horses.
Population pharmacokinetics of dolutegravir in HIV‐infected treatment‐naive patients
Authors: Zhang Jianping , Hayes Siobhán , Sadler Brian M. , Minto Ilisse , Brandt Julie , Piscitelli Steve , Min Sherene , Song Ivy H.
Published: March 2015

Aim

Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment‐naive patients and to evaluate the influence of patient covariates.

Methods

A population pharmacokinetic model was developed using a non‐linear mixed effect modelling approach based on data from 563 HIV‐infected, treatment‐naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10–50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine.

Results

The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h–1, 17.4 l, 2.24 h−1, and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady‐state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co‐infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis.

Conclusions

A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV‐infected treatment‐naive patients.
Longitudinal Clinical Trials with Adaptive Choice of Follow-Up Time
Authors: Jeffries Neal , Geller Nancy L.
Published: March 2015

In longitudinal studies comparing two treatments with a maximum follow-up time there may be interest in examining treatment effects for intermediate follow-up times. One motivation may be to identify the time period with greatest treatment difference when there is a non-monotone treatment effect over time; another motivation may be to make the trial more efficient in terms of time to reach a decision on whether a new treatment is efficacious or not. Here, we test the composite null hypothesis of no difference at any follow-up time versus the alternative that there is a difference at at least one follow-up time. The methods are applicable when a few measurements are taken over time, such as in early longitudinal trials or in ancillary studies. Suppose the test statistic will be used to test the hypothesis of no treatment effect at a fixed follow-up time . In this context a common approach is to perform a pilot study on subjects, and evaluate the treatment effect at the fixed time points and choose as the value of for which is maximized. Having chosen a second trial can be designed. In a setting with group sequential testing we consider several adaptive alternatives to this approach that treat the pilot and second trial as a seamless, combined entity and evaluate Type I error and power characteristics. The adaptive designs we consider typically have improved power over the common, separate trial approach.
Enzalutamide: targeting the androgen signalling pathway in metastatic castration‐resistant prostate cancer
Authors: Schalken Jack , Fitzpatrick John M.
Published: March 2015

Significant progress has been made in the understanding of the underlying cancer biology of castration‐resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.
New cellular mechanisms of gap junction degradation and recycling
Authors: Carette Diane , Gilleron Jérôme , Denizot Jean‐Pierre , Grant Kirsty , Pointis Georges , Segretain Dominique
Published: March 2015

Background Information

Connexins (Cxs), the constitutive proteins of gap junctions, are key actors of many physiological processes. Therefore, alterations of Cx expression and degradation lead to the development of physiopathological disorders. Because of the formation of a double membrane vesicle termed annular gap junction (AGJ), gap junction degradation is a unique physiological process for which many cellular aspects remain unclear.

Results

By using a combination of time‐lapse fluorescence microscopy and high‐resolution transmission electron microscopy, we evidenced new specific cellular events concerning gap junction degradation and recycling. Indeed, by time lapse video microscopy we demonstrated, for the first time to our knowledge, that an entire AGJ can be fully recycled back to the plasma membrane. Moreover, we dissected the degradative processes of gap junction by electron microscopy approaches. Interestingly, in addition to canonical autophagy and heterophagy pathways, previously described, we discovered that both pathways could sometimes intermingle. Strikingly, our results also highlighted a new lysosome‐based autophagy pathway that could play a pivotal role in common autophagy degradation.

Conclusions

The present investigation reveals that AGJ degradation is a more complex process that it was previously thought. First, a complete recycling of the gap junction plaque after its internalisation could occur. Second, the degradation of this peculiar double membrane structure is possible through autophagy, heterophagy, hetero‐autophagy or by lysosomal‐based autophagy. Altogether, this work underlines novel aspects of gap junction degradation that could be extended to other cell biology processes.
Meta‐chlorophenylpiperazine enhances leptin sensitivity in diet‐induced obese mice
Authors: Yan Chunling , Yang Yongjie , Saito Kenji , Xu Pingwen , Wang Chunmei , Hinton Antentor Othrell , Yan Xiaofeng , Wu Qi , Tong Qingchun , Elmquist Joel K , Fukuda Makoto , Xu Yong
Published: March 2015

Background and Purpose

Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti‐obesity leptin therapy in these leptin‐resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research.

Experimental Approach

We first examined the effects of co‐administration of leptin and meta‐chlorophenylpiperazine (mCPP), an agonist of 5‐HT2C and 5‐HT1B receptors, on energy balance in leptin‐resistant diet‐induced obese (DIO) mice. We further assessed leptin‐induced phosphorylation of the STAT‐3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5‐HT2C receptors.

Results

Co‐administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin‐induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5‐HT2C receptors significantly blunted leptin‐induced pSTAT3 in these same hypothalamic regions.

Conclusions and Implications

Our study provides evidence that drugs, which activate 5‐HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO.
Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity
Authors: Dixon Christine L , Harrison Neil L , Lynch Joseph W , Keramidas Angelo
Published: March 2015

Background and Purpose

GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non‐benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non‐benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors.

Experimental Approach

We used rapid ligand application onto macropatches and single‐channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism.

Key Results

At the single‐channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening.

Conclusions and Implications

As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines.
Review: Comprehensive treatments for youth comorbidity – evidence‐guided approaches to a complicated problem
Authors: Bearman Sarah Kate , Weisz John R.
Published: March 2015

Background

Evidence‐based treatments (EBTs) with a single‐disorder focus have improved the potential for youth mental health care, yet may be an imperfect fit to clinical care settings where diagnostic comorbidity and co‐occurring problems are commonplace. Most EBTs were developed to treat one diagnosis or problem (or a small homogenous cluster), but most clinically referred youths present with multiple disorders and problems.

Findings

Three emerging approaches may help address the comorbidity that is so common in treated youths. Conceptually unified treatments target presumed causal and maintaining factors that are shared among more than one disorder or problem area; preliminary open trials and case studies show promising results. Modular protocols combine the ‘practice elements’ that commonly appear in separate single‐disorder EBTs and repackage them into coordinated delivery systems; one modular protocol, MATCH, has produced positive findings in a randomized effectiveness trial. Monitoring and Feedback Systems (MFSs) provide real‐time data on client progress to inform clinical decision‐making, encompassing comorbid and co‐occurring problems; one study shows beneficial effects in everyday practice with diverse youth problems.

Conclusions

All three approaches – conceptually unified, modular, and MFS – can be strengthened by increased research attention to treatment integrity, clinician user‐appeal, design simplicity, and the infrastructure necessary for successful implementation.
Clinical presentation in insulinoma predicts histopathological tumour characteristics
Authors: Wolf Peter , Winhofer Yvonne , Smajis Sabina , Anderwald Christian‐Heinz , Scheuba Christian , Niederle Bruno , Gessl Alois , Luger Anton , Krebs Michael , Koperek Oskar
Published: March 2015

Background

Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72‐h fast. However, the prognostic value of parameters in the standardized 72‐h fast on histopathological tumour criteria and clinical presentation has not been examined.

Methods

In thirty‐three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki‐67 index. Cut‐off values for classical grading (Gclas) were set at G1clas≤2%, G2clas3–20% & G3clas>20% and for modified grading (Gmod) at G1mod<5%, G2mod5–20% & G3mod>20%.

Results

When Gmod criteria were applied, the initial blood glucose was lower in GII/IIImod patients compared to GImod (2·8 ± 0·8 vs 3·8 ± 1·3 mmol/l; P = 0·046). Basal and end of fast levels of insulin (basal insulin 71 ± 61 vs 20 ± 16 mU/l; P < 0·001; end of fast insulin 77 ± 51 vs 21 ± 20 mU/l; P < 0·001) and c‐peptide (basal c‐peptide 5·4 ± 2·4 vs 2·7 ± 1·6 μg/l; P = 0·004; end of fast c‐peptide 5·3 ± 2·4 vs 2·5 ± 1·4 μg/l; P = 0·001) were significantly higher in GII/IIImod than in GImod. No differences between the groups were observed when Gclas criteria were applied. Additionally, close correlations were observed between insulin concentration, Ki‐67 index and tumour size.

Conclusion

This study shows an impact of histopathological tumour characteristics in patients suffering from an insulinoma on clinical presentation during a standardized 72‐h fast. Lower initial blood glucose levels and higher concentrations of insulin and c‐peptide are associated with worse tumour grading and larger tumour size.
The risk of osteoporosis in patients with liver cirrhosis: a meta‐analysis of literature studies
Authors: Lupoli Roberta , Di Minno Alessandro , Spadarella Gaia , Ambrosino Pasquale , Panico Annalisa , Tarantino Luciano , Lupoli Gelsy , Lupoli Giovanni , Di Minno Matteo Nicola Dario
Published: March 2015

Objective

Data about the association between cirrhosis and osteoporosis are contrasting. Thus, we have performed a meta‐analysis of literature studies on this topic.

Design

MEDLINE, Cochrane library, EMBASE, Scopus and Web of Science databases have been searched to retrieve all articles of interest. Data on prevalence of osteoporosis, bone mineral density (BMD) and bone turnover laboratory parameters were compared among cirrhotic patients and control subjects without cirrhosis.

Patients

Studies on patients with liver cirrhosis screened for the presence of osteoporosis were included.

Results

Six case–control studies (372 cirrhotic patients and 1579 controls) were included. The prevalence of osteoporosis was higher in cirrhotic patients than in controls (34·7% vs 12·8%, OR: 2·52, 95%CI: 1·11, 5·69; P = 0·03, I2 = 81%; P = 0·005). Accordingly, a reduced lumbar spine BMD (MD: −0·13, 95%CI: −0·24, −0·02; P = 0·02, I2 = 93%; P < 0·00001) and z‐score (MD: −1·06, 95%CI: −1·79, −0·34; P = 0·004, I2 = 95%; P < 0·00001) were found in cirrhotic patients as compared with controls. In contrast, no significant differences were reported in femoral neck BMD and z‐score.

Interestingly, bone turnover laboratory parameters widely confirmed these results showing higher levels of ALP and D‐Pyr, accompanied by reduced levels of IGF‐1, PTH and 25‐OH‐D in cirrhotic patients as compared with controls.

Conclusions

Despite the high heterogeneity among studies, data showed an increased prevalence of osteoporosis in patients with cirrhosis. This information suggests the need of an accurate screening of bone mineral density in patients with liver cirrhosis to plan an adequate osteoporosis management.
Professionals' perceptions of the rocky routes to successful outcomes for young people in a children's residential school
Authors: Syme Audrey , Hill Malcolm
Published: March 2015

Poor outcomes for young people in and leaving care have been well documented and research has indicated that the expectations of professionals working with children and young people looked after is a significant influence, particularly in relation to education. An evaluation of an independent children's residential school in Scotland provided a rare opportunity to analyse and compare the views of different kinds of staff about desirable outcomes and how successful outcomes could be achieved. Care workers, teachers and specialist support staff shared some views, but also held contrasting expectations, which appeared to be linked to differing emphases in their models for working with young people. This paper offers tentative explanations for such differences and concludes with suggestions on how to help align service staffs' expectations of young people leaving their care.
Sequential healing events of osseointegration at UnicCa® and SLActive® implant surfaces: an experimental study in the dog
Authors: Favero Riccardo , Lang Niklaus P. , Salata Luiz A. , Neto Evandro Carneiro Martins , Caroprese Marino , Botticelli Daniele
Published: March 2015

Aim

To study the sequential events in osseointegration at implants with highly hydrophilic surfaces.

Material and methods

All premolars and the first molars were bilaterally extracted in 12 Beagle dogs. After 3 months, full‐thickness flaps were elevated and two different implants systems with various surfaces were randomly installed in the edentulous premolar region in one side of the mandible. One surface was acid etched and further modified with calcium ions (UnicCa®), while the other was sandblasted with large grits and acid etched (SLActive®). The flaps were sutured to allow a fully submerged healing. The surgery on the other side of the mandible and the sacrifices were planned in such a way to obtain biopsies representing the healing after 1, 2, 4, and 8 weeks (n = 6 per period).

Results

After one week of healing, new bone apposition was found at both surfaces with percentages of 6.9 ± 3.3% and 6.1 ± 4.6% at UnicCa® and SLActive®, respectively. After 2 weeks, the percentages had increased to 29.1 ± 11.9% and 21.6 ± 14.3%, respectively. After 4 and 8 weeks of healing, mean values of 46.3 ± 7.3% and 58.7 ± 15.1% at UnicCa® and 51.2 ± 16.1% and 68.9 ± 15.4% at SLActive® surfaces were found, respectively. None of the differences in percentages were statistically significant. Concomitantly, the old bone was resorbed at both surfaces from about 21–22% after 1 week to about 4–6% after 8 weeks of healing.

Conclusions

The osseointegration process onto moderately rough titanium implant surfaces of high hydrophilicity was very similar for two implant systems that were both nanotechnologically modified.
Glove use among hairdressers: difficulties in the correct use of gloves among hairdressers and the effect of education
Authors: Oreskov Katia W. , Søsted Heidi , Johansen Jeanne D.
Published: March 2015

Background

Hand eczema is frequent among Danish hairdressers, and they are advised to use gloves as protection. However, studies indicate that a significant proportion use gloves inappropriately.

Objectives

To determine whether hairdressers and apprentices use protective gloves in the correct way, and to determine whether a demonstration of correct use could cause an improvement.

Methods

Forty‐three hairdressers and apprentices were asked to perform a hair wash while wearing gloves. The shampoo used was contaminated with an ultraviolet (UV) trace material. Two rounds of hair washing were carried out by each person, interrupted by a demonstration of how to use gloves correctly. Photographs were taken to compare UV contamination before and after the demonstration.

Results

All of the participants (100%) had their hands contaminated during the first round; the area ranged between 0.02 and 101.37 cm2 (median 3.62 cm2). In the second round, 55.8% were contaminated (range 0.00–3.08 cm2; median 0.01 cm2). The reduction in contaminated skin areas was statistically significant (p < 0.001), proving an effect of the glove demonstration. There were no significant differences between hairdressers and apprentices.

Conclusions

Hairdressers and apprentices lack knowledge on how to handle gloves correctly. A short demonstration of correct glove use made a significant difference in the skin protection provided by gloves.
MicroRNA‐93 regulates collagen loss by targeting MMP3 in human nucleus pulposus cells
Authors: Jing Wanli , Jiang Wenxue
Published: March 2015

Objectives

Degenerated disc disease is one of the most common medical conditions in patients suffering from low back pain. Recent studies have shown that microRNAs can regulate cell function in many pathological conditions. The aim of this study was to investigate expression and role of miR‐93 in disc degeneration.

Materials and methods

Quantitative RT‐PCR was employed to investigate level of miR‐93 in degenerative nucleus pulposus (NP) tissues. Then, functional analysis of miR‐93 in regulating collagen II expression was performed. Subsequently, western blotting and luciferase reporter assay were used to detect the target gene.

Results

We showed that miR‐93 was significantly down‐regulated in degenerative NP tissues and its levels were associated with grade of disc degeneration. Overexpression of miR‐93 stimulated type II collagen expression in NP cells. Moreover, MMP3 was identified as a putative target of miR‐93. MiR‐93 inhibited MMP3 expression by directly targeting its 3′UTR, and this was abolished by miR‐93 binding site mutations. Additionally, restoration of MMP3 in miR‐93‐overexpressed NP cells reversed effects of type II collagen expression. Expression of MMP3 inversely correlated with miR‐93 expression in degenerative NP tissues.

Conclusions

Taken together, we demonstrated that miR‐93 contributed to abnormal NP cell type II collagen expression by targeting MMP3, involved in intervertebral disc degeneration.
miR‐709 up‐regulated in hepatocellular carcinoma, promotes proliferation and invasion by targeting GPC5
Authors: Liu Tonggang , Zhang Xuezhong , Sha Kaihui , Liu Xianxian , Zhang Liguo , Wang Bangmao
Published: March 2015

Objectives

Hepatocellular carcinoma (HCC) is one of the most common cancers and is a significant leading cause of cancer‐related deaths worldwide. Emerging evidence has shown that microRNAs (miRNAs) are associated with cancer development and progression. However, up to now little has been known concerning the role of miR‐709 in HCC.

Materials and methods

Real‐time RT‐PCR was performed to detect expression of miR‐709 in HCC cell lines and tissues. To further understand its role in HCC, we restored its expression in HepG2 cell line through transfection with miR‐709 mimics or inhibitors. CCK‐8 proliferation assay, migration assay and invasion assay were used to detect functional roles of miR‐709. Luciferase assay and western blotting were performed to detect the target gene of miR‐709.

Results

We found that miR‐709 was highly expressed in HCC tissues and in HCC cell lines by qRT‐PCR. Re‐expression of miR‐709 in HCC cells remarkably promoted cell migration and invasiveness in vitro. Subsequent investigation revealed that glypican‐5 (GPC5) was a direct and functional target of miR‐709 in HCC cells where overexpression of miR‐709 impaired GPC5‐induced inhibition of proliferation and invasion. Finally, analysis of miR‐709 and GPC5 levels in human HCC tissues revealed that miR‐709 inversely correlated with GPC5 expression.

Conclusions

These results suggest that miR‐709 may positively regulate invasion and metastasis of HCC through targeting GPC5.