bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic Utility of Thyroid Transcription Factor-1 in Ovarian Carcinoma and Its Relationship With Clinicopathologic Prognostic Parameters
Authors: Hakim Sarah A. , Youssef Nermeen S.
Published: December 2015

Although thyroid transcription factor-1 (TTF-1) is considered a relatively sensitive and specific marker for lung and thyroid neoplasms, it can occasionally be expressed in other tumors. Few immunohistochemical studies have been conducted on TTF-1 expression in ovarian carcinomas with discrepant results. To date, only 1 study compared different TTF-1 clones in ovarian carcinoma. This study is designed to evaluate the expression of TTF-1 clones in ovarian carcinomas and investigate TTF-1 association with clinicopathologic prognostic parameters. A retrospective immunohistochemical study was conducted on 62 primary ovarian carcinomas and 15 normal ovarian tissues using 2 clones of TTF-1 antibody (SPT24 and 8G7G3/1). Nuclear expression of SPT24 and 8G7G3/1 clones of TTF-1 was detected in 17.7% and 3.2% of ovarian carcinomas, respectively. Positive cytoplasmic immunostaining of clone SPT24 was detected in 1.6% of cases. In contrast, normal ovarian tissue showed negative expression of both clones. A highly significant difference was observed between both clones regarding their sensitivity in ovarian carcinomas (P=0.004). A significant inverse relationship was observed between TTF-1 (SPT24 clone) expression and tumor stage (P=0.022). TTF-1 expression is not exclusive to lung and thyroid tissue. It is expressed in ovarian carcinomas where clone SPT24 is more sensitive than clone 8G7G3/1. TTF-1 might be of diagnostic utility in evaluating neoplasms of unknown primary origin as well as adenocarcinomas involving the lung in patients with a history of a gynecologic malignancy. Moreover, TTF-1 expression might be a good prognostic factor in ovarian carcinoma.
An Audit of Failed Immunohistochemical Slides in a Clinical Laboratory: The Role of On-Slide Controls
Authors: Cheung Carol C. , Taylor Clive R. , Torlakovic Emina E.
Published: December 2015

Appropriate controls are critical for the correct interpretation of immunohistochemistry (IHC) assays and help to detect unsuccessful/suboptimal slides. We performed an audit of slides that were designated as being “failed” by the IHC laboratory (ie, laboratory-failed slides) of a large North American oncology and transplant center. All slides were run with on-slide controls. The study included analysis of only those failed slides where staining of both internal and external controls were unsuccessful/suboptimal in a period of 65 days. Failed slides were categorized based on the reason why the laboratory failed the slides. The study compared frequencies of failed slides across 9 automated stainers from 2 manufacturers and between class 1 and class 2 biomarkers. Distinction between “failed slides” and “false-negative/false-positive tests” is emphasized. The study included 22,234 IHC slides in the study period. Of those, 452 (2%) were designated as “failed” by the laboratory. Class 1 and class 2 tests showed failure rates of 0.8% and 9%, respectively. The most frequent reason for failed slides on one platform related to “no or weak staining,” whereas the other had more failed slides due to “high signal-to-noise ratio” (P<0.0001, χ2 test). Although the slides were run in groups of the same as well as different IHC protocols, unsuccessful/suboptimal testing typically manifested as individual slides (92%) and not as groups of slides; this indicates that so-called “batch controls” are not suitable as controls for automated platforms. We conclude that in the era of automated IHC staining platforms, on-slide controls allow for the proper identification of IHC slides that should be failed by the IHC laboratory and represent a powerful tool for preventing the reporting of false-negative/false-positive tests.
Comparison Between Real-Time PCR and Pyrosequencing for Detection of BRAF V600E Mutation in Thyroid Fine-Needle Aspirates
Authors: Kim Wook Youn , Kim Hyunkyung , Hwang Tae Sook , Oh Seo Young
Published: December 2015

The BRAF V600E mutation test has proven diagnostic value in thyroid fine-needle aspiration. The real-time polymerase chain reaction (RT-PCR) has recently been introduced as a new method for BRAF mutation detection. We performed BRAF V600E detection in 126 cases of thyroid fine-needle aspiration, using RT-PCR and pyrosequencing. BRAF V600E mutation was detected in 78 (61.9%) of 126 cases by RT-PCR and in 74 (57.8%) by pyrosequencing. Of the 98 papillary thyroid carcinoma samples, the BRAF V600E mutation was identified in 72 by RT-PCR and in 70 by pyrosequencing (sensitivities of 71.6% and 71.4%, respectively). Among 28 benign nodules, 6 false-positive cases were detected by RT-PCR, whereas 4 false-positive cases were detected by pyrosequencing (specificities of 78.6% and 85.7%, respectively). When analyzing 104 cases after excluding equivocal samples, pyrosequencing had a marginally higher specificity than RT-PCR (100% vs. 78.3%, P=0.074). After modifying the cut-off criteria, the low RT-PCR specificity improved to a similar or a slightly lower specificity compared with that of pyrosequencing. In the titration assay mixing the mutant DNA with the wild-type DNA in varying proportions, RT-PCR was sensitive enough to detect the mutation in a mixture containing 0.001% mutant DNA, whereas the limit of detection was 10% for pyrosequencing. In conclusion, compared with pyrosequencing, RT-PCR was more sensitive, faster, and more convenient, but less specific, for detecting the BRAF V600E mutation. A readjustment or modification of the interpretation criteria may be necessary to reduce false-positive RT-PCR results and improve the specificity while maintaining the sensitivity.
pRb and CyclinD1 Complement p16 as Immunohistochemical Surrogate Markers of HPV Infection in Head and Neck Cancer
Authors: Dreyer Johannes H. , Hauck Franziska , Barros Mário H. M. , Niedobitek Gerald
Published: December 2015

Identification of human papillomavirus (HPV) association in head and neck squamous cell carcinoma (HNSCC) is important to identify patients with favorable disease course. However, molecular HPV detection is not universally available. p16 has been proposed as a surrogate marker for HPV infection in HNSCC but, use on its own may result in wrong assignment of some cases to the group of HPV-associated tumors. We have therefore studied 424 HNSCC cases with known p16 and HPV DNA polymerase chain reaction (PCR) status for expression of retinoblastoma protein (pRb) and CyclinD1 by immunohistochemistry using 6-tiered scales (0 to 5) and a combined score (0 to 10). Sixty-one of 424 cases showed overexpression of p16. Of these, 52 cases were HPV DNA-PCR-positive. HPV association strongly correlated with low expression scores for pRb and CyclinD1 individually (scores ≤2) or combined (score sum ≤4), whereas HPV-negative carcinomas showed widely distributed expression scores. High expression scores for pRb or for pRb/CyclinD1 were observed exclusively in HPV DNA-PCR-negative cases. Three of 9 p16-positive/HPV DNA-PCR-negative cases showed high expression of pRb and displayed a high combined pRb/CyclinD1 score. We conclude that HPV-positive HNSCC are characterized by p16 overexpression and low scores for pRb, CyclinD1, and a low combined pRb/CyclinD1 score. High pRb or combined pRb/CyclinD1 scores are strong indicators for HPV-negativity and may justify excluding these cases from further molecular HPV testing. Furthermore p16-positive/HPV DNA-PCR-negative cases show heterogeneous expression of pRb and CyclinD1, including high pRb or high combined pRb/CyclinD1 scores suggesting that at least some of these cases are truly HPV negative.
Fast near-whole brain imaging in adult Drosophila during responses to stimuli and behavior
Authors: Aimon Sophie , Katsuki Takeo , Jia Tongqiu , Grosenick Logan , Broxton Michael , Deisseroth Karl , Sejnowski Terrence J. , Greenspan Ralph J.
Published: December 2015

Whole brain recordings give us a global perspective of the brain in action. In this study, we describe a method using light field microscopy to record near-whole brain calcium and voltage activity, at high speed, in behaving adult flies. We first obtained global activity maps for various stimuli and behaviors. Notably, we found that brain activity increased on a global scale when the fly walked but not when it groomed. This global increase with walking was particularly strong in dopamine neurons. Second, we extracted maps of spatially distinct sources of activity as well as their time series using principal component analysis and independent component analysis. The characteristic shapes in the maps matched the anatomy of sub-neuropil regions and in some cases a specific neuron type. Brain structures that responded to light and odor were consistent with previous reports, confirming the new technique’s validity. We also observed previously uncharacterized behavior-related activity, as well as patterns of spontaneous voltage activity.
CrispRVariants: precisely charting the mutation spectrum in genome engineering experiments
Authors: Lindsay Helen , Burger Alexa , Biyong Berthin , Felker Anastasia , Hess Christopher , Chiavacci Elena , Zaugg Jonas , Anders Carolin , Jinek Martin , Mosimann Christian , Robinson Mark D.
Published: December 2015

CRISPR-Cas9 and related technologies efficiently alter genomic DNA at targeted positions and have far-reaching implications for functional screening and therapeutic gene editing. Understanding and unlocking this potential requires accurate evaluation of editing efficiency. We show that methodological decisions for analyzing sequencing data can significantly affect mutagenesis efficiency estimates and we provide a comprehensive R-based toolkit, CrispRVariants and accompanying web tool CrispRVariantsLite, that resolves and localizes individual mutant alleles with respect to the endonuclease cut site. CrispRVariants-enabled analyses of newly generated and existing genome editing datasets underscore how careful consideration of the full variant spectrum gives insight toward effective guide and amplicon design as well as the mutagenic process.
RaDMaX: a graphical program for the determination of strain and damage profiles in irradiated crystals
Authors: Souilah M. , Boulle A. , Debelle A.
Published: December 2015

RaDMaX(radiation damage in materials analysed with X-ray diffraction) is a user-friendly graphical program that allows the determination of strain and damage depth profiles in ion-irradiated crystals. This task is achieved by fitting experimental X-ray diffraction data, recorded in symmetrical θ–2θ geometry, with a dynamical diffraction model parametrized with variable strain and damage profiles based onB-spline functions. The strain and damage profiles can be graphically manipulated so as to fit the calculated curve to the experimental data. Automatic fitting procedures (generalized simulated annealing and conventional least squares) are also implemented.RaDMaXis free and open source (CeCILL licence) and can be downloaded from http://aboulle.github.io/RaDMaX.
Size and shape of graphene layers in commercial carbon blacks established by Debye refinement
Authors: Andreev Yuri G. , Bruce Peter G.
Published: December 2015

The size and the shape of graphene layers in commercial conductive carbon blacks, Super P and Super S, have been determined from powder X-ray diffraction data. Using a refinement procedure based on the fundamental diffraction equation of Debye, it is shown that the ordered regions within the layers of both materials are of elliptical shape, curved in a cylindrical fashion along the longer axis of the ellipse. The regions are greater in Super P, ellipse axes 5.4 and 2.2 nm, than in Super S, 4.6 and 2.1 nm, and less curved (curvature radii 12.7 and 11.7 nm, respectively). There is no crystallographic registry between layers, which are equidistantly stacked into concentric groups of six or seven, on average.
Anatomy of public-private partnerships: their creation, financing and renegotiations
Authors: Sarmento Joaquim Miranda , Renneboog Luc
Published: December 2015

Purpose

– As public-private partnerships (PPPs) have become more widespread, doubts and criticisms about this type of infrastructural projects have emerged. The authors describe the PPP framework, discuss the financial structure and risk-sharing processes, and dissect the structure and organisation. The authors address the following questions: what are the main organisational characteristics of PPPs? How does the private sector structure and finance PPPs? And why and how are PPP contracts renegotiated? The paper aims to discuss these issues.

Design/methodology/approach

– This paper draws on extensive theoretical and empirical research, which is presented in a literature overview on PPPs and their renegotiations. A comprehensive review is carried out and two case studies are developed to investigate the reasons behind success and failure of PPPs and the renegotiation of contracts.

Findings

– Incomplete contracts and the long duration of concessions can bring uncertainty and change to PPPs. Joint decision making can be difficult due to different parties involved. Renegotiation outcomes tend to rely on the position of the government. In Fertagus, the private sector asked for financial help led to a very balanced agreement. Conversely, Lusoponte renegotiations were initiated by the government, which significantly changed the project. Instead of relying solely on commercial revenues, Lusoponte was substantial financed by public funds.

Research limitations/implications

– Incomplete contracts and the long duration of concessions bring about much uncertainty to PPPs.Ex postdecision making in PPPs in the wake of changing risks is difficult as it necessarily involves negotiations between the public sector and the private firm. The paper shows that marked differences in renegotiation outcomes emerge. In one case study, the private sector asked for financial help and the negotiation outcome was a very balanced agreement. Conversely, renegotiations in a second case were initiated by the government mainly for political reasons, resulted in a significant change in the PPP’s structure, risk, financing, and returns, and yielded a large public losses.

Practical implications

– Contrasting successful and unsuccessful PPPs enables the reader to examine the opportunities and pitfalls in case of PPP renegotiations, which frequently occur. He can gain insight in the determinants of negotiation outcomes and the importance of a governmental PPP entity as well as of an independent monitor such as a court of audits.

Originality/value

– This paper should be useful for both academics and practitioners and should help increase the understanding of the several stages, structures, and renegotiation processes associated with PPPs.
Understanding the motivation and context for alliancing in the Australian construction industry
Authors: Walker Derek H.T. , Lloyd-Walker Beverley M.
Published: December 2015

Purpose

– The purpose of this paper is to explore and explain the circumstances in which a highly collaborative integrated project delivery form such an alliance is the most appropriate choice of delivering infrastructure projects.

Design/methodology/approach

– The paper draws upon two previously published studies on alliancing to enable gathering insights from a quantitative study with some qualitative data that indicates project alliance delivery performance is high and suggests why it may be adopted as a project delivery form. A second qualitative study recently completed and published on integrated collaborative forms of project delivery such as alliances is re-analysed to better understand how and why this form may be successful. Together these two studies allowed a focus on the motivation to form an alliance and specific conditions relating to the alliance party’s level of ability and willingness to deeply collaborate.

Findings

– The motivation to deeply collaborate may be triggered by specific internal and external trigger mechanisms. These are identified in the paper together with discussion about the requirement of parties to have sufficient knowledge, skills, attributes and experience to collaborate at a deeply engaged level.

Research limitations/implications

– The data used in the studies were from large scale infrastructure construction projects. The examples are mainly drawn from countries where collaboration is common and culturally acceptable; results may not apply to cultures, country or workplace, where high levels of competition are seen to be the optimal strategy for project delivery success. Also, the data were drawn from construction project management (PM). Other project-based areas such as professional services for example may present a different context and hence a different rationale.

Practical implications

– The study provides deep insights about the nature of collaboration. It may have wider applicability.

Social implications

– Project organising is a social activity with social implications for how they are delivered that affect internal as well as external stakeholders. Being mindful about the motivation to choose a particular delivery form is important.

Originality/value

– This is a new area of research in PM and the world faces a massive demand for large scale complex projects. This paper may provide a rational to drive policy in project delivery choices.
Implications of the use of different payment models
Authors: Villalba-Romero Felix , Liyanage Champika
Published: December 2015

Purpose

– The purpose of this paper is to illustrate the payment models and financing structures used for road Infrastructure projects under public private partnerships (PPPs) in the UK. Comparison of funding and financial structures in the selected case studies exposes the risks and values of the models of payment utilised. This research also aims to identify relationships with payment certainty and financing debt restructuring.

Design/methodology/approach

– The paper compares several case studies representing the evolution of private finance initiative road infrastructure in the UK context. Templates were completed using semi- structured interviews during data collection; and a qualitative content analysis approach was employed for case study analysis.

Findings

– Lessons learned from using different payment methods show the benefit and limitations of adopting different forms of PPP in road development. Refinancing of projects presents substantial risks to the viability of a project, and benefits gained by the private sector. Further, refinancing brings no significant benefits to the public sector as well.

Practical implications

– Performance of selected case studies highlights emerging issues that need to be considered when adopting a PPP procurement route in roads projects. Financial markets have supported these projects under different risk profiles and payment models. They also have the potential to play a greater part in capitalising long-term investment in road projects and increase private sector participation in infrastructure development, generating more competition and innovation.

Originality/value

– This paper provides case study comparison and practical implications of recent PPP developments in road provision in the UK and the evolution of public policy in the subject.
Two separate key enzymes and two pathway‐specific transcription factors are involved in fusaric acid biosynthesis in Fusarium fujikuroi
Authors: Studt Lena , Janevska Slavica , Niehaus Eva‐Maria , Burkhardt Immo , Arndt Birgit , Sieber Christian M. K. , Humpf Hans‐Ulrich , Dickschat Jeroen S. , Tudzynski Bettina
Published: December 2015

Fusaric acid (FSA) is a mycotoxin produced by several fusaria, including the rice pathogen Fusarium fujikuroi. Genes involved in FSA biosynthesis were previously identified as a cluster containing a polyketide synthase (PKS)‐encoding (FUB1) and four additional genes (FUB2‐FUB5). However, the biosynthetic steps leading to FSA as well as the origin of the nitrogen atom, which is incorporated into the polyketide backbone, remained unknown. In this study, seven additional cluster genes (FUB6‐FUB12) were identified via manipulation of the global regulator FfSge1. The extended FUB gene cluster encodes two Zn(II)2Cys6 transcription factors: Fub10 positively regulates expression of all FUB genes, whereas Fub12 is involved in the formation of the two FSA derivatives, i.e. dehydrofusaric acid and fusarinolic acid, serving as a detoxification mechanism. The major facilitator superfamily transporter Fub11 functions in the export of FSA out of the cell and is essential when FSA levels become critical. Next to Fub1, a second key enzyme was identified, the non‐canonical non‐ribosomal peptide synthetase Fub8. Chemical analyses of generated mutant strains allowed for the identification of a triketide as PKS product and the proposition of an FSA biosynthetic pathway, thereby unravelling the unique formation of a hybrid metabolite consisting of this triketide and an amino acid moiety.
The versatile TolC‐like Slr1270 in the cyanobacterium Synechocystis sp. PCC 6803
Authors: Oliveira Paulo , Martins Nuno M. , Santos Marina , Pinto Filipe , Büttel Zsófia , Couto Narciso A. S. , Wright Phillip C. , Tamagnini Paula
Published: December 2015

Here we report on the functional characterization of the hypothetical protein Slr1270, a TolC homologue in Synechocystis sp. PCC 6803. Analysis of a slr1270 insertion deletion mutant and respective wild‐type revealed that the mutant presents increased susceptibility to antibiotics. In addition, a detailed study of the exoproteome showed that Slr1270 mediates protein secretion. Among the protein substrates dependent on Slr1270 function, we found the S‐layer structural component. Electron microscopy studies of the slr1270 mutant showed that the S‐layer is indeed absent. The requirement of functional Slr1270 for protein secretion and drug resistance mechanisms suggests that Slr1270 plays a role similar to that described for TolC in other bacteria. Additional phenotypic traits could also be observed, including slower growth rates at low temperature, impairment in biofilm formation and increased activity of enzymes detoxifying reactive oxygen species. Furthermore, an increased capacity of outer membrane vesicles (OMVs) formation and release was also found in the slr1270 mutant, a feature that has not yet been observed in bacteria lacking TolC. This work highlights the marked physiological fitness that the TolC‐like Slr1270 bestows to the photosynthetic model Synechocystis sp. PCC 6803 and presents a valuable model for studying OMVs formation and release.
The genome analysis of Candidatus Burkholderia crenata reveals that secondary metabolism may be a key function of the Ardisia crenata leaf nodule symbiosis
Authors: Carlier Aurelien , Fehr Linda , Pinto‐Carbó Marta , Schäberle Till , Reher Raphael , Dessein Steven , König Gabriele , Eberl Leo
Published: December 2015

A majority of Ardisia species harbour Burkholderia sp. bacteria within specialized leaf nodules. The bacteria are transmitted hereditarily and have not yet been cultured outside of their host. Because the plants cannot develop beyond the seedling stage without their symbionts, the symbiosis is considered obligatory. We sequenced for the first time the genome of Candidatus Burkholderia crenata (Ca. B. crenata), the leaf nodule symbiont of Ardisia crenata. The genome of Ca. B. crenata is the smallest Burkholderia genome to date. It contains a large amount of insertion sequences and pseudogenes and displays features consistent with reductive genome evolution. The genome does not encode functions commonly associated with plant symbioses such as nitrogen fixation and plant hormone metabolism. However, we identified unique genes with a predicted role in secondary metabolism in the genome of Ca. B. crenata. Specifically, we provide evidence that the bacterial symbionts are responsible for the synthesis of compound FR900359, a cyclic depsipeptide with biomedical properties previously isolated from leaves of A. crenata.
Microbial eukaryotic distributions and diversity patterns in a deep‐sea methane seep ecosystem
Authors: Pasulka Alexis L. , Levin Lisa A. , Steele Josh A. , Case David H. , Landry Michael R. , Orphan Victoria J.
Published: December 2015

Although chemosynthetic ecosystems are known to support diverse assemblages of microorganisms, the ecological and environmental factors that structure microbial eukaryotes (heterotrophic protists and fungi) are poorly characterized. In this study, we examined the geographic, geochemical and ecological factors that influence microbial eukaryotic composition and distribution patterns withinHydrateRidge, a methane seep ecosystem off the coast ofOregon using a combination of high‐throughput 18SrRNAtag sequencing, terminal restriction fragment length polymorphism fingerprinting, and cloning and sequencing of full‐length18S rRNAgenes. Microbial eukaryotic composition and diversity varied as a function of substrate (carbonate versus sediment), activity (low activity versus active seep sites), sulfide concentration, and region (North versusSouthHydrateRidge). Sulfide concentration was correlated with changes in microbial eukaryotic composition and richness. This work also revealed the influence of oxygen content in the overlying water column and water depth on microbial eukaryotic composition and diversity, and identified distinct patterns from those previously observed for bacteria, archaea and macrofauna in methane seep ecosystems. Characterizing the structure of microbial eukaryotic communities in response to environmental variability is a key step towards understanding if and how microbial eukaryotes influence seep ecosystem structure and function.
A comparison of reproductive parameters of female Amur tigers (Panthera tigris altaica) in the wild and captivity
Authors: GU Jiayin , GUO Yurong , STOTT Philip , JIANG Guangshun , MA Jianzhang
Published: December 2015

A healthy population of captive Amur tigers might assist recovery of the wild population in Northeast China if individuals were properly prepared and considered suitable for release in the wild. We analyzed the breeding records of 68 female Amur tigers from 1995 to 2010 in the Hengdaohezi Felid Breeding Center of China and compared the reproductive parameters of this population to wild female Amur tigers. We found that the reproductive parameters of the captive population (the age of first parturition, length of gestation and litter survival rate) were not significantly different from those of wild Amur tigers. Differences in birth date and litter size between wild and captive populations may be caused by management protocols for the captive population or insufficient field data from the wild population. Reproductive parameters of females giving birth after losing a litter were similar to parameters of females that did not lose a litter, except for birth date. These results provide no indication of major problems in using captive females for a breeding program for release of cubs into the wild, but additional information is still needed to assess their suitability.
Differences between Western and Asian type 2 diabetes patients in the incidence of vascular complications and mortality: A systematic review of randomized controlled trials on lowering blood glucose
Authors: Li Jing , Dong Yajie , Wu Taixiang , Tong Nanwei
Published: December 2015

Background

Differences exist between Western and Asian people with type 2 diabetes (T2D). The aim of the present systematic review was to determine whether there are differences in chronic diabetic vascular complications (CDVCs) and mortality between Western and Asian patients with T2D.

Methods

Three databases (EMBASE, MEDLINE, and Cochrane library) were searched for publications from 1966 to March 2013 describing interventional randomized control trials (RCTs) targeting to lower blood glucose levels. The RCTs included had follow‐up durations of at least 4 years as an endpoint or in their initial design, analyzed effects on mortality and/or CDVCs in T2D and compared differences in mortality and/or CDVCs among patients of different ethnicities.

Results

Two studies, including 19 439 patients with advanced diabetes, were eligible for analysis. Patients were divided into those of Western (including Australia and New Zealand) and Asian ethnicities. The incidence of all‐cause mortality, cardiovascular death, and major coronary events was significantly higher in Western than Asian patients, whereas the incidence of major cerebrovascular events, microvascular events (except for peripheral neuropathy), new or worsening nephropathy, and retinopathy was significantly lower in Western patients. There were no‐between group differences in macrovascular events, including cardiovascular death, non‐fatal myocardial infarction, and non‐fatal stroke.

Conclusions

There are differences in CDVCs and mortality rates between Western and Asian patients with advanced T2D, primarily due to ethnicity‐specific factors (e.g. different genetic background, lifestyle). Knowledge of these disparities may allow more effective monitoring and management of individual patients based on ethnic differences.
Prevalence of diabetes mellitus and its risk factors in urban communities of north Sudan: Population‐based study
Authors: Elmadhoun Wadie M. , Noor Sufian K. , Ibrahim Abd Alaziz A. , Bushara Sarra O. , Ahmed Mohamed H.
Published: December 2015

Background

Diabetes mellitus (DM) is a major health problem in Africa and worldwide. The prevalence of diabetes is expected to increase at alarming rate in Africa. Its estimated that around 20 million Africans are now living with diabetes, comprising a challenge for health systems at present and in the future. The aim of the present study was to determine the prevalence of undiagnosed and diagnosed DM and impaired glucose tolerance (IGT) in adult urban communities of the River Nile State (RNS), north Sudan.

Methods

The present study was a cross‐sectional community‐based study in which participants were randomly selected from the four main cities of the RNS, on a house‐to‐house basis. Blood glucose was tested and all participants completed a questionnaire to obtain demographic, clinical and social data. Blood pressure and anthropometric measures were also recorded.

Results

In all, 954 adults (518 females; 54.3%; mean [±SD] age 39.5 ± 16.7 years; range 18–90 years) participated in the survey. The overall prevalence of DM was 19.1% (182/954), whereas that of IGT was 9.5% (91/954). Among the diabetic group, 125 (68.7%) had known diabetes, whereas 57 (31.3%) were newly diagnosed during the study. Increasing age, a family history of diabetes, central obesity, abnormal body mass index, and hypertension were significant risk factors for DM.

Conclusions

There is high prevalence of DM and glucose intolerance in the urban population of the RNS. Screening for diabetes in individuals with any feature of metabolic syndrome is recommended.
The Concise Guide to PHARMACOLOGY 2015/16: Nuclear hormone receptors
Authors: Alexander Stephen PH , Cidlowski John A , Kelly Eamonn , Marrion Neil , Peters John A , Benson Helen E , Faccenda Elena , Pawson Adam J , Sharman Joanna L , Southan Christopher , Davies Jamie A ,   CGTP Collaborators
Published: December 2015

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found athttp://onlinelibrary.wiley.com/doi/10.1111/bph.13352/full. Nuclear hormone receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the websitewww.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC‐IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR‐DB and GRAC and provides a permanent, citable, point‐in‐time record that will survive database updates.
Endothelin‐1 suppresses insulin‐stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells
Authors: Horinouchi Takahiro , Hoshi Akimasa , Harada Takuya , Higa Tsunaki , Karki Sarita , Terada Koji , Higashi Tsunehito , Mai Yosuke , Nepal Prabha , Mazaki Yuichi , Miwa Soichi
Published: December 2015

Background and Purpose

Endothelin‐1 (ET‐1) reduces insulin‐stimulated glucose uptake in skeletal muscle, inducing insulin resistance. Here, we have determined the molecular mechanisms underlying negative regulation by ET‐1 of insulin signalling.

Experimental Approach

We used the rat L6 skeletal muscle cells fully differentiated into myotubes. Changes in the phosphorylation of Akt was assessed by Western blotting. Effects of ET‐1 on insulin‐stimulated glucose uptake was assessed with [3H]‐2‐deoxy‐d‐glucose ([3H]2‐DG). The C‐terminus region of GPCR kinase 2 (GRK2‐ct), a dominant negative GRK2, was overexpressed in L6 cells using adenovirus‐mediated gene transfer. GRK2 expression was suppressed by transfection of the corresponding short‐interfering RNA (siRNA).

Key Results

In L6 myotubes, insulin elicited sustained Akt phosphorylation at Thr308 and Ser473, which was suppressed by ET‐1. The inhibitory effects of ET‐1 were prevented by treatment with a selective ETA receptor antagonist and a Gq protein inhibitor, overexpression of GRK2‐ct and knockdown of GRK2. Insulin increased [3H]2‐DG uptake rate in a concentration‐dependent manner. ET‐1 noncompetitively antagonized insulin‐stimulated [3H]2‐DG uptake. Blockade of ETA receptors, overexpression of GRK2‐ct and knockdown of GRK2 prevented the ET‐1‐induced suppression of insulin‐stimulated [3H]2‐DG uptake. In L6 myotubes overexpressing FLAG‐tagged GRK2, ET‐1 facilitated the interaction of endogenous Akt with FLAG‐GRK2.

Conclusions and Implications

Activation of ETA receptors with ET‐1 suppressed insulin‐induced Akt phosphorylation at Thr308 and Ser473 and [3H]2‐DG uptake in a GRK2‐dependent manner in skeletal muscle cells. These findings suggest that ETA receptors and GRK2 are potential targets for overcoming insulin resistance.
Long‐term treatment with pegvisomant for acromegaly: a 10‐year experience
Authors: Ramos‐Leví Ana M. , Bernabeu Ignacio , Álvarez‐Escolá Cristina , Aller Javier , Lucas Tomás , de Miguel Paz , Rodríguez‐Cañete Leticia , Sampedro‐Núñez Miguel A. , Halperin Irene , Puig‐Domingo Manuel , Marazuela Mónica
Published: December 2015

Background

Efficacy of the GH‐receptor antagonist pegvisomant (PEG) has differed between preclinical and observational studies mainly due to dose adjustment and IGF‐I normalization criteria. An escape phenomenon has also been described, but its definition and underlying causes have not been fully established.

Objective

To re‐evaluate the outcomes of long‐term PEG in a series of previously published patients and analyse the escape phenomenon.

Methods

We reviewed all patients with acromegaly resistant to SSA in whom PEG was started as monotherapy, who had been included in a previous publication. We prospectively evaluated 64 (56·3% women) from six tertiary care referral hospitals in Spain, for whom data as of June 2014 were available. Escape to PEG was defined as confirmed loss of biochemical control (IGF‐I >1·2xULN), after at least 6 months of previous control with a stable dose of PEG.

Results

Patients were followed up for 13·0 (5·9–34·8) years since diagnosis, and 9·0 (4·1–10·4) years since the first administration of PEG. Fifty‐one (89·5%) patients had an adequate IGF‐I control at the last follow‐up visit, 9 of them without treatment. Tumour growth was reported in 6 of 64 cases (9·4%), none of whom had received prior radiotherapy (P = 0·011). Seven patients died during follow‐up. We found 16 escapes in 10 patients (15·6%). We identified potential underlying causes in 9 cases (tumour regrowth, previous treatment modifications, concomitant menopause and change in testosterone administration). The reason was unknown in 7 escapes, which occurred in 6 patients (9·4%). All patients, except one, achieved subsequent biochemical control after treatment adjustment.

Conclusions

We reassure the efficacy and safety of long‐term PEG. An escape phenomenon may occur, but it can be overcome by adjusting therapy.
Frequency of botulinum toxin injections for spastic equinus: how much is enough?
Authors: Matthews Dennis J
Published: December 2015

This commentary is on the original article by Hastings‐Ison et al. on pages 750–757 of this issue.
New insulin glargine 300 U/ml versus glargine 100 U/ml in Japanese adults with type 1 diabetes using basal and mealtime insulin: glucose control and hypoglycaemia in a randomized controlled trial (EDITION JP 1)
Authors: Matsuhisa M. , Koyama M. , Cheng X. , Takahashi Y. , Riddle M. C. , Bolli G. B. , Hirose T. ,   on behalf of the EDITION JP 1 study group
Published: December 2015

Aim

To compare efficacy and safety of new insulin glargine 300 U/ml (Gla‐300) with that of insulin glargine 100 U/ml (Gla‐100) in Japanese adults with type 1 diabetes.

Methods

The EDITION JP 1 study (NCT01689129) was a 6‐month, multicentre, open‐label, phase III study. Participants (n = 243) were randomized to Gla‐300 or Gla‐100 while continuing mealtime insulin. Basal insulin was titrated with the aim of achieving a fasting self‐monitored plasma glucose target of 4.4–7.2 mmol/l. The primary endpoint was change in glycated haemoglobin (HbA1c) over 6 months. Safety measures included hypoglycaemia and change in body weight.

Results

Gla‐300 was non‐inferior to Gla‐100 for the primary endpoint of HbA1c change over the 6‐month period {least squares [LS] mean difference 0.13 % [95 % confidence interval (CI) −0.03 to 0.29]}. The annualized rate of confirmed (≤3.9 mmol/l) or severe hypoglycaemic events was 34 % lower with Gla‐300 than with Gla‐100 at night [rate ratio 0.66 (95 % CI 0.48–0.92)] and 20 % lower at any time of day [24 h; rate ratio 0.80 (95 % CI 0.65–0.98)]; this difference was most pronounced during the first 8 weeks of treatment. Severe hypoglycaemia was infrequent. The basal insulin dose increased in both groups (month 6 dose: Gla‐300 0.35 U/kg/day, Gla‐100 0.29 U/kg/day). A between‐treatment difference in body weight change over 6 months favouring Gla‐300 was observed [LS mean difference −0.6 kg (95 % CI −1.1 to −0.0); p = 0.035]. Adverse event rates were comparable between the groups.

Conclusions

In Japanese adults with type 1 diabetes using basal plus mealtime insulin, less hypoglycaemia was observed with Gla‐300 than with Gla‐100, particularly during the night, while glycaemic control did not differ.
Aleglitazar, a dual peroxisome proliferator‐activated receptor‐α/γ agonist, improves insulin sensitivity, glucose control and lipid levels in people with type 2 diabetes: findings from a randomized, double‐blind trial
Authors: Stirban A. O. , Andjelkovic M. , Heise T. , Nosek L. , Fischer A. , Gastaldelli A. , Herz M.
Published: December 2015

The present single‐centre, randomized, double‐blind, placebo‐controlled phase II study investigated the effect of the balanced dual peroxisome proliferator‐activated receptor‐α/γ agonist aleglitazar on whole‐body and liver insulin sensitivity, β‐cell function and other components of cardiometabolic syndrome after 16 weeks of treatment in patients with type 2 diabetes inadequately controlled with metformin monotherapy who received once‐daily 150 µg aleglitazar or matching placebo as add‐on therapy to metformin. Baseline and 16‐week assessments included a two‐step hyperinsulinaemic–euglycaemic clamp, followed by a hyperglycaemic clamp, as well as evaluation of glycated haemoglobin (HbA1c), lipids and safety variables. The primary endpoint was change in whole‐body insulin sensitivity (M‐value) from baseline compared with placebo, derived from the second clamp step. M‐value improved significantly from baseline with aleglitazar (n = 16) compared with placebo (n = 24; p = 0.05 for difference between arms). We found statistically significant treatment differences with aleglitazar versus placebo in fasting hepatic insulin resistance index (p = 0.01), and in total glucose disposal (p = 0.03) at the second insulin infusion step. Aleglitazar treatment resulted in significant improvements in HbA1c and lipids and was well tolerated.
Brivaracetam, a selective high‐affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action
Authors: Nicolas Jean‐Marie , Hannestad Jonas , Holden Daniel , Kervyn Sophie , Nabulsi Nabeel , Tytgat Dominique , Huang Yiyun , Chanteux Hugues , Staelens Ludovicus , Matagne Alain , Mathy François‐Xavier , Mercier Joël , Stockis Armel , Carson Richard E. , Klitgaard Henrik
Published: December 2015

Objective

Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high‐affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivara‐cetam (BRV) for its rate of brain penetration and its onset of action.BRVwas compared with levetiracetam (LEV).

Methods

In vitro permeation studies were performed using Caco‐2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRVandLEV) and dog (LEVonly). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using theSV2APETtracer [11C]UCB‐J. The time course ofPETtracer displacement was measured following single intravenous (IV) dosing withLEVorBRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood–brain barrier permeability (permeability surface area product,PS) values and then predict brain kinetics in man.

Results

In rodents,BRVconsistently showed a faster entry into the brain thanLEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability ofBRVwas also demonstrated in human cells in vitro.PBPKmodeling predicted that, followingIVdosing to human subjects,BRVmight distribute to the brain within a few minutes compared with approximately 1 h forLEV(PSof 0.315 and 0.015 ml/min/g forBRVandLEV, respectively). These data were supported by a nonhuman primatePETstudy showing fasterSV2A occupancy byBRVcompared withLEV.

Significance

These preclinical data demonstrate thatBRVhas rapid brain entry and fast brainSV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit ofBRVfor treatment of acute seizures remains to be confirmed in clinical studies.
Modes of functional biodiversity control on tree productivity across the European continent
Authors: Ratcliffe Sophia , Liebergesell Mario , Ruiz‐Benito Paloma , Madrigal González Jaime , Muñoz Castañeda Jose M. , Kändler Gerald , Lehtonen Aleksi , Dahlgren Jonas , Kattge Jens , Peñuelas Josep , Zavala Miguel A. , Wirth Christian
Published: December 2015

Aim

The relative contribution of community functional diversity and composition to ecosystem functioning is a critical question in ecology in order to enable better predictions of how ecosystems may respond to a changing climate. However, there is little consensus about which modes of functional biodiversity are most important for tree growth at large spatial scales. Here we assessed the relative importance of climate, functional diversity and functional identity (i.e. the community mean values of four key functional traits) for tree growth across the European continent, spanning the northern boreal to the southern Mediterranean forests.

Location

Finland, Germany, Sweden, Spain and Wallonia (Belgium).

Methods

Using data from five European national forest inventories we applied a hierarchical linear model to estimate the sensitivity of tree growth to changes in climate, functional diversity and functional identity along a latitudinal gradient.

Results

Functional diversity was weakly related to tree growth in the temperate and boreal regions and more strongly in the Mediterranean region. In the temperate region, where climate was the most important predictor, functional diversity and identity had a similar importance for tree growth. Functional identity was strongest at the latitudinal extremes of the continent, largely driven by strong changes in the importance of maximum height along the latitudinal gradient.

Main conclusions

Functional diversity is an important driver of tree growth in the Mediterranean region, providing evidence that niche complementarity may be more important for tree growth in water‐limited forests. The strong influence of functional identity at the latitudinal extremes indicates the importance of a particular trait composition for tree growth in harsh climates. Furthermore, we speculate that this functional identity signal may reflect a trait‐based differentiation of successional stages rather than abiotic filtering due to water or energy limitation.
Children with moderate‐high infection with Entamoeba coli have higher percentage of body and abdominal fat than non‐infected children
Authors: Zavala G. A. , García O. P. , Campos‐Ponce M. , Ronquillo D. , Caamaño M. C. , Doak C. M. , Rosado J. L.
Published: December 2015

Background

Intestinal parasites, virus and bacterial infections are positively associated with obesity and adiposity in vitro and in animal models, but conclusive evidence of this relationship in humans is lacking. The aim of this cross‐sectional study was to determine differences in adiposity between infected and non‐infected children, with a high prevalence of intestinal parasitic infection and obesity.

Subjects

A total of 296 school‐aged children (8.0 ± 1.5 years) from a rural area in Querétaro, Mexico, participated in this study. Anthropometry (weight, height and waist circumference) and body fat (DXA) were measured in all children. A fresh stool sample was collected from each child and analysed for parasites. Questionnaires related to socioeconomic status and clinical history were completed by caretakers.

Results

Approximately 11% of the children were obese, and 19% were overweight. The overall prevalence of infection was 61%. Ascaris lumbricoides was the most prevalent soil transmitted helminth (16%) followed by hookworm. Entamoeba coli was the predominant protozoa (20%) followed by Endolimax nana, Balantidium coli, Entamoeba histolytica/dispar, Iodamoeba bütschlii and Giardia lamblia. Children with moderate–heavy infection of E. coli had significantly higher waist circumference, waist‐to‐height ratio, body and abdominal fat than children not infected or with light‐intensity infection (p < 0.05).

Conclusion

These findings raise the possibility that a moderate or heavy infection with E. coli may contribute to fat deposition and thereby have long‐term consequences on human health. Further studies are needed to better understand if E. coli contributes directly to fat deposition and possible mechanisms.