bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and pharmacodynamics of PF‐05231023, a novel long‐acting FGF21 mimetic, in a first‐in‐human study
Authors: Dong Jennifer Q. , Rossulek Michelle , Somayaji Veena R. , Baltrukonis Daniel , Liang Yali , Hudson Krischan , Hernandez‐Illas Martha , Calle Roberto A.
Published: May 2015

Aims

The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF‐05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).

Methods

T2DM subjects (glycosylated haemoglobin: 7.0–10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF‐05231023 (0.5–200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride – an early marker of drug activity.

Results

No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF‐05231023 levels peaked immediately post‐IV dosing, with mean terminal half‐lives of 6.5–7.7 h and 66.5– 96.6 h for intact C‐ and N‐termini, respectively. Intact C‐terminus exposures increased proportionally with increasing dose, whereas N‐terminus exposures appeared to trend higher than dose‐proportionally. Although no apparent effect on plasma glucose was seen, dose‐dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low‐density lipoprotein cholesterol and an increase in high‐density lipoprotein cholesterol were observed in the high‐dose groups.

Conclusions

Single IV doses of PF‐05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF‐05231023 upon repeated administration.
Impact of visceral leishmaniasis and curative chemotherapy on cytochrome P450 activity in Brazilian patients
Authors: Lanchote Vera Lucia , Almeida Roque , Barral Aldina , Barral‐Netto Manoel , Marques Maria Paula , Moraes Natália V. , da Silva Angela M. , Souza Tania M. V. , Suarez‐Kurtz Guilherme
Published: May 2015

Aims

The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil.

Methods

Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2–3 days (phase 2) and 3–6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5‐hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9).

Results

Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10–1.31), 1.45 (1.32–1.57) and 1.35 (1.26–1.44) ml min–1 kg–1; omeprazole/5‐hydroxyomeprazole ratio, 0.78 (0.61–0.94), 0.45 (0.27–0.63) and 0.37 (0.20‐0.55); losartan/E3174 ratio, 0.66 (0.39–0.92), 0.35 (0.20–0.50) and 0.35 (0.16–0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases.

Conclusion

The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post‐chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed.
Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3‐kinase / ERK–MMP–laminin5γ2 signaling pathway
Authors: Liu Xiao , Wang Ji‐Hui , Li Shun , Li Lin‐Lin , Huang Min , Zhang Yong‐Hong , Liu Yang , Yang Yuan‐Tao , Ding Rui , Ke Yi‐Quan
Published: May 2015

Vasculogenic mimicry (VM) refers to the process by which highly aggressive tumor cells mimic endothelial cells to form vessel‐like structures that aid in supplying enough nutrients to rapidly growing tumors. Histone deacetylases (HDACs) regulate the expression and activity of numerous molecules involved in cancer initiation and progression. Notably, HDAC3 is overexpressed in the majority of carcinomas. However, thus far, no data are available to support the role of HDAC3 in VM. In this study, we subjected glioma specimens to immunohistochemical and histochemical double‐staining methods and found that VM and HDAC3 expression were related to the pathological grade of gliomas. The presence of VM correlated with HDAC3 expression in glioma tissues. The formation of tubular structures, as determined by the tube formation assay to evaluate VM, was impaired in U87MG cells when transfected by siRNA or treated with an HDAC3 inhibitor. Importantly, the expression of VM‐related molecules such as MMP‐2/14 and laminin5γ2 was also affected when HDAC3 expression was altered. Furthermore, U87MG cells were treated with a phosphoinositide 3‐kinase (PI3K) inhibitor or/and ERK inhibitor and found that the PI3K and ERK signaling pathways play key roles in VM; whereas, in VM, the two signaling pathways did not act upstream or downstream from each other. Taken together, our findings showed that HDAC3 contributed to VM in gliomas, possibly through the PI3K/ERK–MMPs–laminin5γ2 signaling pathway, which could potentially be a novel therapeutic target for gliomas.
Mammary tissue microenvironment determines T cell‐dependent breast cancer‐associated inflammation
Authors: Takahashi Kei , Nagai Nao , Ogura Keisuke , Tsuneyama Koichi , Saiki Ikuo , Irimura Tatsuro , Hayakawa Yoshihiro
Published: May 2015

Although the importance of the host tissue microenvironment in cancer progression and metastasis has been established, the spatiotemporal process establishing a cancer metastasis‐prone tissue microenvironment remains unknown. In this study, we aim to understand the immunological character of a metastasis‐prone microenvironment in a murine 4T1 breast tumor model, by using the activation of nuclear factor‐κb (NF‐κB) in cancer cells as a sensor of inflammatory status and by monitoring its activity by bioluminescence imaging. By using a 4T1 breast cancer cell line stably expressing an NF‐κB/Luc2 reporter gene (4T1 NF‐κB cells), we observed significantly increased bioluminescence approximately 7 days after metastasis‐prone orthotopic mammary fat‐pad inoculation but not ectopic s.c. inoculation of 4T1 NF‐κB cells. Such in vivo NF‐κB activation within the fat‐pad 4T1 tumor was diminished in immune‐deficient SCID or nude mice, or T cell‐depleted mice, suggesting the requirement of host T cell‐mediated immune responses. Given the fat‐pad 4T1 tumor expressed higher inflammatory mediators in a T cell‐dependent mechanism compared to the s.c. tumor, our results imply the importance of the surrounding tissue microenvironment for inflaming tumors by collaborating with T cells to instigate metastatic spread of 4T1 breast cancer cells.
Synergistic antiproliferative effect of imatinib and adriamycin in platelet‐derived growth factor receptor‐expressing osteosarcoma cells
Authors: Yamaguchi Sayaka I. , Ueki Arisa , Sugihara Eiji , Onishi Nobuyuki , Yaguchi Tomonori , Kawakami Yutaka , Horiuchi Keisuke , Morioka Hideo , Matsumoto Morio , Nakamura Masaya , Muto Akihiro , Toyama Yoshiaki , Saya Hideyuki , Shimizu Takatsune
Published: May 2015

Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme‐linked immunosorbent assay‐based screening of such mouse tumor lysates identified platelet‐derived growth factor–BB (PDGF‐BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non‐malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet‐derived growth factor‐BB induced activation of both MEK–ERK and phosphatidylinositol 3‐kinase–protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF‐BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.
Chemokine (C‐C motif) ligand 3 detection in the serum of persons exposed to asbestos: A patient‐based study
Authors: Xu Jiegou , Alexander David B. , Iigo Masaaki , Hamano Hirokazu , Takahashi Satoru , Yokoyama Takako , Kato Munehiro , Usami Ikuji , Tokuyama Takeshi , Tsutsumi Masahiro , Tamura Mouka , Oguri Tetsuya , Niimi Akio , Hayashi Yoshimitsu , Yokoyama Yoshifumi , Tonegawa Ken , Fukamachi Katsumi , Futakuchi Mitsuru , Sakai Yuto , Suzui Masumi , Kamijima Michihiro , Hisanaga Naomi , Omori Toyonori , Nakae Dai , Hirose Akihiko , Kanno Jun , Tsuda Hiroyuki
Published: May 2015

Exposure to asbestos results in serious risk of developing lung and mesothelial diseases. Currently, there are no biomarkers that can be used to diagnose asbestos exposure. The purpose of the present study was to determine whether the levels or detection rate of chemokine (C‐C motif) ligand 3 (CCL3) in the serum are elevated in persons exposed to asbestos. The primary study group consisted of 76 healthy subjects not exposed to asbestos and 172 healthy subjects possibly exposed to asbestos. The secondary study group consisted of 535 subjects possibly exposed to asbestos and diagnosed with pleural plaque (412), benign hydrothorax (10), asbestosis (86), lung cancer (17), and malignant mesothelioma (10). All study subjects who were possibly exposed to asbestos had a certificate of asbestos exposure issued by the Japanese Ministry of Health, Labour and Welfare. For the primary study group, levels of serum CCL3 did not differ between the two groups. However, the detection rate of CCL3 in the serum of healthy subjects possibly exposed to asbestos (30.2%) was significantly higher (P < 0.001) than for the control group (6.6%). The pleural plaque, benign hydrothorax, asbestosis, and lung cancer groups had serum CCL3 levels and detection rates similar to that of healthy subjects possibly exposed to asbestos. The CCL3 chemokine was detected in the serum of 9 of the 10 patients diagnosed with malignant mesothelioma. Three of the patients with malignant mesothelioma had exceptionally high CCL3 levels. Malignant mesothelioma cells from four biopsy cases and an autopsy case were positive for CCL3, possibly identifying the source of the CCL3 in the three malignant mesothelioma patients with exceptionally high serum CCL3 levels. In conclusion, a significantly higher percentage of healthy persons possibly exposed to asbestos had detectable levels of serum CCL3 compared to healthy unexposed control subjects.
Regulation of UHRF1 by microRNA‐9 modulates colorectal cancer cell proliferation and apoptosis
Authors: Zhu Mingchen , Xu Yijun , Ge Mengyuan , Gui Zhen , Yan Feng
Published: May 2015

The UHRF1 protein is pivotal for DNA methylation and heterochromatin formation, leading to decreased expressions of tumor suppressor genes and contributing to tumorigenesis. However, the factors that modulate UHRF1 expression in colorectal cancer (CRC) remain unclear. Here we showed that, compared with corresponding normal tissues, UHRF1 was upregulated and microRNA‐9 (miR‐9) was downregulated in CRC tissues. The expression of UHRF1 was inversely correlated with overall survival rates of patients with CRC. Overexpression of miR‐9 in CRC cell lines significantly attenuated CRC cell proliferation and promoted cell apoptosis. The expression of UHRF1 was markedly reduced in pre‐miR‐9 transfected CRC cells. Using luciferase reporter assay, we confirmed that miR‐9 was a direct upstream regulator of UHRF1. Finally, analysis of miR‐9 and UHRF1 levels in human CRC tissues revealed that expression of miR‐9 was inversely correlated with UHRF1 expression. Collectively, our results offer in vitro validation of the concept that miR‐9 could repress the expression of UHRF1, and function as a tumor‐suppressive microRNA in CRC. It may serve as a prognostic and therapeutic marker for CRC.
How to rapidly construct a spatial–numerical representation in preliterate children (at least temporarily)
Authors: Patro Katarzyna , Fischer Ursula , Nuerk Hans‐Christoph , Cress Ulrike
Published: May 2015

Spatial processing of numbers has emerged as one of the basic properties of humans’ mathematical thinking. However, how and when number–space relations develop is a highly contested issue. One dominant view has been that a link between numbers and left/right spatial directions is constructed based on directional experience associated with reading and writing. However, some early forms of a number–space link have been observed in preschool children who cannot yet read and write. As literacy experience is evidently not necessary for number–space effects, we are searching for other potential sources of this association. Here we propose and test a hypothesis that the number–space link can be quickly constructed in preschool children's cognition on the basis of spatially oriented visuo‐motor activities. We trained 3‐ and 4‐year‐old children with a non‐numerical spatial movement task (left‐to‐right or right‐to‐left), where via touch screen children had to move a frog across a pond. After the training, children had to perform a numerosity comparison task. After left‐to‐right training, we observed a SNARC‐like effect (reactions to smaller numbers were faster on the left side, and reactions to larger numbers on the right side), and after right‐to‐left training a reverse effect. These results are the first to show a causal link between visuo‐motor activities and number–space associations in children before they learn to read and write. We argue that simple activities, such as manual games, dominant in a given society, might shape number–space associations in children in a way similar to lifelong reading training.
Investigating cognitive transfer within the framework of music practice: genetic pleiotropy rather than causality
Authors: Mosing Miriam A. , Madison Guy , Pedersen Nancy L. , Ullén Fredrik
Published: May 2015

The idea of far transfer effects in the cognitive sciences has received much attention in recent years. One domain where far transfer effects have frequently been reported is music education, with the prevailing idea that music practice entails an increase in cognitive ability (IQ). While cross‐sectional studies consistently find significant associations between music practice and IQ, randomized controlled trials, however, report mixed results. An alternative to the hypothesis of cognitive transfer effects is that some underlying factors, such as shared genes, influence practice behaviour and IQ causing associations on the phenotypic level. Here we explored the hypothesis of far transfer within the framework of music practice. A co‐twin control design combined with classical twin‐modelling based on a sample of more than 10,500 twins was used to explore causal associations between music practice and IQ as well as underlying genetic and environmental influences. As expected, phenotypic associations were moderate (r = 0.11 and r = 0.10 for males and females, respectively). However, the relationship disappeared when controlling for genetic and shared environmental influences using the co‐twin control method, indicating that a highly practiced twin did not have higher IQ than the untrained co‐twin. In line with that finding, the relationship between practice and IQ was mostly due to shared genetic influences. Findings strongly suggest that associations between music practice and IQ in the general population are non‐causal in nature. The implications of the present findings for research on plasticity, modularity, and transfer are discussed.
Prevalence of normal TSH value among patients with autonomously functioning thyroid nodule
Authors: Treglia Giorgio , Trimboli Pierpaolo , Verburg Frederik A. , Luster Markus , Giovanella Luca
Published: May 2015

Background

International guidelines significantly diverge on the effectiveness of thyroid scintigraphy (TS) in the initial work‐up of thyroid nodules. In particular, the role of TS to detect or exclude the presence of autonomously functioning thyroid nodules (AFTN) in patients with normal serum thyrotropin (TSH) is still a matter to debate. Here, we aimed to review the literature on the prevalence of normal TSH value among patients with AFTN and meta‐analyse data of the retrieved eligible papers.

Materials and Methods

A comprehensive literature search of studies published from January 2000 to December 2014 on AFTN detected by TS was performed. Records reporting serum TSH values in AFTN were selected. Pooled prevalence of AFTN with normal TSH values was calculated on a per‐patient analysis including 95% confidence intervals (95% CI).

Results

Eight records including 2761 AFTN were selected for the meta‐analysis. Pooled prevalence of AFTN with normal TSH detected by TS was 50% (95% CI: 32–68%). Selection bias in the included studies and heterogeneity among studies were potential limitations of the meta‐analysis.

Conclusions

Present meta‐analysis shows that about one in two patients with AFTN demonstrated by TS has a TSH value within normal references. As a consequence, TSH measurement may not be considered as effective as a single tool to detect or exclude AFTN, and TS remains mandatory.
Novel fusion between the breakpoint cluster region and platelet‐derived growth factor receptor‐alpha genes in a patient with chronic myeloid leukemia‐like neoplasm: undetectable residual disease after imatinib therapy
Authors: Cluzeau Thomas , Lippert Eric , Cayuela Jean‐Michel , Maarek Odile , Migeon Marina , Noguera Maria‐Elena , Dombret Hervé , Rea Delphine
Published: May 2015

Rare patients suffering from myeloid neoplasms share clinical and cytological features indistinguishable from chronic myeloid leukemia (CML) but lack the BCR‐ABL1 fusion gene. Several studies provide evidence that alterations in genes encoding tyrosine kinase receptors such as the platelet‐derived growth factor receptor (PDGFR) may be involved in the pathogenesis of these disorders. Here we describe a patient with a rare CML‐like disease in whom we identified a novel in‐frame BCR‐PDGFRA rearrangement joining BCR exon 17 to PDGFRA exon 13, resulting in overexpression of PDGFRA. The design of a specific quantitative PCR assay to monitor the molecular response during treatment with imatinib, a multitargeted tyrosine kinase inhibitor (TKI) with activity against ABL, c‐Kit, and PDGFRA revealed an outstanding disease control with durably undetectable BCR‐PDGFRA transcripts. Multiple TKIs are currently available yet with distinct target profiles; thus, accurate molecular diagnosis and monitoring tools are essential to establish tailored treatments and assess response to therapy in this type of rare hematological malignancy.
Securities Transaction Tax and Market Quality – the Case of France
Authors: Gomber Peter , Haferkorn Martin , Zimmermann Kai
Published: May 2015

We study the French Securities Transaction Tax implementation of 1 August 2012. Although a similar tax is planned to be introduced across 11 European countries, consequences for market quality are yet to be thoroughly assessed. We show that liquidity demand and supply significantly drop. Even though the French proposal exempts professional liquidity provision, we find increased spreads and a declined order book depth resulting in additional transaction costs for market participants besides the tax. As all venues trading French stocks are affected, we further find that STT threatens inter‐market information transmission by impairing price coordination among fragmented markets in Europe.
A modified surgical technique for penile amputation and preputial ablation in the horse
Authors: Wylie C. E. , Payne R. J.
Published: May 2015

The aim of this study was to describe a modified surgical technique for treatment of severe penile pathology, and the long‐term outcome. The surgery consisted of subischial urethrostomy and penile amputation with preputial ablation, with the horse in dorsal recumbency. A redundant section of the penis root and body was left in situ, rather than being retroflexed as described elsewhere. Follow‐up was obtained using a structured owner telephone questionnaire. The 15 cases included: 11 squamous cell carcinomas (73.3%); 2 melanomas; one chronic preputial discharge with no associated neoplasia; and one paraphimosis following routine sedation. Length of survival ranged from 0.9 to 74.6 months (median 25.1 months). From the 14 horses with follow‐up, 9 survived >18 months (64.3%) [Correction added on 17 August 2015, after first online publication: The percentage in the preceding sentence was wrong and has been corrected to '64.3%' from '69.2%']. Four euthanasias were due to presenting or post operative complications, while 2 were unrelated to the procedure. This procedure presents a simplified, viable option for treatment of extensive mixed penile lesions; reducing surgical complexity and time in comparison to previously described techniques requiring retroversion.
Inhibition of hedgehog signalling attenuates UVB‐induced skin photoageing
Authors: Kim Wanyeon , Kim EunGi , Yang Hee Jung , Kwon TaeWoo , Han SeoYoung , Lee Sungmin , Youn HyeSook , Jung Youngmi , Kang ChulHee , Youn BuHyun
Published: May 2015

The hedgehog (Hh) signalling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis and progression of a variety of aggressive human cancers including skin cancer. Despite its importance, little is known about its role in photoageing, a type of UV‐induced skin lesions. In this study, we investigated the involvement of Hh signalling in the photoageing process as well as the use of an Hh‐regulating alkaloid compound as a novel therapeutic drug to regulate photoageing in keratinocytes. We found that UVB induced Hh signalling by the expression of Hh ligands and Hh‐mediated transcription factors, respectively. Moreover, UVB‐induced Hh activation relied on mitogen‐activated protein kinase (p38, ERK and JNK) activity and inflammatory responses (upregulation of COX‐2, IL‐1β, IL‐6 and TNF‐α), resulting in premature senescence and photoageing in vitro and in vivo. Notably, a selected Hh inhibitor, evodiamine, mediated photoageing blockade in a mouse skin model. Taken together, our findings demonstrated that Hh signalling is associated with UVB‐induced photoageing, while pharmacological inhibition of Hh signalling significantly reduced experimental photoageing, indicating its potential for use as a therapeutic target for this disease.
RBM28, a protein deficient in ANE syndrome, regulates hair follicle growth via miR‐203 and p63
Authors: Warshauer Emily , Samuelov Liat , Sarig Ofer , Vodo Dan , Bindereif Albrecht , Kanaan Moien , Gat Uri , Fuchs‐Telem Dana , Shomron Noam , Farberov Luba , Pasmanik‐Chor Metsada , Nardini Gil , Winkler Eyal , Meilik Benjamin , Petit Isabelle , Aberdam Daniel , Paus Ralf , Sprecher Eli , Nousbeck Janna
Published: May 2015

Alopecia–neurological defects–endocrinopathy (ANE) syndrome is a rare inherited hair disorder, which was shown to result from decreased expression of the RNA‐binding motif protein 28 (RBM28). In this study, we attempted to delineate the role of RBM28 in hair biology. First, we sought to obtain evidence for the direct involvement of RBM28 in hair growth. When RBM28 was downregulated in human hair follicle (HF) organ cultures, we observed catagen induction and HF growth arrest, indicating that RBM28 is necessary for normal hair growth. We also aimed at identifying molecular targets of RBM28. Given that an RBM28 homologue was recently found to regulate miRNA biogenesis in C. elegans and given the known pivotal importance of miRNAs for proper hair follicle development, we studied global miRNA expression profile in cells knocked down for RBM28. This analysis revealed that RBM28 controls the expression of miR‐203. miR‐203 was found to regulate in turn TP63, encoding the transcription factor p63, which is critical for hair morphogenesis. In conclusion, RBM28 contributes to HF growth regulation through modulation of miR‐203 and p63 activity.
Modulation of stratum corneum lipid composition and organization of human skin equivalents by specific medium supplements
Authors: Thakoersing Varsha S. , van Smeden Jeroen , Boiten Walter A. , Gooris Gert S. , Mulder Aat A. , Vreeken Rob J. , El Ghalbzouri Abdoelwaheb , Bouwstra Joke A.
Published: May 2015

Our in‐house human skin equivalents contain all stratum corneum (SC) barrier lipid classes, but have a reduced level of free fatty acids (FAs), of which a part is mono‐unsaturated. These differences lead to an altered SC lipid organization and thereby a reduced barrier function compared to human skin. In this study, we aimed to improve the SC FA composition and, consequently, the SC lipid organization of the Leiden epidermal model (LEM) by specific medium supplements. The standard FA mixture (consisting of palmitic, linoleic and arachidonic acids) supplemented to the medium was modified, by replacing protonated palmitic acid with deuterated palmitic acid or by the addition of deuterated arachidic acid to the mixture, to determine whether FAs are taken up from the medium and are incorporated into SC of LEM. Furthermore, supplementation of the total FA mixture or that of palmitic acid alone was increased four times to examine whether this improves the SC FA composition and lipid organization of LEM. The results demonstrate that the deuterated FAs are taken up into LEMs and are subsequently elongated and incorporated in their SC. However, a fourfold increase in palmitic acid supplementation does not change the SC FA composition or lipid organization of LEM. Increasing the concentration of the total FA mixture in the medium resulted in a decreased level of very long chain FAs and an increased level of mono‐unsaturated FAs, which lead to deteriorated SC lipid properties. These results indicate that SC lipid properties can be modulated by specific medium supplements.
NKp46 regulates the production of serine proteases and IL‐22 in human mast cells in urticaria pigmentosa
Authors: Ueshima Chiyuki , Kataoka Tatsuki R. , Hirata Masahiro , Koyanagi Itsuko , Honda Tetsuya , Tsuruyama Tatsuaki , Okayama Yoshimichi , Seiyama Akitoshi , Haga Hironori
Published: May 2015

NKp46 (natural cytotoxic receptor 1/CD335) is expressed on natural killer cells and Th2‐type innate lymphocytes. However, NKp46 expression in human mast cells has not yet been reported. Here, we explored the expression of, and possible role played by, NKp46 in such cells. NKp46 protein was expressed in human mast cells in urticaria pigmentosa principally of the tryptase‐positive/chymase‐negative type (MCT), but not in human non‐neoplastic skin mast cells of the tryptase‐positive/chymase‐positive (MCTC) type. NKp46 expression was also evident in the human neoplastic mast cell line HMC1.2. NKp46 knockdown changed the phenotype of this cell line from MCT to MCTC and downregulated GrB production, but did not influence IL‐22 production. An agonistic anti‐NKp46 antibody upregulated production of GrB and IL‐22, but did not change the MCT‐like phenotype of HMC1.2 cells. NKp46 was thus involved in the production of serine proteases and IL‐22 in human mast cells.
Recombinant erythroid differentiation regulator 1 inhibits both inflammation and angiogenesis in a mouse model of rosacea
Authors: Kim Miri , Kim Kyung‐Eun , Jung Haw Young , Jo Hyunmu , Jeong Seo‐won , Lee Jahyung , Kim Chang Han , Kim Heejong , Cho Daeho , Park Hyun Jeong
Published: May 2015

The erythroid differentiation regulator 1 (Erdr1), which is a novel and highly conserved factor, was recently reported to be negatively regulated by IL‐18 and to play a crucial role as an antimetastatic factor. IL‐18 is a proinflammatory cytokine that functions as an angiogenic mediator in inflammation. Rosacea is a chronic inflammatory skin disorder that is characterized by abnormal inflammation and vascular hyperactivity of the facial skin. To determine whether Erdr1 contributes to the regulation of the chronic inflammatory process in the development of rosacea, an immunohistochemical analysis was performed in healthy donors and patients with rosacea. In this study, we showed that Erdr1 was downregulated, whereas IL‐18 was upregulated, in patients with rosacea, which led us to question the role of Erdr1 in this disorder. Moreover, a rosacea‐like BALB/c mouse model was used to determine the role of Erdr1 in rosacea in vivo. LL‐37 injection induced typical rosacea features, including erythema, telangiectasia and inflammation. Treatment with recombinant Erdr1 (rErdr1) resulted in a significant reduction of erythema, inflammatory cell infiltration (including CD4+ and CD8+ T cells), and microvessel density with vascular endothelial growth factor (VEGF). Taken together, our findings suggest that rErdr1 may be involved in attenuating the inflammation and angiogenesis associated with the pathogenesis of rosacea. Thus, these results provide new insight into the mechanism involved in this condition and indicate that rErdr1 could be a potential target for therapeutic intervention of rosacea.
Tracing differences between male and female breast cancer: both diseases own a different biology
Authors: Kornegoor Robert , van Diest Paul J , Buerger Horst , Korsching Eberhard
Published: May 2015

Aims

Male breast cancer (MBC) is a rare and poorly characterized disease. In the present study we used a novel biomathematical model to further characterize MBC and to identify differences between male and female breast cancer (FBC).

Methods and results

A total of 134 cases of MBC were stained immunohistochemically for 13 key oncoproteins, and staining percentages were used in a mathematical model to identify dependency patterns between these proteins. The results were compared with a large group of FBC (n = 728). MBC and FBC clearly differed on the molecular level. In detail, the results suggest a different role for progesterone receptor (PR) compared to oestrogen receptor (ER) in MBC, while in FBC ER and PR show a similar pattern. In addition, Androgen receptor (AR) seems to be a more powerful effector in MBC. Grades 1 and 2 tumours were clearly separated from grade 3 tumours, and luminal types A and B tumours also showed a different pattern.

Conclusions

Defined morphological and molecular phenotypes can be identified in MBC, but these seem to be the result of different molecular mechanisms and perhaps multiple genetic pathways, as characterized previously in FBC, emphasizing the rising concept that MBC and FBC should be regarded as different and unique diseases.
The Reverse Gender Gap in Ethnic Discrimination: Employer Stereotypes of Men and Women with Arabic Names,
Authors: Arai Mahmood , Bursell Moa , Nekby Lena
Published: May 2015

We examine differences in the intensity of employer stereotypes of men and women with Arabic names in Sweden by testing how much work experience is needed to eliminate the disadvantage of having an Arabic name on job applications. Employers are first sent curriculum vitaes (CVs) of equal merit in a field experiment setup. Arabic-named CVs are thereafter enhanced with more relevant work experience than Swedish-named CVs. The results indicate a reverse gender gap in employer stereotypes because initial differences in the number of callbacks disappear for female applicants when Arabic-named CVs are enhanced but remain strong and significant for male applicants. Thus, contrary to what is often assumed about the interaction of gender and ethnicity, we find that Arabic men face stronger discrimination in the labor market than Arabic women.
Birthing, Nativity, and Maternal Depression: Australia and the United States,
Authors: Martinson Melissa L. , Tienda Marta
Published: May 2015

This study analyzes two birth cohort surveys, the Longitudinal Study of Australian Children and Early Childhood Longitudinal Study, to examine variation in maternal depression by nativity, duration of residence, age at migration, and English proficiency in Australia and the United States. Both countries have long immigrant traditions and a common language. The results demonstrate that US immigrant mothers are significantly less depressed than native-born mothers, but maternal depression does not differ by nativity in Australia. Moreover, the association between duration of residence and maternal depression is not linear: Recent arrivals and long-term residents exhibit the highest depression levels. Lack of English proficiency exacerbates maternal depression in Australia, but protects against depression in the United States. Differences in immigration regimes and welfare systems likely contribute to the differing salience of nativity for maternal depression.
Life cycle and host range of Phycita sp. rejected for biological control of prickly acacia in Australia
Authors: Dhileepan K. , Lockett C. J. , Balu A. , Murugesan S. , Perovic D. J. , Taylor D. B. J.
Published: May 2015

Prickly acacia (Vachellia nilotica subsp. indica), a native of the Indian subcontinent, is a serious weed of the grazing areas of northern Australia and is a target for classical biological control. Native range surveys in India identified a leaf webber, Phycita sp. (Lepidoptera: Pyralidae) as a prospective biological control agent for prickly acacia. In this study, we report the life cycle and host‐specificity test results Phycita sp. and highlight the contradictory results between the no‐choice tests in India and Australia and the field host range in India. In no‐choice tests in India and Australia, Phycita sp. completed development on two of 11 and 16 of 27 non‐target test plant species, respectively. Although Phycita sp. fed and completed development on two non‐target test plant species (Vachellia planifrons and V. leucophloea) in no‐choice tests in India, there was no evidence of the insect on the two non‐target test plant species in the field. Our contention is that oviposition behaviour could be the key mechanism in host selection of Phycita sp., resulting in its incidence only on prickly acacia in India. This is supported by paired oviposition choice tests involving three test plant species (Acacia baileyana, A. mearnsii and A. deanei) in quarantine in Australia, where eggs were laid only on prickly acacia. However, in paired oviposition choice trials, only few eggs were laid, making the results unreliable. Although oviposition choice tests suggest that prickly acacia is the most preferred and natural host, difficulties in conducting choice oviposition tests with fully grown trees under quarantine conditions in Australia and the logistic difficulties of conducting open‐field tests with fully grown native Australian plants in India have led to rejection of Phycita sp. as a potential biological control agent for prickly acacia in Australia.
How do people live life successfully with Parkinson's disease?
Authors: Kang Mi‐Young , Ellis‐Hill Caroline
Published: May 2015

Aims and objectives

The aim of this paper is to explore how people live life successfully with Parkinson's disease and what contributed to the level of success.

Objectives

To examine the level of success as defined by people with Parkinson's disease. To find what contributed to the level of success.

Background

Self‐care support has gained importance for supporting people with their chronic diseases including Parkinson's disease. Although self‐care and life adjustments can improve patients’ general well‐being, it is unclear which approaches best facilitate positive adjustments to illness.

Design

Semi‐structured interviews with participants with Parkinson's disease.

Methods

Eight participants living with Parkinson's disease for 2–16 years were recruited from a Parkinson's disease voluntary group in the UK. Interviews covered their perceived level of success and the factors which they perceived led to that success. Thematic analysis was used to analyse the data.

Results

Participants rated a high level of success in living with Parkinson's disease with an average personal rating 75/100 despite facing difficulties. Successful living was perceived to have taken place when people were either (1) able to return to their usual state of health or (2) considered themselves to be stable within a new/readjusted state of health. Aspects which were perceived to support positive psychosocial adjustment included a positive mindset, determination, acceptance of new challenges and family support.

Conclusion

Maintaining usual life and physical ability is the major concern among the people with Parkinson's disease. It would be helpful for health care professionals to identify what constitutes a ‘usual’ life for that person and to support them to develop a positive mindset and acceptance of new challenges, drawing on the determination of the person as well as any available family support.

Relevance to clinical practice

In supporting self‐care, it is helpful to gain information about the subjective experience of living with Parkinson's disease including their perceived level of success at the time and what led to that perceived success for that person.
Installing and thereafter removing an aberrant prosthesis elicited opposite remodelling responses in growing mouse temporomandibular joints
Authors: Zhang H.‐Y. , Liu Y.‐D. , Yang H.‐X. , Zhang M. , Liao L.‐F. , Wan X.‐H. , Wang M.‐Q.
Published: May 2015

Temporomandibular joint (TMJ) displays a high remodelling capability. The current purpose was to investigate the differences between mandibular condylar remodelling responses of growing mice to installation and removal of unilateral anterior crossbite (UAC) prosthesis. Twenty‐four mice were divided into one mock control group and two UAC groups. Unilateral anterior crossbite was created by installing a pair of prosthesis to left‐side maxillary and mandibular incisors. Unilateral anterior crossbite was removed in removal group at 3 weeks but remained in UAC group. Temporomandibular joints were sampled at 7 weeks. Changes in condylar cartilage and subchondral bone were assessed by histology and in vivo micro‐CT. Real‐time PCR and immunohistochemistry were performed to evaluate expression changes in ADAMTS‐5, MMP‐3, MMP‐9, MMP‐13, IL‐1, TNF‐α, OPG and RANKL. Statistical analysis was performed at α = 0·05. Temporomandibular joint cartilage degradation was induced by UAC as previously reported but was reversed by removal of UAC. The dropped cartilage thickness, chondrocyte number and collagen II‐positive area, the increased expression levels of Adamts‐5, Mmp3, 9, 13, Tnf‐α and Il‐1β in cartilage, the decreased ratio of OPG/RANKL in both condylar cartilage and subchondral bone, the loss of TMJ subchondral bone and the increase in the TRAP‐positive cells in subchondral bone were all reversed in the removal group (P < 0·05). The growing mouse TMJ condyle displays a high remodelling capability which can be degenerative and rehabilitative, respectively, in response to placement and thereafter removal of the aberrant prosthesis. Eliminating aberrant prosthesis is helpful to promote the degraded condyle to recover.
Airway compromise in children with anterior neck burns: Beware the scalded child
Authors: Hyland Ela J , Harvey John G , Martin Andrew JP , Holland Andrew JA
Published: May 2015

Aim

The aim of the study was to describe characteristics of children with anterior neck burns admitted to our Paediatric Intensive Care Unit (PICU) and to highlight potential airway complications associated with these injuries, especially in children with scalds.

Methods

Retrospective review of children with anterior neck burns requiring admission to PICU January 2004–December 2013.

Results

Fifty‐two children with anterior neck burns were admitted; average age 6.6 years. Thirty sustained flame/explosion injuries; 22 scalds. Seventy‐nine per cent were male. Mean total body surface area (TBSA) burn 21%. Forty‐seven were intubated. Some primary reasons for intubation included unconsciousness, inhalational/ingestion/direct airway injury and large TBSA. Majority, however, required intubation for airway complications secondary to subcutaneous/soft tissue anterior neck oedema not associated with airway injury/ingestion/inhalational burns. The scalds subgroup mean age was 2.3 years. Eighty‐two per cent were male. Mean TBSA 18%. There were no inhalational/ingestion/airway injuries. Nineteen children were intubated; average 9.3 h post‐injury. Majority (63%) were intubated post‐arrival in the Burn Unit, compared with flame/explosion group (32%). Primary reasons for intubation included large burns, although majority (74%) required intubation for airway complications secondary to subcutaneous and soft tissue anterior neck oedema. For the flame/explosion group this was the case in only 46%, with other primary reasons such as unconsciousness or inhalational injury being the immediate precedent.

Conclusion

These results demonstrate that subcutaneous and soft tissue oedema secondary to anterior neck burns may contribute to airway narrowing and compromise requiring intubation. When assessing children's airways, evolving oedema should be recognised and higher observation or early intubation considered regardless of the mechanism of injury.
Bacterial Urinary Tract Infections Associated with Transitional Cell Carcinoma in Dogs
Authors: Budreckis D.M. , Byrne B.A. , Pollard R.E. , Rebhun R.B. , Rodriguez C.O. , Skorupski K.A.
Published: May 2015

Background

Urinary tract infections (UTI) are believed to be common in dogs with transitional cell carcinoma (TCC), but incidence and contributing factors have not been reported.

Objectives

To determine the frequency and bacterial agents associated withUTIin dogs withTCCand define contributing factors.

Animals

Eighty‐five dogs with a history of urogenitalTCCundergoing treatment with chemotherapy that had at least 1 urine culture performed.

Methods

Medical records and culture results were retrospectively reviewed and ultrasound images were reviewed when available. Clinical factors were evaluated statistically for association with positive culture.

Results

Fifty‐five percent (47/85) of dogs had at least 1 positive culture during the course of treatment. Female dogs (80%, 40/50) were more likely than male dogs (29%, 10/35) to have at least 1 positive culture. Ultrasound examination determined that female dogs were more likely to have urethral (74%, 31/42) or trigonal tumor involvement (71%, 30/42) compared to male dogs (32%, 9/28 and 43%, 12/28, respectively). The most commonly isolated organisms wereStaphylococcusspp. (23.9%, 29/121) andEscherichia coli(19.8%, 24/121). Dogs with urethral involvement ofTCCwere significantly more likely to have at least 1 positive culture than dogs without urethral involvement (75%, 30/40 versus 30%, 9/30).

Conclusions

Urinary tract infectionis common in dogs withTCChighlighting the importance of regular monitoring for bacterial cystitis in dogs withTCC. In addition, clinical factors such as tumor location and sex may be predictive of positive culture and can help clinicians assess the risk ofUTI.
Survival benefit with IMRT following narrow‐margin hepatectomy in patients with hepatocellular carcinoma close to major vessels
Authors: Wang Wei‐Hu , Wang Zhi , Wu Jian‐Xiong , Zhang Tao , Rong Wei‐Qi , Wang Li‐Ming , Jin Jing , Wang Shu‐Lian , Song Yong‐Wen , Liu Yue‐Ping , Ren Hua , Fang Hui , Wang Wen‐Qing , Liu Xin‐Fan , Yu Zi‐Hao , Li Ye‐Xiong
Published: May 2015

Background & Aims

To investigate the role of post‐operative intensity‐modulated radiotherapy (IMRT) in patients receiving narrow‐margin hepatectomy for hepatocellular carcinoma (HCC) located close to the major vessels.

Methods

This exploratory study involved 181 HCC patients. Of them, 116 were treated with narrow‐margin (<1.0 cm) hepatectomy. Thirty‐three of the 116 underwent postoperative IMRT (Group A), while 83 did not receive radiotherapy (Group B). The remaining 65 patients underwent wide‐margin (≥1.0 cm) hepatectomy (Group C). Prognosis and patterns of recurrence were assessed in the three groups.

Results

The 3‐year overall survival (OS) and disease‐free survival (DFS) rates were 89.1 and 64.2% in Group A, 67.7 and 52.2% in Group B and 86.0 and 60.1% in Group C respectively. The OS and DFS of Group A and Group C patients surpassed those of Group B patients (Group A vs. B, P = 0.009 and P = 0.038; and Group C vs. B, P = 0.002 and P = 0.010). Patients in Groups A and C experienced significantly fewer early recurrences than did patients in Group B (P = 0.002). Furthermore, patients in Groups A and C experienced substantially fewer intrahepatic marginal (P = 0.048) and diffuse recurrences (P = 0.018) and extrahepatic metastases (P = 0.038) than did patients in Group B. No patient developed radiation‐induced liver disease.

Conclusions

Post‐operative IMRT following narrow‐margin hepatectomy may be a favourable therapy for both its safety profile and clinical benefit in patients with HCC located close to the major vessels.
Ischaemia‐modified albumin: a marker of bacterial infection in hospitalized patients with cirrhosis
Authors: Giannone Ferdinando A. , Domenicali Marco , Baldassarre Maurizio , Bartoletti Michele , Naldi Marina , Laggetta Maristella , Bertucci Carlo , Colecchia Antonio , Viale Pierluigi , Bernardi Mauro , Caraceni Paolo
Published: May 2015

Background & Aims

Patients with cirrhosis present structural changes of human serum albumin (HSA) affecting non‐oncotic functions. Ischaemia‐modified albumin (IMA), which reflects the capacity to bind cobalt, has been associated to patient mortality during acute‐on‐chronic liver failure. This study aimed to assess whether circulating IMA is elevated in advanced cirrhosis and its relationship with severity of cirrhosis and specific complications.

Methods

A total of 127 cirrhotic patients hospitalized for an acute complication of the disease and 44 healthy controls were enrolled. Plasma IMA and IMA to albumin ratio (IMAr) were measured with a cobalt‐binding assay. HSA isoforms carrying post‐transcriptional molecular changes were assessed with HPLC‐ESI‐MS. The effect of endotoxemia on IMA was evaluated in rats with CCl4‐cirrhosis.

Results

IMA/IMAr is significantly higher in cirrhotic patients than in controls, but no correlations were found with prognostic scores. IMA did not correlate with the altered HSA isoforms. Ascites, renal impairment and hepatic encephalopathy did not influence IMA/IMAr levels. In contrast, IMA/IMAr is significantly higher in infected than non‐infected patients. ROC curves showed that IMA/IMAr had similar discriminating performances for bacterial infection as C‐reactive protein (CRP). Moreover, CRP and IMA were independently associated with bacterial infection. Consistently, endotoxin injection significantly increased IMA in cirrhotic, but not in healthy rats.

Conclusions

IMA is elevated in patients with advanced cirrhosis. The IMA level does not correlate with disease severity scores, but it is specifically associated to bacterial infection, showing a discriminating performance similar to CRP. Further investigations to assess IMA as a novel diagnostic test for bacterial infection are advocated.