bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical phase I study of elpamotide, a peptide vaccine for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors
Authors: Okamoto Isamu , Arao Tokuzo , Miyazaki Masaki , Satoh Taroh , Okamoto Kunio , Tsunoda Takuya , Nishio Kazuto , Nakagawa Kazuhiko
Published: September 2012

Targeting of tumor angiogenesis with vaccines is a potentially valuable approach to cancer treatment. Elpamotide is an immunogenic peptide derived from vascular endothelial growth factor receptor 2, which is expressed at a high level in vascular endothelial cells. We have now carried out a phase I study to evaluate safety, the maximum tolerated dose, and potential pharmacodynamic biomarkers for this vaccine. Ten HLA‐A*24:02‐positive patients with advanced refractory solid tumors received elpamotide s.c. at dose levels of 0.5, 1.0, or 2.0 mg once a week on a 28‐day cycle. Five patients experienced an injection site reaction of grade 1 and 2, which was the most frequent adverse event. In the 1.0 mg cohort, one patient experienced proteinuria of grade 1 and another patient developed both hypertension and proteinuria of grade 1. No adverse events of grade 3 or higher were observed, and the maximum tolerated dose was therefore not achieved. The serum concentration of soluble vascular endothelial growth factor receptor 2 decreased significantly after elpamotide vaccination. Microarray analysis of gene expression in PBMCs indicated that several pathways related to T cell function and angiogenesis were affected by elpamotide vaccination, supporting the notion that this peptide induces an immune response that targets angiogenesis in the clinical setting. In conclusion, elpamotide is well tolerated and our biomarker analysis indicates that this anti‐angiogenic vaccine is biologically active. Clinical trial registration no. UMIN000008336.
Importance of direct macrophage ‐ Tumor cell interaction on progression of human glioma
Authors: Komohara Yoshihiro , Horlad Hasita , Ohnishi Koji , Fujiwara Yukio , Bai Bing , Nakagawa Takenobu , Suzu Shinya , Nakamura Hideo , Kuratsu Jun‐ichi , Takeya Motohiro
Published: September 2012

We previously showed tumor‐associated macrophages/microglia (TAMs) polarized to the M2 phenotype were significantly involved in tumor cell proliferation and poor clinical prognosis in patients with high grade gliomas. However, the detailed molecular mechanisms involved in the interaction between TAMs and tumor cells have been unclear. Current results reveal that, in coculture with human macrophages, BrdU incorporation was significantly elevated in glioma cells, and signal transducer and activator of transcription‐3 (Stat3) activation was found in both cell types. Direct mixed coculture led to stronger Stat3 activation in tumor cells than did indirect separate coculture in Transwell chamber dishes. Screening with an array kit for phospho‐receptor tyrosine kinases revealed that phosphorylation of macrophage‐colony stimulating factor receptor (M‐CSFR, CD115, or c‐fms) is possibly involved in this cell–cell interaction; M‐CSFR activation was detected in both cell types. Coculture‐induced tumor cell activation was suppressed by siRNA‐mediated downregulation of the M‐CSFR in macrophages and by an inhibitor of M‐CSFR (GW2580). Immunohistochemical analysis of phosphorylated (p)M‐CSFR, pStat3, M‐CSF, M2 ratio, and MIB‐1(%) in high grade gliomas revealed that higher staining of pM‐CSFR in tumor cells was significantly associated with higher M‐CSF expression and higher MIB‐1(%). Higher staining of pStat3 was associated with higher MIB‐1(%). High M2 ratios were closely correlated with high MIB‐1(%) and poor clinical prognosis. Targeting these molecules or deactivating M2 macrophages might be useful therapeutic strategies for high grade glioma patients.
REG4 contributes to the invasiveness of pancreatic cancer by upregulating MMP‐7 and MMP‐9
Authors: He Xu‐Jun , Jiang Xiao‐Ting , Ma Ying‐Yu , Xia Ying‐Jie , Wang Hui‐Ju , Guan Tian‐Pei , Shao Qin‐Shu , Tao Hou‐Quan
Published: September 2012

Recent studies have shown that overexpression of regenerating gene family member 4 (REG4) is associated with the initiation and progression of pancreatic cancer. In our study, we explored the role of REG4 in the invasion of pancreatic cancer. Real‐time PCR and Western blot analysis were used to determine REG4 expression in pancreatic cancer cell lines. An MTT assay was carried out to test the effect of REG4 on the growth of pancreatic cancer cells. The involvement of REG4 in cancer cell invasion was examined by Transwell invasion assay. Two MMPs, MMP‐7 and MMP‐9, were identified from a pool of candidate genes as being related to REG4‐induced cell invasion by PCR and Western blotting. Immunohistochemistry was used to confirm the correlation between REG4 and the two MMPs. High expression of REG4 was found in BXPC‐3 cells and its culture media. But in PANC‐1 and ASPC‐1 cell lines, REG4 expression levels were very low, and no detectable protein was found in the culture medium. The MTT and Transwell invasion assays showed that recombinant REG4 protein and BXPC‐3 conditioned media significantly promoted the proliferation and invasiveness of pancreatic cancer cells. It was also shown that MMP‐7 and MMP‐9 are upregulated by REG4 induction using real‐time PCR and Western blotting analysis. Immunohistochemical study further verified this result. In conclusion, REG4 promotes not only growth but also in vitro invasiveness of pancreatic cancer cells by upregulating MMP‐7 and MMP‐9.
Nuclear receptor coactivator RAC3 inhibits autophagy
Authors: Fernandez Larrosa Pablo Nicolas , Alvarado Cecilia Viviana , Rubio Maria Fernanda , Ruiz Grecco Marina , Micenmacher Sabrina , Martinez‐Noel Giselle Astrid , Panelo Laura , Costas Monica Alejandra
Published: September 2012

RAC3 is an oncogene naturally overexpressed in several tumors. Besides its role as coactivator, it can exert several protumoral cytoplasmic actions. Autophagy was found to act either as a tumor suppressor during the early stages of tumor development, or as a protector of the tumor cell in later stages under hypoxic conditions. We found that RAC3 overexpression inhibits autophagy when induced by starvation or rapamycin and involves RAC3 nuclear translocation‐dependent and ‐independent mechanisms. Moreover, hypoxia inhibits the RAC3 gene expression leading to the autophagy process, allowing tumor cells to survive until angiogenesis occurs. The interplay between RAC3, hypoxia, and autophagy could be an important mechanism for tumor progression and a good target for a future anticancer therapy.
Expression and roles of Wilms' tumor 1‐associating protein in glioblastoma
Authors: Jin Du‐Il , Lee Sang Weon , Han Myoung‐Eun , Kim Hyun‐Jung , Seo Seon‐Ae , Hur Gi‐Yeong , Jung Shin , Kim Bong‐Seon , Oh Sae‐Ock
Published: September 2012

Glioblastoma is a diffusely growing malignant brain tumor and among the most aggressive of all tumors. Wilms' tumor 1‐associating protein (WTAP) is a nuclear protein that has been associated with regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, those in other cells are largely unknown. Here, we show for the first time that WTAP is overexpressed in glioblastoma. Moreover we found that WTAP regulates migration and invasion of glioblatoma cells. Specific knockdown by siRNA or overexpression by cDNA regulated migration and invasion of cancer cells. In xenograft study, WTAP overexpression made cancer cells more tumorigenic. In the investigation for its underlying mechanism, we found that the activity of epidermal growth factor receptor can be regulated by WTAP. These results reveal a novel function of WTAP and suggest its clinical application.
Synthesis and Anti‐HIV Properties of New Carbamate Prodrugs of AZT
Authors: Solyev Pavel N. , Shipitsin Alexander V. , Karpenko Inna L. , Nosik Dmitry N. , Kalnina Ludmila B. , Kochetkov Sergey N. , Kukhanova Marina K. , Jasko Maxim V.
Published: September 2012

A series of new 5′‐O‐carbamate prodrugs of AZT have been prepared. The stability in biological media, anti‐HIV properties and pharmacokinetic parameters in dogs were evaluated. The compounds display moderate anti‐HIV activity in cell culture. After oral administration of carbamate IV in dogs, both intact prodrug IV and released AZT were discovered in dog blood. Pharmacokinetic parameters of the compound IV were estimated. Half‐life (T1/2) of AZT released after oral administration of IV in dogs was close to that after administration of AZT itself, and time to the maximum concentration (Tmax) of AZT released from IV was two and three times longer compared with that of AZT and H‐phosphonate AZT, respectively. Acute toxicity was more than five times less if compared with AZT. As a result, we consider this series of carbamate derivatives of AZT as perspective for development of anti‐HIV agents.
A randomized, controlled trial of narrow‐band imaging vs high‐definition white light for adenoma detection in patients at high risk of adenomas
Authors: East J. E. , Ignjatovic A. , Suzuki N. , Guenther T. , Bassett P. , Tekkis P. P. , Saunders B. P.
Published: September 2012

Aim  The study aimed to investigate whether narrow‐band imaging (NBI) can enhance adenoma detection in patients at high risk for adenomas compared with high‐definition white‐light endoscopy (WLE). High risk was defined as three or more adenomas at last colonoscopy, history of colorectal cancer and positive faecal occult blood test.

Method  Two hundred and fourteen patients were randomized 1:1 to examination with NBI or WLE. The primary outcome measure was the proportion of patients with at least one adenoma detected. Secondary outcomes included total adenomas and polyps, flat adenomas, nonadenomatous polyps, advanced adenomas and patients with three or five or more adenomas. A post hoc analysis to examine the effect of endoscopist and bowel preparation was performed.

Results  There was no significant difference in the proportion of patients with at least one adenoma: NBI 73%vs WLE 66%, odds ratio 1.40 (95% CI 0.78–2.52), P = 0.26. There was no significant difference for any secondary outcome measure except for the number of flat adenomas which was significantly greater with NBI [comparison ratio 2.66 (95% CI 1.52–4.63), P = 0.001]. Post hoc analysis indicated that one of three endoscopists performed significantly better for adenoma detection with NBI than WLE [comparison ratio 1.92 (95% CI 1.07–3.44), P = 0.03]. Good bowel preparation was associated with significantly improved adenoma detection with NBI [comparison ratio 1.55 (95% CI 1.01–2.22), P = 0.04] but not with fair preparation.

Conclusion  Overall NBI did not improve detection compared with WLE in a group of patients at high risk for colorectal adenomas, but specific subgroups might benefit.
Public opinion of organ donation: a survey in Iran
Authors: Broumand Mohammadali , Parsapoor Alireza , Asghari Fariba
Published: September 2012

Introduction

The objective of this study was to assess the views of Tehran citizens in regard to donating their organs in case of brain death.

Methods

In this cross‐sectional study, conducted between February 2009 and November 2010, two interviewers contacted 1379 people through random digit dialing for phone interviews. Phone calls were made between 6 and 9 pmon a workday, and those reaching companies or organizations were excluded. The interviewee was selected randomly from among the household members, and those 18 yr and older were included in the study.

Results

Of the 1379 people eligible for entering the study, 706 consented to have the interview (response rate = 51%). Among the respondents, 84.6% were willing to donate. Of these, 94.6% were willing to complete a donor card as well, but only 10.7% of them already had one.

Conclusion

There should be simple processes for the public to declare their decision about organ donation in case of brain death. People should be encouraged to communicate their wishes with others so that family members can decide about their organ donation more easily.
Effects of the dual PPAR‐α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat
Authors: Bénardeau A. , Verry P. , Atzpodien E.‐A. , Funk J. M. , Meyer M. , Mizrahi J. , Winter M. , Wright M. B. , Uhles S. , Sebokova E.
Published: September 2012

Aims

To evaluate the effects of aleglitazar, a dual peroxisome proliferator‐activated receptor‐α/γ agonist, on the development of diabetes‐related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats.

Methods

Six‐week‐old, male ZDF rats received aleglitazar 0.3 mg/kg/day or vehicle as food admix for 13 weeks (n = 10 per group). Age‐matched male Zucker lean rats served as non‐diabetic controls. Plasma and renal markers were measured at several time points. Histopathology and quantitative immunohistochemistry were performed at 13 weeks.

Results

Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3 ± 0.3 vs. 26.1 ± 1.0 mmol/l) were significantly reduced at 12 weeks with aleglitazar versus vehicle‐treated ZDF rats (both p < 0.01), while aleglitazar preserved near‐normal plasma insulin levels. Aleglitazar prevented the development of hypertriglyceridaemia (1.4 ± 0.1 vs. 8.5 ± 0.9 mmol/l) and reduced plasma non‐esterified fatty acids (0.09 ± 0.02 vs. 0.26 ± 0.04 mmol/l) relative to vehicle‐treated animals (both p < 0.01). Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar versus vehicle‐treated rats (both p < 0.01). Consistent with its effect on glycaemic control, aleglitazar protected β‐cell morphology, as evidenced by preservation of islet integrity, and reduction of β‐cell apoptosis and islet fibrosis. Aleglitazar prevented renal glomerular hypertrophy, podocyte degeneration, glomerulosclerosis, tubulo‐interstitial lesions and development of cataracts.

Conclusions

Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes‐associated structural and functional changes in the ZDF rat.
KH902 suppresses high glucose‐induced migration and sprouting of human retinal endothelial cells by blocking VEGF and PIGF
Authors: Chen X. , Li J. , Li M. , Zeng M. , Li T. , Xiao W. , Li J. , Wu Q. , Ke X. , Luo D. , Tang S. , Luo Y.
Published: September 2012

Aims

Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are upregulated in many ocular neovascular diseases such as diabetic retinopathy (DR). KH902 is a recombinant fusion protein with its binding ligand taken from the domains of VEGF receptor‐1 (VEGFR‐1) and VEGF receptor‐2 (VEGFR‐2) and can bind all VEGF‐A isoforms and PlGF. The aim of this study was to investigate the underlying mechanisms of anti‐angiogenic effects of KH902.

Methods

The toxic effect of KH902 on cultured human retinal endothelial cells (HRECs) was measured by Annexin V/PI staining and MTT assay. The concentrations of secreted VEGF and PlGF were measured by ELISA. The migration of HRECs was assessed by scratch wound and transwell assay. The sprouting of HRECs was determined by tube formation assay. The protein levels of Src, p‐Src, PI3K, Akt1, p‐Akt1, Erk1/2 and p‐Erk1/2 were measured by Western blot.

Results

KH902 at the concentrations from 100 ng/ml to 100 µg/ml had no cytotoxicity to cultured HRECs. KH902 bound not only VEGF165, but also PlGF that were secreted by HRECs under high glucose condition. A 500 ng/ml of KH902 significantly suppressed high glucose‐induced migration and sprouting of HRECs through downregulating the expression of PI3K and inhibiting the activation of Src, Akt1 and Erk1/2.

Conclusion

Our study indicates that KH902 suppresses high glucose‐induced migration and sprouting of HRECs through not only binding VEGF, but also PlGF to inhibit the activation of Src‐Akt1‐Erk1/2 pathway. KH902 is a drug that potentially inhibits angiogenic pathways involving in DR or other ocular neovascular diseases.
Efficacy and tolerability of taspoglutide versus pioglitazone in subjects with type 2 diabetes uncontrolled with sulphonylurea or sulphonylurea‐metformin therapy: a randomized, double‐blind study (T‐emerge 6)
Authors: Pratley R. E. , Urosevic D. , Boldrin M. , Balena R. ,   for the T‐emerge 6 Study Group
Published: September 2012

Aims

This study compared the efficacy and tolerability of taspoglutide versus pioglitazone in subjects with type 2 diabetes inadequately controlled with sulphonylurea ± metformin.

Methods

In this double‐blind, double‐dummy, parallel‐group trial, 760 subjects (49% male, age 56.4 years, diabetes duration 8.8 years, body mass index 32.7 kg/m2 and haemoglobin A1c [HbA1c] 8.3%) were randomized (1 : 1 : 1) to subcutaneous injections of taspoglutide 10 or 20 mg once weekly or oral pioglitazone 45 mg daily. The primary endpoint was change in HbA1c after 24 weeks.

Results

Mean (±s.e.) HbA1c reductions with taspoglutide 10 (−1.18 ± 0.08%) and 20 mg (−1.36 ± 0.08%) were non‐inferior to pioglitazone (−1.30 ± 0.08%) (p = 0.21 and 0.37, respectively); mean treatment differences were 0.12 (95% confidence interval: −0.03, –0.26) and −0.06 (−0.20, 0.08) for taspoglutide 10 and 20 mg versus pioglitazone. Mean (±s.e.) changes in body weight (kg) were −0.8 ± 0.3, −1.0 ± 0.3 and 3.6 ± 0.3 for taspoglutide 10 and 20 mg and pioglitazone, respectively; 8, 11 and 1% of patients achieved ≥5% weight loss. A higher incidence of adverse events (AEs) occurred with taspoglutide, predominantly gastrointestinal disturbances and injection‐site reactions, resulting in higher rates of discontinuation versus pioglitazone. No treatment differences in serious AEs were observed.

Conclusions

Taspoglutide offered good glycaemic control similar to pioglitazone, while achieving beneficial weight loss rather than weight gain, but was associated with more AEs. Due to the higher than expected discontinuation rates, mainly because of gastrointestinal intolerability, the taspoglutide clinical programme was stopped.
Shared influence of pathogen and host genetics on a trade‐off between latent period and spore production capacity in the wheat pathogen, Puccinia triticina
Authors: Pariaud Bénédicte , van den Berg Femke , van den Bosch Frank , Powers Stephen J. , Kaltz Oliver , Lannou Christian
Published: September 2012

Crop pathogens are notorious for their rapid adaptation to their host. We still know little about the evolution of their life cycles and whether there might be trade‐offs between fitness components, limiting the evolutionary potential of these pathogens. In this study, we explored a trade‐off between spore production capacity and latent period in Puccinia triticina, a fungal pathogen causing leaf rust on wheat. Using a simple multivariate (manova) technique, we showed that the covariance between the two traits is under shared control of host and pathogen, with contributions from host genotype (57%), pathogen genotype (18.4%) and genotype × genotype interactions (12.5%). We also found variation in sign and strength of genetic correlations for the pathogen, when measured on different host varieties. Our results suggest that these important pathogen life‐history traits do not freely respond to directional selection and that precise evolutionary trajectories are contingent on the genetic identity of the interacting host and pathogen.
Epidermal morphogenesis during progressive in vitro 3D reconstruction at the air–liquid interface
Authors: Frankart Aurélie , Malaisse Jérémy , De Vuyst Evelyne , Minner Frédéric , de Rouvroit Catherine Lambert , Poumay Yves
Published: September 2012

Keratinocyte monolayers, cultured in immersed conditions, constitute a frequently used in vitro model system to study keratinocytes behaviour in response to environmental assaults. However, monolayers lack the keratinocyte terminal differentiation and the organization of the epidermal tissue, which are observed in vivo. Advancements of in vitro techniques were used to reconstruct three‐dimensional equivalents that mimic human epidermis in terms of layering, differentiation and barrier function. Here, we update a published method and illustrate the progressive morphogenesis responsible for in vitro reconstruction. The analysis of cell proliferation, expression of differentiation markers and barrier efficacy demonstrate the excellent similarity of the reconstructed tissue with normal human epidermis. Availability of epidermal tissue during its reconstruction phase in culture appears crucial for studies intending to challenge the barrier function.
Androgen actions on the human hair follicle: perspectives
Authors: Inui Shigeki , Itami Satoshi
Published: September 2012

Androgens stimulate beard growth but suppress hair growth in androgenetic alopecia (AGA). This condition is known as ‘androgen paradox’. Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone. In hair follicles, 5α‐reductase type 1 and 2, androgen receptors (AR) and AR coactivators can regulate androgen sensitivity of dermal papillae (DP). To regulate hair growth, androgens stimulate production of IGF‐1 as positive mediators from beard DP cells and of TGF‐β1, TGF‐β2, dickkopf1 and IL‐6 as negative mediators from balding DP cells. In addition, androgens enhance inducible nitric oxide synthase from occipital DP cells and stem cell factor for positive regulation of hair growth in beard and negative regulation of balding DP cells. Moreover, AGA involves crosstalk between androgen and Wnt/β‐catenin signalling. Finally, recent data on susceptibility genes have provided us with the impetus to investigate the molecular pathogenesis of AGA.
A rising tide of blue‐absorbing biliprotein photoreceptors – characterization of seven such bilin‐binding GAF domains in Nostoc sp. PCC7120
Authors: Ma Qiong , Hua Huan‐Huan , Chen Yu , Liu Bin‐Bin , Krämer Anna Laura , Scheer Hugo , Zhao Kai‐Hong , Zhou Ming
Published: September 2012

Cyanobacteriochromes are photochromic sensory photoreceptors in cyanobacteria that are related to phytochromes but cover a much broader spectral range. Using a homology search, a group of putative blue‐absorbing photoreceptors was identified in Nostoc sp. PCC 7120 that, in addition to the canonical chromophore‐binding cysteine of cyanobacteriochromes, have a conserved extra cysteine in a DXCF motif. To assess their photochemical activities, putative chromophore‐binding GAF domains were expressed in Escherichia coli together with the genes for phycocyanobilin biosynthesis. All except one covalently bound a chromophore and showed photoreversible photochromic responses, with absorption at approximately 420 nm for the 15Z states formed in the dark, and a variety of red‐shifted absorption peaks in the 490–600 nm range for the 15E states formed after light activation. Under denaturing conditions, the covalently bound chromophores were identified as phycocyanobilin, phycoviolobilin or mixtures of both. The canonical cysteines and those of the DXCF motifs were mutated, singly or together. The canonical cysteine is responsible for stable covalent attachment of the bilin to the apo‐protein at C31. The second linkage from the cysteine in the DXCF motif, probably to C10 of the chromophore, yields blue‐absorbing rubin‐type 15Z chromophores, but is lost in most cases upon photoconversion to the 15E isomers of the chromophores, and also when denatured with acidic urea.
A plant's perspective of extremes: terrestrial plant responses to changing climatic variability
Authors: Reyer Christopher P.O. , Leuzinger Sebastian , Rammig Anja , Wolf Annett , Bartholomeus Ruud P. , Bonfante Antonello , de Lorenzi Francesca , Dury Marie , Gloning Philipp , Abou Jaoudé Renée , Klein Tamir , Kuster Thomas M. , Martins Monica , Niedrist Georg , Riccardi Maria , Wohlfahrt Georg , de Angelis Paolo , de Dato Giovanbattista , François Louis , Menzel Annette , Pereira Marízia
Published: September 2012

We review observational, experimental, and model results on how plants respond to extreme climatic conditions induced by changing climatic variability. Distinguishing between impacts of changing mean climatic conditions and changing climatic variability on terrestrial ecosystems is generally underrated in current studies. The goals of our review are thus (1) to identify plant processes that are vulnerable to changes in the variability of climatic variables rather than to changes in their mean, and (2) to depict/evaluate available study designs to quantify responses of plants to changing climatic variability. We find that phenology is largely affected by changing mean climate but also that impacts of climatic variability are much less studied, although potentially damaging. We note that plant water relations seem to be very vulnerable to extremes driven by changes in temperature and precipitation and that heatwaves and flooding have stronger impacts on physiological processes than changing mean climate. Moreover, interacting phenological and physiological processes are likely to further complicate plant responses to changing climatic variability. Phenological and physiological processes and their interactions culminate in even more sophisticated responses to changing mean climate and climatic variability at the species and community level. Generally, observational studies are well suited to study plant responses to changing mean climate, but less suitable to gain a mechanistic understanding of plant responses to climatic variability. Experiments seem best suited to simulate extreme events. In models, temporal resolution and model structure are crucial to capture plant responses to changing climatic variability. We highlight that a combination of experimental, observational, and/or modeling studies have the potential to overcome important caveats of the respective individual approaches.
Widespread decreases in topsoil inorganic carbon stocks across China's grasslands during 1980s–2000s
Authors: Yang Yuanhe , Fang Jingyun , Ji Chengjun , Ma Wenhong , Mohammat Anwar , Wang Shifeng , Wang Shaopeng , Datta Arindam , Robinson David , Smith Pete
Published: September 2012

Soil carbon (C) stocks consist of inorganic and organic components, ~1.7 times larger than the total of the C stored in vegetation and the atmosphere together. Significant soil C losses could thus offset any C sink in vegetation, creating a positive feedback to climate change. However, compared with the susceptible sensitivity of organic matter decay to climate warming, soil inorganic carbon (SIC) stocks are often assumed to be relatively stable. Here, we evaluated SIC changes across China's grasslands over the last two decades using data from a recent regional soil survey during 2001–2005 and historical national soil inventory during the 1980s. Our results showed that SIC stocks in the top 10 cm decreased significantly between the two sampling periods, with a mean rate of 26.8 (95% confidence interval: 15.8–41.7) g C m−2 yr−1. The larger decreases in SIC stocks were observed in those regions with stronger soil acidification and richer soil carbonates. The lost SIC could be released to the atmosphere as carbon dioxide, redistributed to the deeper soil layer, and transferred to the nearby regions. The fraction of soil carbonates entering into the atmosphere may diminish the strength of terrestrial C sequestration and amplify the positive C‐climate feedback.
F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort
Authors: Schwarz J. , Astermark J. , Menius E. D. , Carrington M. , Donfield S. M. , Gomperts E. D. , Nelson G. W. , Oldenburg J. , Pavlova A. , Shapiro A. D. , Winkler C. A. , Berntorp E. ,   from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort
Published: September 2012

Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
HLA‐A, ‐B, ‐DR allele group frequencies in 7007 kidney transplant list patients in 27 UK centres
Authors: Burt C. , Cryer C. , Fuggle S. , Little A.‐M. , Dyer P.
Published: September 2012

This observational study aims to determine the HLA specificity frequencies of patients on the UK renal transplant list, which can be used as a resource for those laboratories that support the UK renal transplant programme. Whilst the HLA specificity frequencies may differ from that of the general population, it is the individuals on the transplant list who are in need of a new kidney, which has to be provided from the general population. Any differences in protein allele frequencies between this patient population and the general population are likely to be minimal because of the very large number of patients included. The HLA‐A, ‐B and ‐DR allele group frequencies from 7007 patients on the UK kidney transplant list (August, 2009) were analysed. HLA types had been submitted to NHSBT to register patients on the UK deceased donor kidney waiting list. The data were submitted from 27 different registering centres throughout the UK. Within this data set, 25 different HLA‐A, 50 HLA‐B and 18 HLA‐DR allele groups were present. The most common allele groups at each locus were ‐A2 (phenotype frequency 42.6%), ‐B44 (phenotype frequency 23.3%) and –DR4 (phenotype frequency 29.8%). The least common allele groups at each locus were ‐A19, ‐ A43, ‐B16, ‐B21, ‐B22, ‐B83 and ‐DR5. Reports of HLA frequency (protein allotype) data from populations as large as this are not readily available adding value to this observational study.
Measuring water‐borne cortisol in Poecilia latipinna:is the process stressful, can stress be minimized and is cortisol correlated with sex steroid release rates?
Authors: Gabor C. R. , Contreras A.
Published: September 2012

The stress of water‐borne hormone collection process was examined in sailfin mollies Poecilia latipinna. Baseline release rates of the stress hormone cortisol were measured and minimum confinement time for water sampling was evaluated for a standard 60 min v. a 30 min protocol. A 30 min hormone collection period reflects release rates over 60 min. Potential stress response to confinement in the beaker for the water‐borne collection process was tested over 4 days. There was no evidence of stress due to the collection methods, as cortisol release rates did not differ significantly across four sequential days of handling for P. latipinna. Males and females did not differ significantly in baseline cortisol release rates. Baseline cortisol release rates from fish immediately after being collected in the field were also not significantly different than those in the 4 day confinement experiment. After exposure to a novel environment, however, P. latipinna mounted a stress response. Stress may also affect sex steroids and behaviour but cortisol release rates were not significantly correlated with sex steroids [11‐ketotestosterone (KT), testosterone, or oestradiol], or mating attempts. The correlation between water‐borne release rates and plasma steroid levels was validated for both cortisol and KT. Finally, normalizing cortisol release rates using standard length in lieu of mass is viable and accurate. Water‐borne hormone assays are a valuable tool for investigating questions concerning the role of hormones in mediating stress responses and reproductive behaviours in P. latipinna and other livebearing fishes.
The blood chemical status of Atlantic cod Gadus morhua following capture by jig and demersal longline with differential hook removal methods
Authors: Mandelman J. W. , Morrison R. A. , Cavin J. M. , Farrington M. A.
Published: September 2012

Common haematological [haematocrit (Hct)], primary (serum cortisol) and secondary (serum glucose and plasma lactate) analytes were utilized to compare blood biochemical status of Gadus morhua captured rapidly by jig with that of G. morhua captured by commercial demersal longline. In general, the physiological status of G. morhua, despite blind hook times, was significantly more disrupted (pronounced haemo‐concentration and significantly elevated concentrations of cortisol, glucose and lactate) following longline capture relative to capture by jig, while no differences were detected among longline‐caught fish as a function of dehooking method (or concomitant extent of overt physical trauma). Blood profiles from the more stressed G. morhua, a possible function of more extended longline hook times, were similar to the most stressed values reported for this species. The results also demonstrate that, although acute blood biochemical status is an effective gauge of relative stress, it does not reflect physical injury status, which has been shown to exert a strong influence on delayed mortality in previous studies in this species. Thus, acute blood chemical status alone may not be the most complete predictor of mortality. Future studies should evaluate physiological repercussions from capture–handling against physical trauma during more extended post‐release periods for this species.
Diel dualism in the energy consumption of the European catfish Silurus glanis
Authors: Slavík O. , Horký P.
Published: September 2012

Twenty individuals of the largest European freshwater predator, the European catfish Silurus glanis, were tagged with electromyogram (EMG) physiological telemetry sensors. The fish were observed during diel cycles during the spring and summer in the Elbe and Berounka Rivers, Czech Republic. The purpose of this study was to determine whether diel dualism in the activity of S. glanis occurs naturally or is induced by the laboratory environment and by the conditions occurring in aquaculture. The results obtained from the riverine environment tended to show dualism in the use of the light and dark phases of the day because 35% of the individuals varied from a site‐specific common diel activity pattern. The EMG values increased in accordance with the mass (M) of the fish. To eliminate the influence of M on individual energy consumption, the EMG records were analysed in terms of the EMG:M ratios. High individual variability was found in these ratios. The diel activity pattern of the individuals with relatively high energy consumption differed from the common diel activity pattern. In contrast, the fish that adopted the common diel activity pattern displayed relatively low energy consumption. The results of this study indicated that dualism and energy consumption are related. The EMG values also varied with the values of the environmental variables. Increasing temperature was associated with high EMG values, whereas the EMG values decreased with increasing flow.
A phylogenetic analysis of relationships among genera of Conopidae (Diptera) based on molecular and morphological data
Authors: Gibson Joel F. , Skevington Jeffrey H. , Kelso Scott
Published: September 2012

Members of the family Conopidae (Diptera) have been the focus of little targeted phylogenetic research. The most comprehensive test of phylogenetic support for the present subfamily classification of Conopidae is presented here using 66 specimens, including 59 species of Conopidae and seven outgroup taxa. Relationships among subfamily clades are also explored. A total of 6824 bp of DNA sequence data from five gene regions (12S ribosomal DNA, cytochrome c oxidase subunit I, cytochrome b, 28S ribosomal DNA and alanyl‐tRNA synthetase) are combined with 111 morphological characters in a combined analysis using both parsimony and Bayesian methods. Parsimony analysis recovers three shortest trees. Bayesian analysis recovers a nearly identical tree. Five monophyletic subfamilies of Conopidae are recovered. The rarely acknowledged Zodioninae is restored, including the genera Zodion and Parazodion. The genus Sicus is removed from Myopinae. Morphological synapomorphies are discussed for each subfamily and inter‐subfamily clade, including a comprehensive review of the character interpretaions of previous authors. Included are detailed comparative illustrations of male and female genitalia of representatives of all five subfamilies with new morphological interpretation.
Effect of blueberry juice on clearance of buspirone and flurbiprofen in human volunteers
Authors: Hanley Michael J. , Masse Gina , Harmatz Jerold S. , Cancalon Paul F. , Dolnikowski Gregory G. , Court Michael H. , Greenblatt David J.
Published: September 2012

Aim

The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9).

Methods

A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co‐treatment with BBJ.

Results

BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50) of less than 2%, but without evidence of mechanism‐based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre‐incubation, consistent with mechanism‐based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration−time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03).

Conclusion

The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9.
Extracellular factors and immunosuppressive drugs influencing insulin secretion of murine islets
Authors: Auer V J , Janas E , Ninichuk V , Eppler E , Weiss T S , Kirchner S , Otto A M , Stangl M J
Published: September 2012

Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will contribute to an improved clinical outcome of islet transplantations. In this study, functional activity of isolated murine islets was measured by glucose-stimulated insulin secretion (GSIS) and by electrophysiological measurements using patch-clamp. Cultivating islets with soluble fibronectin or laminin, as opposed to with coated laminin, markedly increased GSIS. Addition of cyclosporin A reduced GSIS and suppressed glucose-induced spike activity. Tacrolimus affected neither GSIS nor spike activity, indicating a different mechanism. To evaluate the influence of proinflammatory cytokines, islets were incubated with interleukin (IL)-1β, tumour necrosis factor (TNF)-α or with supernatants from cultured Kupffer cells, the main mediators of inflammation in the hepatic sinusoids. IL-1β exerted a bimodal effect on insulin secretion, stimulating below 2 ng/ml and suppressing above 10 ng/ml. Soluble laminin in combination with a stimulatory IL-1β concentration further increased insulin secretion by 20% compared to IL-1β alone, while with high IL-1β concentrations soluble laminin slightly attenuated GSIS inhibition. TNF-α alone did not affect GSIS, but with stimulatory IL-1β concentrations completely abolished it. Similarly, supernatants derived from Kupffer cells exerted a bimodal effect on GSIS. Our data suggest that improved insulin secretion of transplanted islets could be achieved by including soluble laminin and low IL-1β concentrations in the islet cultivation medium, and by a simultaneous inhibition of cytokine secretion from Kupffer cells.
Time‐contingent pacing and exercise therapy accounting for postexertional malaise and central sensitization in chronic fatigue (central sensitivity) syndrome
Authors: Nijs Jo , Van Cauwenbergh Deborah , De Kooning Margot , Ickmans Kelly
Published: September 2012

Eur J Clin Invest 2012; 42 (12): 1363–1365
Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics
Authors: Haenisch Britta , Nöthen Markus M. , Molderings Gerhard J.
Published: September 2012

Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease‐associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized.
The relationship between the levels of nurses’ competence and the length of their clinical experience: a tentative model for nursing competence development
Authors: Takase Miyuki
Published: September 2012

Aims and objectives.  To explore the relationship between the levels of nurses’ competence and the length of their clinical experience, in order to provide a tentative model of the continuing competence of nurses.

Background.  The professional development of employees has attracted great interest. This interest has led to the development of various models that illustrate how employees develop their competence throughout their careers. However, little is known of how nurses maintain and develop their competence throughout their career pathways.

Design.  A cross‐sectional design was used.

Methods.  Using a survey method, five dimensions of self‐assessed nursing competence and the length of the nurses’ clinical practice were measured (n = 325). Each dimension of competence was plotted against the length of their clinical experience using locally weighted scatterplot smoothing. Then, the shapes of the plots were analysed by fractional polynomial regression analysis.

Results.  Overall, the relationships between the levels of nursing competence and the length of clinical experience were illustrated by curves with a rapid increase in competence levels at the early stage of the nursing career and a slower increase later. These curves were modelled by either a logarithmic, square‐root function or its reciprocal. The results supported the learning curve model.

Conclusions.  The competence development of nurses may be characterised by two distinctive periods: a rapid growth period followed by stable periods. However, the modality of the growth may be different depending on which dimension of nursing competence is in focus.

Relevance to clinical practice.  The level of nursing competence directly affects the quality of care provided to patients. The findings of the study enable healthcare organisations to take proactive approaches to enhance nurses’ competence by identifying when and how to assist nurses.
The reported expression of pain and distress by people with an intellectual disability
Authors: McKenzie Karen , Smith Marion , Purcell Ann‐Marie
Published: September 2012

Aims and objectives.  To explore the assumption that people with ID are unable to communicate effectively about pain by examining the extent to which they were reported as using language and behaviour that was readily understandable to others to communicate pain as distinct from distress.

Background.  The healthcare needs of people with an intellectual disability (ID) are frequently overlooked or dealt with inappropriately. One proposed reason is the difficulty that such individuals have in communicating about their pain.

Design.  A postal questionnaire‐based mixed method design was used.

Methods.  Data from carer reports (n = 29) of the ways people with ID supported expressed pain and distress were categorised and analysed using descriptive statistics and thematic content analysis.

Results.  Nineteen of the 22 people who used verbal communication were reported to express pain using words that would be understandable to someone else, often accompanied by behavioural indications of the location of the pain. The language and behaviour that were reported as being used to express distress was more idiosyncratic, and there was little overlap between this and the ways in which pain was expressed.

Conclusion.  The results provide some challenges to the view that people with ID are necessarily unable to communicate effectively about their pain and support the view that pain and distress can be conceptually distinguished and differentially communicated by some people with ID.

Relevance to clinical practice.  The results suggest that many people with ID can be active participants in describing their experience of pain and that nurses should attempt to obtain this information directly from the individual during the diagnostic process. Nurses should be mindful of the distinction between pain and distress and should not respond to signs of distress in this group as being indicative of pain, without carrying out further assessment.
HRTEM of 1DSnTe@SWNT nanocomposite located on thin layers of graphite
Authors: KUMSKOV A.S. , ELISEEV A.A. , FREITAG B. , KISELEV N.A.
Published: September 2012

The method for imaging of highly sensitive nanostructures unstable under electron beam irradiation is introduced. To reduce charge and thermally generated beam damage, highly conductive multilayered graphene or thin graphite layers were used as supports for nanostructures. Well‐defined crystalline structure of graphite layers enables image reconstruction by Fourier filtering and allows maintaining high quality of images. The approach was tested for imaging of highly sensitive quasi one‐dimensional SnTe nanocrystals hosted inside single‐walled carbon nanotubes. Relying on the filtered images and the image simulation, the structure of one‐dimensional SnTe was established as a chain of fcc NaCl type unit cells, connected by the [001] edges with <110> direction coinciding with nanotube axis.