bluuebunny/crossref_metadata_2025 huggingface dataset:
Collagen-platelet interactions: recognition and signalling
Authors: Farndale Richard W. , Siljander Pia R. , Onley David J. , Sundaresan Pavithra , Knight C. Graham , Barnes Michael J.
Published: August 2015

The collagen-platelet interaction is central to haemostasis and may be a critical determinant of arterial thrombosis, where subendothelium is exposed after rupture of atherosclerotic plaque. Recent research has capitalized on the cloning of an important signalling receptor for collagen, glycoprotein VI, which is expressed only on platelets, and on the use of collagen-mimetic peptides as specific tools for both glycoprotein VI and integrin α2ϐ1. We have identified sequences, GPO and GFOGER (where O denotes hydroxyproline), within collagen that are recognized by the collagen receptors glycoprotein VI and integrin α2ϐ1 respectively, allowing their signalling properties and specific functional roles to be examined. Triple-helical peptides containing these sequences were used to show the signalling potential of integrin α2ϐ1, and to confirm its important contribution to platelet adhesion. Glycoprotein VI appears to operate functionally on the platelet surface as a dimer, which recognizes GPO motifs that are separated by four triplets of collagen sequence. These advances will allow the relationship between the structure of collagen and its haemostatic activity to be established.
Caspase activation
Authors: Boatright Kelly M. , Salvesen Guy S.
Published: August 2015

Caspase activation is the 'point of no return' commitment to cell death. Synthesized as inactive zymogens, it is essential that the caspases remain inactive until the death signal is received. It is known for the downstream executioner caspases-3 and -7 that the activation event is proteolytic cleavage, and this had been assumed to apply to the initiator caspases as well. However, recent studies conducted on caspases-2, -8 and -9 have challenged this tenet of caspase activation. In this review we focus on the molecular details of caspase activation, with emphasis on recent work that provides a pleasing explanation for the differential requirements for the activation of executioner and initiator caspases.
Phosphoinositides and membrane traffic at the trans-Golgi network.
Authors: Choudhury Rawshan R. , Hyvola Noora , Lowe Martin
Published: August 2015

Cargo proteins moving along the secretory pathway are sorted at the TGN (trans-Golgi network) into distinct carriers for delivery to the plasma membrane or endosomes. Recent studies in yeast and mammals have shown that formation of these carriers is regulated by PtdIns(4)P. This phosphoinositide is abundant at the TGN and acts to recruit components required for carrier formation to the membrane. Other phosphoinositides are also present on the TGN, but the extent to which they regulate trafficking is less clear. Further characterization of phosphoinositide kinases and phosphatases together with identification of new TGN-associated phosphoinositide-binding proteins will reveal the extent to which different phosphoinositides regulate TGN trafficking, and help define the molecular mechanisms involved.
Single-molecule live-cell imaging of clathrin-based endocytosis.
Authors: Kirchhausen Tomas , Boll Werner , van Oijen Antoine , Ehrlich Marcelo
Published: August 2015

Clathrin-coated vesicles carry traffic from the plasma membrane to endosomes. We report here the first real-time visualization of cargo sorting and endocytosis by clathrin-coated pits in living cells. We have visualized the formation of coats by monitoring the incorporation of fluorescently tagged clathrin or its adaptor AP-2 (adaptor protein 2), and have followed clathrin-mediated uptake of transferrin, single LDL (low-density lipoprotein) and single reovirus particles. The intensity of a cargo-loaded clathrin cluster grows steadily during its lifetime, and the time required to complete assembly is proportional to the size of the cargo particle. These results are consistent with a nucleation-growth mechanism and an approximately constant growth rate. There are no preferred nucleation sites. A proportion of the nucleation events appear to be abortive. Cargo incorporation occurs primarily or exclusively in a newly formed coated pit, and loading appears to commit that pit to finish assembly. Our data led to a model in which coated pits initiate randomly, but collapse with high likelihood unless stabilized, presumably by cargo capture.
Functional role of lipid rafts in CD20 activity?
Authors: Janas Eva , Priest Richard , Malhotra Rajneesh
Published: August 2015

CD20 is a B-lymphocyte-specific integral membrane protein, implicated in the regulation of transmembrane calcium conductance, cell-cycle progression and B-lymphocyte proliferation. CD20 is proposed to function as a SOCC (store-operated calcium channel). SOCCs are activated by receptor-stimulated calcium depletion of intracellular stores. Sustained calcium conductivity across the plasma membrane mediated by SOCC activity is required for long-term calcium-dependent processes, such as transcriptional control and gene expression. Cross-linking of CD20 by antibodies (e.g. Rituxan) has been reported to induce a rapid redistribution of CD20 into specialized microdomains at the plasma membrane, known as lipid rafts. Recruitment of CD20 into lipid rafts and its homo-oligomerization are suggested to be crucial for CD20 activity and regulation. This review outlines recent biochemical studies characterizing the role of CD20 in calcium signalling in B-lymphocytes and evaluates an engagement of lipid rafts in the regulation of CD20-mediated calcium conductivity.
Activation by c-Myc of transcription by RNA polymerases I, II and III
Authors: Gomez-Roman Natividad , Felton-Edkins Zoë A. , Kenneth Niall S. , Goodfellow Sarah J. , Athineos Dimitris , Zhang Jingxin , Ramsbottom Ben A. , Innes Fiona , Kantidakis Theodoros , Kerr Elaine R. , Brodie Jacqueline , Grandori Carla , White Robert J.
Published: August 2015

The proto-oncogene product c-Myc can induce cell growth and proliferation. It regulates a large number of RNA polymerase II-transcribed genes, many of which encode ribosomal proteins, translation factors and other components of the biosynthetic apparatus. We have found that c-Myc can also activate transcription by RNA polymerases I and III, thereby stimulating production of rRNA and tRNA. As such, c-Myc may possess the unprecedented capacity to induce expression of all ribosomal components. This may explain its potent ability to drive cell growth, which depends on the accumulation of ribosomes. The activation of RNA polymerase II transcription by c-Myc is often inefficient, but its induction of rRNA and tRNA genes can be very strong in comparison. We will describe what is known about the mechanisms used by c-Myc to activate transcription by RNA polymerases I and II.
Evolution of the diverse biological roles of inositols
Authors: Michell Robert H.
Published: August 2015

Several of the nine hexahydroxycylohexanes (inositols) have functions in Biology, with myo-inositol (Ins) in most of the starring roles; and Ins polyphosphates are amongst the most abundant organic phosphate constituents on Earth. Many Archaea make Ins and use it as a component of diphytanyl membrane phospholipids and the thermoprotective solute di-L-Ins-1,1′-phosphate. Few bacteria make Ins or use it, other than as a carbon source. Those that do include hyperthermophilic Thermotogales (which also employ di-l-Ins-1,1′-phosphate) and actinomycetes such as Mycobacterium spp. (which use mycothiol, an inositol-containing thiol, as an intracellular redox reagent and have characteristic phosphatidylinositol-linked surface oligosaccharides). Bacteria acquired their Ins3P synthases by lateral gene transfer from Archaea. Many eukaryotes, including stressed plants, insects, deep-sea animals and kidney tubule cells, adapt to environmental variation by making or accumulating diverse inositol derivatives as ‘compatible’ solutes. Eukaryotes use phosphatidylinositol derivatives for numerous roles in cell signalling and regulation and in protein anchoring at the cell surface. Remarkably, the diradylglycerol cores of archaeal and eukaryote/bacterial glycerophospholipids have mirror image configurations: sn-2,3 and sn-1,2 respectively. Multicellular animals and amoebozoans exhibit the greatest variety of functions for PtdIns derivatives, including the use of PtdIns(3,4,5)P3 as a signal. Evolutionarily, it seems likely that (i) early archaeons first made myo-inositol approx. 3500 Ma (million years) ago; (ii) archeons brought inositol derivatives into early eukaryotes (approx. 2000 Ma?); (iii) soon thereafter, eukaryotes established ubiquitous functions for phosphoinositides in membrane trafficking and Ins polyphosphate synthesis; and (iv) since approx. 1000 Ma, further waves of functional diversification in amoebozoans and metazoans have introduced Ins(1,4,5)P3 receptor Ca2+ channels and the messenger role of PtdIns(3,4,5)P3.
Inhibition of 2,3-oxidosqualene: β-amyrin-cyclase, S-adenosyl-l-methionine: cycloartenol C-24-methyltransferase and cycloeucalenol: obtusifoliol isomerase by rationally designed molecules containing a tertiary amine function
Authors: RAHIER ALAIN , BOUVTER PIERRETTE , CATTEL LUIGI , NARULA ACHARAN , BENVENISTE PIERRE
Published: August 2015

25-Azacycloartanol (I), 2-aza-2-dihydrosqualene (II) and Tridemorph (2,6-dimethyl-N-tridecylmorpholine)(III) are potent inhibitors of higher plant sterol biosynthesis. The first two molecules have been designed using rational enzymological concepts. I, II and III were shown to inhibit the S-adenosyl-l-methionine: cycloartenol C-24-methyltransferase, the 2,3-oxidosqualene: β- amyrin-cyclase and the cycloeucalenol: obtusifoliol isomerase, respectively. Inhibition was demonstrated either in vivo on bramble cell suspensions or in vitro on microsomes from maize seedlings. Each inhibitor has been shown to have a high affinity for its presumed enzymic target and only negligible inhibitory action on the other two enzymes. The applications of these results to further physiological studies are discussed.
Transformer‐based inverter with reduced number of switches for renewable energy applications
Authors: Gandomi Amin Ashraf , Saeidabadi Saeid , Hosseini Seyed Hossein , Babaei Ebrahim , Sabahi Mehran
Published: August 2015

Multilevel inverters generate high‐level voltage with high quality and low‐harmonic distortion, and these unique properties have increased their applications in renewable energy sources. However, these inverters require several passive components and a complex pulse width modulation (PWM) control method. Besides, they suffer from voltage balancing problems. In this work, a new inverter has proposed that generates seven‐level voltage from one DC source by reduced number of switches which does not exhibit any voltage balancing problem. The proposed inverter without any extra boost circuit is able to increase the input voltage. The voltage stress on all the switches in the proposed inverter is the same. In this study, variable amplitude phase disposition PWM control method that is compatible with the proposed inverter is developed. Moreover, extended structure of the proposed inverter and its new algorithm in generating all odd and even voltage levels are proposed. To validate the performance of the inverter, a prototype has been built and tested and also its performance has been modelled using PSCAD/EMTDC software package. Very good agreement has been achieved between experimental results and simulations.
The Impact of Preoperative Depression and Health State on Quality-of-Life Outcomes after Anterior Cervical Diskectomy and Fusion
Authors: Alvin Matthew D. , Miller Jacob A. , Lubelski Daniel , Nowacki Amy S. , Scheman Judith , Mathews Manu , McGirt Matthew J. , Benzel Edward C. , Mroz Thomas E.
Published: August 2015

Study Design

Retrospective cohort study.

Objective

We sought to assess the predictive value of preoperative depression and health state on 1-year quality-of-life outcomes after anterior cervical diskectomy and fusion (ACDF).

Methods

We analyzed 106 patients who underwent ACDF. All patients had either bilateral or unilateral cervical radiculopathy. Preoperative and 1-year postoperative health outcomes were assessed based on the visual analog scale, Pain Disability Questionnaire (PDQ), Patient Health Questionnaire (PHQ-9), and EuroQol-5 Dimensions (EQ-5D) questionnaire. Univariable and multivariate regression analyses were performed to assess for preoperative predictors of 1-year change in health status according to the EQ-5D.

Results

Compared with preoperative health states, the ACDF cohort showed statistically significant improved PDQ (78.5 versus 57.9), PHQ-9 (9.7 versus 5.3), and EQ-5D (0.55 versus 0.68) scores at 1 year postoperatively and surpassed the minimum clinically important difference for the EQ-5D of 0.1 units (all p ≤ 0.01). Multivariate linear regression indicated that anxiolytic use and higher EQ-5D preoperative scores were associated with less 1-year postoperative improvement in health status. Although not statistically significant, clinically important effects of preoperative depression, as measured by the PHQ-9, were observed on postoperative QOL outcome (−0.006, 95% confidence interval −0.014 to 0.001).

Conclusions

Of patients who undergo ACDF with similar preoperative QOL health states, those with a greater degree of depression may have lower improvements in postoperative QOL compared with those with less depression. Patients with anxiety and better preoperative health states also attain less 1-year QOL improvements.
The Appointment of Judges by Ministers
Authors: Hanretty Chris
Published: August 2015

I investigate appointment to the Court of Appeal and House of Lords between 1880 and 2005. Exploiting the fact that appointment is almost invariably from within the ranks of existing High Court judges and using a conditional logit model, I test for effects of legal, professional, and political factors on appointment prospects. Although there is no advantage to having the same political affiliation as the appointing lord chancellor, judges are more likely to be promoted if they were previously appointed by the incumbent party.
Student feedback: a learning and teaching performance indicator
Authors: Kinash Shelley , Naidu Vishen , Knight Diana , Judd Madelaine-Marie , Nair Chenicheri Sid , Booth Sara , Fleming Julie , Santhanam Elizabeth , Tucker Beatrice , Tulloch Marian
Published: August 2015

Purpose

– The paper aims to disseminate solutions to common problems in student evaluation processes. It proposes that student evaluation can be applied to quality assurance and improving learning and teaching. The paper presents solutions in the areas of: presenting outcomes as performance indicators, constructing appropriate surveys, improving response rates, reporting student feedback to students and student engagement as a feature of university quality assurance.

Design/methodology/approach

– The research approach of this paper is comparative case study, allowing in-depth exploration of multiple perspectives and practices at seven Australian universities. Process and outcome data were rigorously collected, analysed, compared and contrasted.

Findings

– The paper provides empirical evidence for student evaluation as an instrument of learning and teaching data analysis for quality improvement. It suggests that collecting data about student engagement and the student experience will yield more useful data about student learning. Furthermore, findings indicate that students benefit from more authentic inclusion in the evaluation process and outcomes.

Research limitations/implications

– Because of the chosen research approach, the research results may lack generalisability. Therefore, researchers are encouraged to test the proposed propositions further and apply to their own university contexts.

Practical implications

– The paper includes recommendations at the institution- and sector-wide levels to effectively use student evaluation as a university performance indicator and as a tool of change.

Originality/value

– This paper fulfils an identified need to examine student evaluation processes across institutions and focuses on the role of student evaluation in quality assurance.
Social participation experiences of mothers of children with cerebral palsy in an Iranian context
Authors: Dehghan Leila , Dalvandi Asghar , Rassafiani Mehdi , Hosseini Seyed Ali , Dalvand Hamid , Baptiste Sue
Published: August 2015

Background/aim

Social participation is increasingly of interest in research that investigates the impact of caring for a child with a disability. Little has been investigated about the social participation experiences of mothers of children with cerebral palsy (CP). This study explored social participation among Iranian mothers of children with CP.

Methods

The conventional qualitative content analysis method was utilised. Data were collected via in‐depth semi‐structured interviews with 14 mothers (aged 26–45 years) of children with CP with the gross motor function classification system expanded & revised levels III–V. Constant comparative analysis was deployed for data analysis.

Results

The results were identified and classified into three main themes: (i) polarisation of positive and negative feelings; (ii) challenges to mothers’ social activity; and (iii) striving to engage in society.

Conclusion

In the Iranian context, mothers of children with CP are facing many challenges to social participation and seem to have been neglected by the health‐care system. One of the priorities of Iranian health policy makers may be developing, establishing and implementing social support to enable the mothers to participate in social activities. Furthermore, occupational therapists can contribute and guide mothers’ social participation by creating programs to develop and utilise skills for them.
The Homicide–Suicide Phenomenon: Findings of Psychological Autopsies
Authors: Knoll James L. , Hatters‐Friedman Susan
Published: August 2015

Homicide–suicide represents a single episode of violence which may decimate an entire family. This study aimed to further describe motives and context of these tragedies. Psychological autopsies were completed for 18 homicide–suicide cases in Dallas, Texas. This included postevent interviews with surviving family members and review of police and coroner records. Two‐thirds of perpetrators had made either verbal or written threats prior to the homicide–suicide. A simplified typology describing victim–perpetrator relationship and motive type is suggested for future studies and clinical ease. Two‐thirds of perpetrators fell into the category of Intimate‐Possessive, most of whom were depressed men who were abusing substances and undergoing separation. Additional categories included Intimate‐Ailing, Filial‐Revenge, Familial‐Psychotic, and Friend‐Psychotic. Further, implications from this psychological autopsy study regarding risk assessment include use of collateral interviews regarding threats and past violence.
A Comprehensive and Harmonized Digital Forensic Investigation Process Model
Authors: Valjarevic Aleksandar , Venter Hein S.
Published: August 2015

Performing a digital forensic investigation (DFI) requires a standardized and formalized process. There is currently neither an international standard nor does a global, harmonized DFI process (DFIP) exist. The authors studied existing state‐of‐the‐art DFIP models and concluded that there are significant disparities pertaining to the number of processes, the scope, the hierarchical levels, and concepts applied. This paper proposes a comprehensive model that harmonizes existing models. An effort was made to incorporate all types of processes proposed by the existing models, including those aimed at achieving digital forensic readiness. The authors introduce a novel class of processes called concurrent processes. This is a novel contribution that should, together with the rest of the model, enable more efficient and effective DFI, while ensuring admissibility of digital evidence. Ultimately, the proposed model is intended to be used for different types of DFI and should lead to standardization.
Suspect Height Estimation Using the Faro Focus3D Laser Scanner
Authors: Johnson Monique , Liscio Eugene
Published: August 2015

At present, very little research has been devoted to investigating the ability of laser scanning technology to accurately measure height from surveillance video. The goal of this study was to test the accuracy of one particular laser scanner to estimate suspect height from video footage. The known heights of 10 individuals were measured using an anthropometer. The individuals were then recorded on video walking along a predetermined path in a simulated crime scene environment both with and without headwear. The difference between the known heights and the estimated heights obtained from the laser scanner software were compared using a one‐way t‐test. The height estimates obtained from the software were not significantly different from the known heights whether individuals were wearing headwear (p = 0.186) or not (p = 0.707). Thus, laser scanning is one technique that could potentially be used by investigators to determine suspect height from video footage.
The Influence of Selected Fingerprint Enhancement Techniques on Forensic DNA Typing of Epithelial Cells Deposited on Porous Surfaces
Authors: Tsai Li‐Chin , Lee Cheng‐Chang , Chen Chun‐Chieh , Lee James Chun‐I , Wang Sheng‐Meng , Huang Nu‐En , Linacre Adrian , Hsieh Hsing‐Mei
Published: August 2015

Fingerprints deposited at crime scene can be a source of DNA. Previous reports on the effects of fingerprint enhancement methods have focused mainly on fingermarks deposited in blood or saliva. Here, we evaluate the effects of fingerprint enhancement methods on fingerprints deposited on porous surfaces. We performed real‐time quantification and STR typing, the results of which indicated that two methods (iodine fuming and 1,2‐indanedione in ethyl acetate enhancement) had no effect on the quantity of DNA isolated and resultant STR alleles when compared to control samples. DNA quantities and allele numbers were lower for samples enhanced with silver nitrate and 1,2‐indanedione in acetic acid when compared to control samples. Based on DNA quantity, quality, and observable stochastic effects, our data indicated that iodine fuming and 1,2‐indanedione in ethyl acetate were the preferred options for the enhancement of fingerprints on porous surfaces.
Most Challenging of Contexts
Authors: Corsaro Nicholas , Engel Robin S.
Published: August 2015

Research Summary

The use of focused deterrence to reduce lethal violence driven by gangs and groups of chronic offenders has continued to expand since the initial Boston Ceasefire intervention in the 1990s, where prior evaluations have shown relatively consistent promise in terms of violence reduction. This study focuses on the capacity of focused deterrence to impact lethal violence in a chronic and high‐trajectory homicide setting: New Orleans, Louisiana. Using a two‐phase analytical design, our evaluation of the Group Violence Reduction Strategy (GVRS) observed the following findings: (a) GVRS team members in the City of New Orleans closely followed model implementation; (b) homicides in New Orleans experienced a statistically significant reduction above and beyond changes observed in comparable lethally violent cities; (c) the greatest changes in targeted outcomes were observed in gang homicides, young Black male homicides, and firearms violence; and (d) the decline in targeted violence corresponded with the implementation of the pulling levers notification meetings. Moreover, the observed reduction in crime outcomes was not empirically associated with a complementary violence‐reduction strategy that was simultaneously implemented in a small geographic area within the city.

Policy Implications

The findings presented in this article demonstrate that focused deterrence holds considerable promise as a violence prevention approach in urban contexts with persistent histories of lethal violence, heightened disadvantage, and undermined police (and institutional) legitimacy. The development of a multiagency task force, combined with unwavering political support from the highest levels of government within the city, were likely linked to high programmatic fidelity. Organizationally, the development of a program manager and intelligence analyst, along with the use of detailed problem analyses and the integration of research, assisted the New Orleans working group in identifying the highest risk groups of violent offenders to target for the GVRS notification sessions. The impacts on targeted violence were robust and consistent with the timing of the intervention.
amplisas: a web server for multilocus genotyping using next‐generation amplicon sequencing data
Authors: Sebastian Alvaro , Herdegen Magdalena , Migalska Magdalena , Radwan Jacek
Published: August 2015

Next‐generation sequencing (NGS) technologies are revolutionizing the fields of biology and medicine as powerful tools for amplicon sequencing (AS). Using combinations of primers and barcodes, it is possible to sequence targeted genomic regions with deep coverage for hundreds, even thousands, of individuals in a single experiment. This is extremely valuable for the genotyping of gene families in which locus‐specific primers are often difficult to design, such as the major histocompatibility complex (MHC). The utility of AS is, however, limited by the high intrinsic sequencing error rates of NGS technologies and other sources of error such as polymerase amplification or chimera formation. Correcting these errors requires extensive bioinformatic post‐processing of NGS data. Amplicon Sequence Assignment (amplisas) is a tool that performs analysis of AS results in a simple and efficient way, while offering customization options for advanced users. amplisas is designed as a three‐step pipeline consisting of (i) read demultiplexing, (ii) unique sequence clustering and (iii) erroneous sequence filtering. Allele sequences and frequencies are retrieved in excel spreadsheet format, making them easy to interpret. amplisas performance has been successfully benchmarked against previously published genotyped MHC data sets obtained with various NGS technologies.
IgG4‐related disease
Authors: Kubo Kanae , Yamamoto Kazuhiko
Published: August 2015

Immunoglobulin G4‐related disease (IgG4‐RD) is a regional or systemic fibro‐inflammatory disease of unknown etiology. It presents a distinctive histopathological appearance of dense lymphoplasmacytic infiltrates with abundant IgG4‐positive plasma cells, storiform fibrosis and obliterative phlebitis with the appearance of inflammatory swelling or tumefactive lesions. This new disease entity includes a wide variety of diseases such as Mikulicz disease, autoimmune pancreatitis, Riedel thyroiditis, interstitial nephritis and retroperitoneal fibrosis. Glucocorticoid therapy can resolve the clinical and pathological abnormalities and impaired organ function. IgG4‐RD was recognized internationally in 2011, and new evidence has accumulated regarding its pathogenesis, clinical features and treatment. In this review, we outline our present understanding of IgG4‐RD.
Functional significance of subjective response to alcohol across levels of alcohol exposure
Authors: Bujarski Spencer , Hutchison Kent E. , Prause Nicole , Ray Lara A.
Published: August 2015

Pre‐clinical neurobiological models of addiction etiology including both the allostatic model and incentive sensitization theory suggest that alcohol consumption among alcohol‐dependent (AD) individuals will be dissociated from hedonic reward as positive reinforcement mechanisms wane in later stage dependence. The aims of this study are to test this claim in humans by examining the relationship between dimensions of subjective responses to alcohol (SR) and alcohol craving across levels of alcohol exposure. Non‐treatment‐seeking drinkers (n = 205) completed an i.v. alcohol challenge (final target breath alcohol concentration = 0.06 g/dl) and reported on SR and craving. Participants were classified as light‐to‐moderate drinkers (LMD), heavy drinkers (HD) or AD. Analyses examined group differences in SR and craving response magnitude, as well as concurrent and predictive associations between SR domains and craving. At baseline, LMD and AD reported greater stimulation than HD, which carried over post‐alcohol administration. However, stimulation was dose‐dependently associated with alcohol craving in HD only. Furthermore, lagged models found that stimulation preceded craving among HD only, whereas this hypothesized pattern of results was not observed for craving preceding stimulation. Sedation was also positively associated with craving, yet no group differences were observed. In agreement with the prediction of diminished positive reinforcement in alcohol dependence, this study showed that stimulation/hedonic reward from alcohol did not precede craving in AD, whereas stimulation was dose‐dependently associated with and preceded craving among non‐dependent HD.
The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically‐based pharmacokinetic model
Authors: Emoto Chie , Fukuda Tsuyoshi , Venkatasubramanian Raja , Vinks Alexander A.
Published: August 2015

Aims

Sirolimus is an mTOR inhibitor metabolized by CYP3A4 and CYP3A5. Reported effects of CYP3A5 polymorphisms on sirolimus pharmacokinetics (PK) have shown unexplained discrepancies across studies. We quantitatively assessed the effect of CYP3A5*3 status on sirolimus PK by in vitro assessment and simulation using a physiologically‐based PK (PBPK) model. In addition, we explored designs for an adequately powered pharmacogenetic association study.

Method

In vitro metabolism studies were conducted to confirm individual CYP contribution to sirolimus metabolism. PK profiles were simulated in CYP3A5 expressers and non‐expressers with a PBPK model. The pre‐dose concentration predictions were used as the outcome parameter to estimate the required sample size for a pharmacogenetic association study.

Results

Sirolimus metabolism was inhibited by over 90% by ketoconazole, a CYP3A specific inhibitor. The PBPK model developed based on CLint of recombinant CYP3A4, CYP3A5 and CYP2C8 predicted a small CYP3A5*3 effect on simulated sirolimus PK profiles. A subsequent power analysis based on these findings indicated that at least 80 subjects in an enrichment design, 40 CYP3A5 expressers and 40 non‐expressers, would be required to detect a significant difference in the predicted trough concentrations at 1 month of therapy (P < 0.05, 80% power).

Conclusions

This study suggests that CYP3A5 contribution to sirolimus metabolism is much smaller than that of CYP3A4. Observed discrepancies across studies could be explained as the result of inadequate sample size. PBPK model simulations allowed mechanism‐based evaluation of the effects of CYP3A5 genotype on sirolimus PK and provided preliminary data for the design of a future prospective study.
Quaternion Julia Set Shape Optimization
Authors: Kim Theodore
Published: August 2015

We present the first 3D algorithm capable of answering the question: what would a Mandelbrot‐like set in the shape of a bunny look like? More concretely, can we find an iterated quaternion rational map whose potential field contains an isocontour with a desired shape? We show that it is possible to answer this question by casting it as a shape optimization that discovers novel, highly complex shapes. The problem can be written as an energy minimization, the optimization can be made practical by using an efficient method for gradient evaluation, and convergence can be accelerated by using a variety of multi‐resolution strategies. The resulting shapes are not invariant under common operations such as translation, and instead undergo intricate, non‐linear transformations.
Personality, attrition and weight loss in treatment seeking women with obesity
Authors: Dalle Grave R. , Calugi S. , Compare A. , El Ghoch M. , Petroni M. L. , Colombari S. , Minniti A. , Marchesini G.
Published: August 2015

Studies on small samples or in single units applying specific treatment programmes found an association between some personality traits and attrition and weight loss in individuals treated for obesity. We aimed to investigate whether pre‐treatment personality traits were associated with weight loss outcomes in the general population of women with obesity. Attrition and weight loss outcomes after 12 months were measured in 634 women with obesity (mean age, 48; body mass index (BMI), 37.8 kg m−2) seeking treatment at eight Italian medical centres, applying different medical/cognitive behavioural programmes. Personality traits were assessed with the Temperament and Character Inventory (TCI), eating disorder features with the Binge Eating Scale (BES) and Night Eating Questionnaire (NEQ). Within the 12‐month observation period, 32.3% of cases were lost to follow‐up. After adjustment for demographic confounders and the severity of eating disorders, noTCIpersonality traits were significantly associated with attrition, while low scores of the novelty seeking temperament scale remained significantly associated with weight loss ≥10% (odds ratio, 0.983; 95% confidence interval, 0.975–0.992). Additional adjustment for education and job did not change the results. We conclude that personality does not systematically influence attrition in women with obesity enrolled into weight loss programmes in the community, whereas an association is maintained between novelty seeking and weight loss outcome. Studies adapting obesity interventions on the basis of individual novelty seeking scores might be warranted to maximize the results on body weight.
Synchronous mantle cell lymph node lymphoma and pulmonary adenocarcinoma: a case report with literature review
Authors: Braham Emna , Zarrouk Mourad , Mlika Mouna , Kilani Tarek , El Mezni Faouzi
Published: August 2015

Background and Aims

Coexistence of mantle cell lymphoma and lung adenocarcinoma is extremely rare. The aim of this study is to present the first case of incidental discovery of primary lung adenocarcinoma associated to lymph node mantle cell lymphoma.

Methods

A 45 year‐old man, admitted for inguinal mass appeared since three months. Physical examination showed a 1 cm axillary and 3 cm inguinal adenopathies which were hard and fixed. A biopsy of inguinal mass revealed mantle cell lymphoma. Assessment of disease extension found a right superior lobe tumor with mediastinal lymphadenopathies. Fibreoptic bronchoscopy was normal. A fine needle biopsy of lung tumor was performed to determinate the nature of the pulmonary lesion. Histopathological findings were consistent with primary poor differentiated pulmonary adenocarcinoma with TTF‐1 expression. A first mediastinoscopy was realized to verify mediastinal lymphadenopathies; frozen section showed a mantle cell lymphoma. A right lobectomy was then performed confirming the diagnosis of lung adenocarcinoma.

Then, the patient was treated for the mantle cell lymphoma by 6 cures of alternating RCHOP and RDHAP (dexamethasone, high‐dose Ara‐Cytarabine and cisplatin) regimens followed by autologous stem cell transplantation.

Results

The patient died because of treatment complications 3 years after diagnosis.

Conclusion

Progresses are necessary to understand the pathogenesis of of synchronous occurrence of both diseases.
A RCT of telehealth for COPD patient's quality of life: the whole system demonstrator evaluation
Authors: Rixon Lorna , Hirani Shashivadan P. , Cartwright Martin , Beynon Michelle , Doll Helen , Steventon Adam , Henderson Catherine , Newman Stanton P.
Published: August 2015

Introduction/Objectives

Despite some concerns that the introduction of telehealth (TH) may lead to reductions in quality of life (QoL), lower mood and increased anxiety in response to using assistive technologies to reduce health care utilisation and manage long term conditions, this research focuses on the extent to which providing people with tools to monitor their condition can improve QoL.

Methods

The Chronic Obstructive Pulmonary Disease (COPD) cohort of the Whole Systems Demonstrator Trial is a pragmatic General Practitioner (GP) clustered randomised controlled trial (RCT) evaluating TH in the UK from three regions in England. All patients at a participating GP practice were deemed eligible for inclusion in the study if they were diagnosed with COPD.

Results

447 participants completed baseline and either a short (4 months) or long term (12 months) follow‐up. There was a trend of improved QoL and mood in the TH group at longer‐term follow‐up, but not short term follow‐up. Emotional functioning (g = 0.280 95%CI, 0.051–0.510) and mastery reached (g = 2.979 95%CI, 0–0.46) significance at P < 0.05 (all Hedges g <0.3).

Conclusions

TH showed minimal benefit to QoL in COPD patients who were not preselected to be at increased risk of acute exacerbations. Benefits were more likely in disease specific measures at longer term follow‐up. TH is a complex intervention and should be embedded in a service that is evidenced based. Outcome measures must be sensitive enough to detect changes in the target population for the specific intervention.
Elucidation of the structure of retroviral proteases: a reminiscence
Authors: Jaskolski Mariusz , Miller Maria , Mohana Rao J. K. , Gustchina Alla , Wlodawer Alexander
Published: August 2015

Determinations of only a very few protein structures had consequences comparable to the impact exerted by the structure of the protease encoded by HIV‐1, published just over 25 years ago. The structure of this relatively small protein and its cousins from other retroviruses provided a clear target for a spectacularly successful structure‐assisted drug design effort that offered new hope for controlling the then‐escalating AIDS epidemic. This reminiscence is limited primarily to work conducted at the National Cancer Institute, and is not meant to be a comprehensive history of the field, but is rather an attempt to provide a very personal account of how the structures of this most thoroughly studied crystallographic target were determined.
Eutrophication effects on greenhouse gas fluxes from shallow‐lake mesocosms override those of climate warming
Authors: Davidson Thomas A. , Audet Joachim , Svenning Jens‐Christian , Lauridsen Torben L. , Søndergaard Martin , Landkildehus Frank , Larsen Søren E. , Jeppesen Erik
Published: August 2015

Fresh waters make a disproportionately large contribution to greenhouse gas (GHG) emissions, with shallow lakes being particular hot spots. Given their global prevalence, how GHG fluxes from shallow lakes are altered by climate change may have profound implications for the global carbon cycle. Empirical evidence for the temperature dependence of the processes controlling GHG production in natural systems is largely based on the correlation between seasonal temperature variation and seasonal change in GHG fluxes. However, ecosystem‐level GHG fluxes could be influenced by factors, which while varying seasonally with temperature are actually either indirectly related (e.g. primary producer biomass) or largely unrelated to temperature, for instance nutrient loading. Here, we present results from the longest running shallow‐lake mesocosm experiment which demonstrate that nutrient concentrations override temperature as a control of both the total and individual GHG flux. Furthermore, testing for temperature treatment effects at low and high nutrient levels separately showed only one, rather weak, positive effect of temperature (CH4 flux at high nutrients). In contrast, at low nutrients, the CO2 efflux was lower in the elevated temperature treatments, with no significant effect on CH4 or N2O fluxes. Further analysis identified possible indirect effects of temperature treatment. For example, at low nutrient levels, increased macrophyte abundance was associated with significantly reduced fluxes of both CH4 and CO2 for both total annual flux and monthly observation data. As macrophyte abundance was positively related to temperature treatment, this suggests the possibility of indirect temperature effects, via macrophyte abundance, on CH4 and CO2 flux. These findings indicate that fluxes of GHGs from shallow lakes may be controlled more by factors indirectly related to temperature, in this case nutrient concentration and the abundance of primary producers. Thus, at ecosystem scale, response to climate change may not follow predictions based on the temperature dependence of metabolic processes.
Morpho‐anatomical traits of root and non‐enzymatic antioxidant system of leaf tissue contribute to waterlogging tolerance in Brachiaria grasses
Authors: Jiménez Juan de la Cruz , Cardoso Juan Andrés , Dominguez Moralba , Fischer Gerhard , Rao Idupulapati
Published: August 2015

Soil waterlogging is a major abiotic stress that affects the growth and yield of forage grasses in the tropics. Brachiaria forage grasses are widely planted in the tropics to sustain livestock production. An outdoor study was conducted using plastic cylinders under drained and waterlogged soil conditions in order to identify root and shoot traits associated with waterlogging tolerance in Brachiaria ruziziensis (waterlogging sensitive) and Brachiaria humidicola (waterlogging tolerant). For that reason, dry mass, leaf chlorophyll content, photosynthetic efficiency, root morpho‐anatomical traits (aerenchyma, stele proportion, suberin deposition) and total non‐enzymatic antioxidant activity in leaf tissue were determined. Under waterlogging, reductions of shoot biomass, chlorophyll loss, impairment of photosynthetic efficiency and diminution of antioxidant system were found in B. ruziziensis but not in B. humidicola. In B. humidicola an increase of the antioxidant system in response to waterlogging was found. Under waterlogging, both grasses showed an increase in root aerenchyma, reduction of root stele proportion and shorter roots than plants grown under drained conditions. We conclude that a combination of greater aerenchyma formation, smaller stele proportions, increased suberin deposition in the outer part of the root and an escalation of the non‐enzymatic antioxidant system acts to enhance root aeration and prevent the deleterious effect of reactive oxygen species in plants of B. humidicola subjected to waterlogged conditions.
Ulcerative colitis outpatient management: development and evaluation of tools to support primary care practitioners
Authors: Bennett A. L. , Buckton S. , Lawrance I. , Leong R. W. , Moore G. , Andrews J. M.
Published: August 2015

Background

Current models of care for ulcerative colitis (UC) across healthcare systems are inconsistent with a paucity of existing guidelines or supportive tools for outpatient management.

Aims

This study aimed to produce and evaluate evidence‐based outpatient management tools for UC to guide primary care practitioners and patients in clinical decision‐making.

Methods

Three tools were developed after identifying current gaps in the provision of healthcare services for patients with UC at a Clinical Insights Meeting in 2013. Draft designs were further refined through consultation and consolidation of feedback by the steering committee. Final drafts were developed following feasibility testing in three key stakeholder groups (gastroenterologists, general practitioners and patients) by questionnaire. The tools were officially launched into mainstream use in Australia in 2014.

Results

Three quarters of all respondents liked the layout and content of each tool. Minimal safety concerns were aired and those, along with pieces of information that were felt to be omitted, that were reviewed by the steering committee and incorporated into the final documents. The majority (over 80%) of respondents felt that the tools would be useful and would improve outpatient management of UC.

Conclusion

Evidence‐based outpatient clinical management tools for UC can be developed. The concept and end‐product have been well received by all stakeholder groups. These tools should support non‐specialist clinicians to optimise UC management and empower patients by facilitating them to safely self‐manage and identify when medical support is needed.
Disability and Domination: Lessons from Republican Political Philosophy
Authors: O'Shea Tom
Published: August 2015

The republican ideal of non‐domination identifies the capacity for arbitrary interference as a fundamental threat to liberty that can generate fearful uncertainty and servility in those dominated. I argue that republican accounts of domination can provide a powerful analysis of the nature of legal and institutional power that is encountered by people with mental disorders or cognitive disabilities. In doing so, I demonstrate that non‐domination is an ideal which is pertinent, distinctive, and desirable in thinking through psychological disability. Finally, I evaluate republican strategies for contesting domination, focusing on the limits of contestatory democracy, and proposing a participatory alternative which better addresses problems of political agency in the mentally disordered and cognitively disabled.
Better to Exploit than to Neglect? International Clinical Research and the Non‐Worseness Claim
Authors: Malmqvist Erik
Published: August 2015

Clinical research is increasingly ‘offshored’ to developing countries, a practice that has generated considerable controversy. It has recently been argued that the prevailing ethical norms governing such research are deeply puzzling. On the one hand, sponsors are not required to offshore trials, even when participants in developing countries would benefit considerably from these trials. On the other hand, if sponsors do offshore, they are required not to exploit participants, even when the latter would benefit from and consent to exploitation. How, it is asked, can it be worse to exploit the global poor than to neglect them when exploitation is voluntary and makes them better off? The present article seeks to respond to this challenge. I argue that mutually beneficial and voluntary exploitation can be worse than neglect when — as is typically true of exploitative international research — it takes advantage of unjust background conditions. This is because, in such cases, exploitation overlaps with another, less familiar wrong: complicity in injustice. Recognising complicity as a distinct wrong should make us judge exchanges arising from background injustice more harshly than we typically do, in research and elsewhere.
Minimally invasive non‐surgical approach for the treatment of periodontal intrabony defects: a retrospective analysis
Authors: Nibali Luigi , Pometti Daniela , Chen Tzu‐Ting , Tu Yu‐Kang
Published: August 2015

Aim

The aim of this retrospective analysis was to assess healing of intrabony defects treated with minimally invasive non‐surgical therapy (MINST).

Methods

A retrospective analysis was carried out in 35 consecutive intrabony defects treated by MINST (without any adjuncts) in 23 non‐smoking patients. All defects had a radiographic intrabony component > 3 mm and had clinical and radiographic data available at baseline and 12 after treatment. Pre‐ and post‐treatment radiographs were analysed and bone levels were compared by multilevel linear regression adjusted by latent variable method.

Results

Following MINST, the average PPD and CAL reduction in the intra‐bony defects were 3.12 mm and 2.78 mm respectively (p < 0.001). The average radiographic intrabony vertical defect depth was reduced by 2.93 mm (from 6.74 mm to 3.81 mm) (p < 0.001), whereas the average defect angle changed from and 28.5° at baseline to 44.4° at re‐evaluation (p < 0.001). Smaller initial defect angles and deeper initial defect depths were associated with greater defect depth reduction. Greater initial defect angles were associated with less defect angle change.

Conclusions

This paper shows considerable clinical and radiographic improvements after MINST, therefore bringing evidence to support its efficacy for the treatment of intrabony defects in non‐smokers.