bluuebunny/crossref_metadata_2025 huggingface dataset:
Soil fertility induces coordinated responses of multiple independent functional traits
Authors: Jager Melissa M. , Richardson Sarah J. , Bellingham Peter J. , Clearwater Michael J. , Laughlin Daniel C.
Published: December 2014

A central goal of functional ecology is to determine how independent functional traits are selectively filtered by environmental conditions to improve our understanding of the mechanisms of community assembly. Soil fertility clearly influences community composition, but it is unclear which plant functional traits are most strongly associated with gradients of increasing nutrient limitation.

We hypothesized that leaf economic traits and stem tissue density would be strongly associated with soil fertility given their direct relationship to soil resource acquisition and use. In contrast, we hypothesized that functional traits that are commonly associated with competition for light (maximum height), shade tolerance (seed mass) and resistance to disturbance (bark thickness) would be unrelated to soil fertility.

We measured 13 functional traits from 30 tree species occurring in 40 plots across a soil fertility gradient in a mature warm temperate rain forest in Northland, New Zealand. Principal component analysis was used to assess the dimensionality and independence of the functional traits and the soil properties, and regression was used to determine the relationships between community‐weighted mean traits and the soil fertility gradient.

We observed a coordinated response of multiple independent traits to soil fertility. Consistent with our hypothesis, species associated with low‐fertility soils had comparatively ‘slower’ leaves (i.e. low SLA and leaf N and P, and high LDMC and thickness) and higher stem tissue density than species associated with high‐fertility soils.

Unexpectedly, we observed that species associated with low‐fertility soils had larger maximum heights, thicker bark and lower seed mass. Tall trees can persist on poor soils. Thick bark may be a defensive strategy for trees growing in resource‐limited sites and large‐seeded shade‐tolerant species can persist in fertile soils where light is more limiting.

Synthesis. Species sorting can occur over short distances in ecosystems where topographically driven variation in soil fertility leads to complete compositional turnover. Inferences about species distributions based on single‐trait spectrums can be misleading when environmental gradients sort species by filtering multiple independent traits simultaneously. Identifying the multidimensional trait combinations that promote fitness will advance both theory development and ecological restoration.
‘It's Kind of Saving them a Job isn't it?’ The Consumption Work of Household Recycling
Authors: Wheeler Kathryn , Glucksmann Miriam
Published: December 2014

Consumers play an integral role in societal divisions of labour. Rather than simply consume, they frequently perform labour. Incorporating consumers into the division of labour poses a challenge to this foundational and enduring concept, given its traditional focus on the technical division of tasks/skills within a labour process. Yet, insofar as completion of a circuit of production, distribution, exchange and consumption is predicated on consumers undertaking work in order to/after they consume, analysis of the division of labour would be incomplete without their inclusion. This paper uses the case of household recycling to demonstrate the importance of ‘consumption work’ for the organization of the waste management industry in England. By sorting their waste, consumers initiate a new economic process, providing feedstock (such as metals, plastics and paper) which in turn creates jobs/profits within the recycling, processing and manufacturing industries. Consumers also reconfigure public and private sector responsibilities when they sort their recyclable materials from general household waste, revealing the interdependency of consumption work with labour conducted under different socio-economic relations and across differing socio-economic domains. This paper makes the case for a renewed conception of division of labour to account for transformations and interconnections between work of different forms within contemporary society.
Children's reading profiles on exiting the Reading Recovery programme: do they predict sustained progress?
Authors: Holliman Andrew J. , Hurry Jane , Bodman Sue
Published: December 2014

The aim of this study was to identify reading profiles, which predict the literacy progress of Reading Recovery graduates. Reading Recovery is an intensive remediation for children after the first year of school. Children were assessed at exit from the programme and at 3‐month, 6‐month and 12‐month follow‐up points. Text Reading Level made unique contributions to word reading, spelling and writing at all time points and was consistently the best predictor of word reading. Phonological processing also made unique contributions to word reading and spelling. Reading comprehension was found to be the best predictor of National Curriculum sublevels for reading and writing, 12 months later. These findings indicate that levelled texts, as employed in Reading Recovery, provide a good indication of progress in word reading, spelling and writing after the programme has been discontinued, but also present a case for assessing other reading skills (e.g., phonological processing and reading comprehension) in order to help predict sustained progress in literacy.
Food Demand in Russia: Heterogeneous Consumer Segments over Time
Authors: Staudigel Matthias , Schröck Rebecca
Published: December 2014

The Russian food system has undergone substantial changes. However, knowledge on how economic transition has affected the structural parameters of food demand is lacking. Based on a two‐stageLES‐LA/AIDSmodel and annual panel data from the Russia Longitudinal Monitoring Survey (1995–2010), we provide a comprehensive set of food demand elasticities for Russia along two dimensions. First, we estimate demand parameters for three characteristic time periods in order to trace changes during transition. Second, to account for the Russian population's diversity, we derive elasticities for five different consumer segments. These groups are established by a cluster analysis based on households' food purchases. Our findings suggest that demand for food is far from satiated in Russia. We find generally high unconditional expenditure and own‐price elasticities for food. Both expenditure and own‐price elasticities show slight decreases in absolute terms over time. Low expenditure elasticities for staple foods like bread or cereals and high values for luxury goods such as meat, alcohol and tobacco suggest considerable changes in the composition of food baskets with further income growth. Results indicate that food production at home loses in importance while more affluent households in particular increase their demand for food consumption away from home.
Reflections on esophageal columnar metaplasia (Barrett)‐ANNO 2015
Authors: Tytgat Guido NJ
Published: December 2014

Esophageal columnar metaplasia (ECM) (Barrett's esophogus) continues to generate clinical and basic attention. Yet many questions remain unanswered and global consensus on important issues is often still lacking. This article discusses a selection of certain recent findings and reflects on some remaining uncertainties of this intriguing disease.
‘Please put a date to your letters …’: The Textual Evidence for Dr William Cullen's Management of His Epistolary Practice
Authors: Shuttleton David E.
Published: December 2014

The archive of William Cullen's ‘Consultations’ held at the Royal College of Physicians of Edinburgh is one of the most comprehensive records of an eighteenth‐century epistolary medical practice. This essay presents findings coming out of the detailed textual analysis undertaken to establish appropriate editorial protocols for a digital edition. Close textual scrutiny forms the bedrock of scholarly editing and is essential for establishing the status of individual documents, but the aim here is to show how bringing such attention to bear can illuminate broader questions concerning how Cullen managed such a prompt and personal epistolary service.
Negative Hemodynamic Effects of Pantoprazole at High Infusion Rates in Mice
Authors: Unsöld Bernhard , Teucher Nils , Didié Michael , Sossalla Samuel , Jacobshagen Claudius , Seidler Tim , Schillinger Wolfgang , Hasenfuß Gerd
Published: December 2014

Background

Pantoprazole has been shown to exert a negative inotropic effect in isolated myocardium. The purpose of this study was to evaluate the hemodynamic effects of pantoprazole in vivo in healthy myocardium and in the setting of heart failure.

Methods and Results

Healthy mice and mice with heart failure 4 weeks after myocardial infarction induced by permanent LAD ligation were instrumented with a Millar Mikrotip conductance catheter to record pressure–volume loops. Pantoprazole was infused at rates of 3 and 10 mg/kg/min intravenously, and hemodynamic parameters were recorded. Infusion of pantoprazole at increasing rates lead to a significant decline of end systolic LV pressure by decreasing heart rate, myocardial contractility and arterial elastance. These effects were quick, beginning immediately with the infusion and usually reaching a plateau after 2 or 3 min of infusion. The effects on blood pressure and heart rate were of comparable size in healthy mice and mice with MI. However, in sham‐operated mice, there was a compensatory increase in stroke volume that sufficed to maintain cardiac output at a constant level, which was missing in mice with MI. In 4 of 13 mice with MI infusion of 10 mg/kg/min pantoprazole lead to pump failure, which was lethal in 2 of these animals.

Conclusion

At higher infusion rates, pantoprazole is able to induce negative hemodynamic responses. In particular, in the setting of heart failure, these effects can lead to significant impairment of cardiac function. Therefore, high infusion rates of pantoprazole should be avoided especially in heart failure patients.
Hepatitis C seroconversion in methadone maintenance treatment programs in Wuhan, China
Authors: Zhou Wang , Wang Xia , Zhou Sheng , Xie Nianhua , Liu Pulin , Luo Li , Peng Jinsong , Liu Manqing , Desrosiers Alethea , Schottenfeld Richard , Chawarski Marek C.
Published: December 2014

Background and aims

To decrease infectious disease transmission, China is expanding methadone maintenance treatment (MMT). This study evaluated the prevalence of hepatitis C virus (HCV) infection at MMT entry, seroconversion rates after admission and potential risk factors for HCV seroconversion during MMT in Wuhan, China.

Design

Cross‐sectional survey of all patients entering MMT and prospective follow‐up of patients HCV seronegative at admission.

Setting

All MMT clinics in Wuhan, China.

Participants

A total of 12 755 opiate‐dependent individuals entering MMT between May 2006 and June 2011; 1200 participants HCV seronegative at admission were followed.

Measurements

Serological tests for HCV and self‐report data on risk behaviors at MMT admission; urine toxicology results and repeated assessments of serological status and risk behaviors during treatment on patients HCV seronegative at admission.

Findings

HCV seroprevalence at admission was 72.1% [95% confidence interval (CI) = 71.3–72.9%] and 555/1200 (46.3%, 95% CI = 43.5–49.1%) patients seroconverted to HCV during MMT. The mean time to HCV seroconversion was 3 (95% CI = 2.84–3.07) years with a cumulative seroconversion rate of 34.5 (95% CI = 31.5–36.9) per 100 person‐years. Significant predictors of HCV conversion included injection drug use in the past 30 days [relative hazard (RH) 2.0, 95% CI: 1.6 – 2.4, P=0.002] and the rate of opiate‐positive urine tests during MMT (RH 2.0, 95% CI = 1.3–3.1, P<0.001).

Conclusions

Methadone maintenance treatment patients in Wuhan, China show a high prevalence of hepatitis C virus at admission (72.1%) and a high rate of seroconversion during treatment (46.3%). Seroconversion is associated with continuing injection drug use.
A Novel Homozygous Nonsense Mutation in the PVRL4 Gene and Expansion of Clinical Spectrum of EDSS1
Authors: Raza Syed Irfan , Nasser Dar Rashid , Shah Anwar Ali , Ahmad Wasim
Published: December 2014

Ectodermal dysplasias (EDs) belong to a group of genetic diseases which result from alterations in ectoderm‐derived appendages including hair, nail, teeth and sweat glands. Ectodermal dysplasia syndactyly syndrome (EDSS1) is one of the rare forms of ED caused by mutations in nectin‐4, encoded by the PVRL4 gene. The present study described clinical investigation of the EDSS1 identified in a large consanguineous family. Furthermore, DNA sequence analysis revealed a novel homozygous nonsense mutation (181C>T, p.Asp61*) in the PVRL4 gene.
Choroidal thickness and high myopia: a case–control study of young Chinese men in Singapore
Authors: Gupta Preeti , Saw Seang‐Mei , Cheung Carol Y. , Girard Michael J. A. , Mari Jean Martial , Bhargava Mayuri , Tan Colin , Tan Mellisa , Yang Adeline , Tey Frederick , Nah Gerard , Zhao Paul , Wong Tien Yin , Cheng Ching‐Yu
Published: December 2014

Purpose

To determine the distribution of choroidal thickness (CT) and ocular factors associated with CT in high myopic eyes in comparison with emmetropic eyes of young healthy adults.

Methods

A case–control study of 648 young, male subjects, including 520 high myopes and 128 emmetropes. Choroidal imaging was performed using enhanced depth imaging spectral domain optical coherence tomography. Images were postprocessed using adaptive compensation for quality enhancement. CT was measured at nine locations, including subfovea and 1.5 and 3 mm nasal, temporal, superior and inferior to fovea.

Results

The CT at the subfovea was significantly thinner (mean ± standard error: 225.87 ± 5.51 μm) for high myopes compared to emmetropes (375.15 ± 6.58 μm, p < 0.001). Likewise, CT in high myopic group was significantly thinner than emmetropic control group at all locations (p for trend <0.001 for all locations). Distribution of CT showed a markedly different pattern in high myopic eyes (thickest superiorly at 3 mm, 265.97 ± 5.97 μm) and emmetropic eyes (thickest subfoveally, 375.15 ± 6.58 μm). Choroid was thinnest at nasal 3 mm location in both the myopic (108.85 ± 3.97 μm) and emmetropic (238.25 ± 6.72 μm) groups. Among the ocular factors studied, axial length, posterior staphyloma and chorio‐retinal atrophy were the significant predictors of CT.

Conclusions

Highly myopic eyes have significantly thinner choroid and showed different distribution pattern, compared to emmetropes. Axial length, posterior staphyloma and chorio‐retinal atrophy are the strongest determinants of CT.
Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health
Authors: Bhandage A. K. , Hellgren C. , Jin Z. , Olafsson E. B. , Sundström‐Poromaa I. , Birnir B.
Published: December 2014

Aim

The concept of nerve‐driven immunity recognizes a link between the nervous and the immune system. γ‐aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells (PBMCs) was influenced by gender, pregnancy or mental health.

Methods

We used RT‐qPCR to determine the mRNA expression level in PBMCs from men (n = 16), non‐pregnant women (n = 19), healthy pregnant women (n = 27) and depressed pregnant women (n = 15).

Results

The ρ2 subunit had the most prominent expression level of the GABA‐A receptor subunits in all samples. The δ and ρ2 subunits were up‐regulated by pregnancy, whereas the ε subunit was more frequently expressed in healthy pregnant women than non‐pregnant women who, in turn, commonly expressed the α6 and the γ2 subunits. The β1 and ε subunits expression was altered by depression in pregnant women. The GABA‐B1 receptor was up‐regulated by depression in pregnant women, while the transporters NKCC1 and KCC4 were down‐regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs.

Conclusion

The results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMCs.
Lipid Signalling Dynamics at the β‐cell Plasma Membrane
Authors: Wuttke Anne
Published: December 2014

Pancreatic β‐cells are clustered in islets of Langerhans and secrete insulin in response to increased concentrations of circulating glucose. Insulin in turn acts on liver, muscle and fat tissue to store energy and normalize the blood glucose level. Inappropriate insulin release may lead to impaired glucose tolerance and diabetes. In addition to glucose, other nutrients, neural stimuli and hormonal stimuli control insulin secretion. Many of these signals are perceived at the plasma membrane, which is also the site where insulin granules undergo exocytosis. Therefore, it is not surprising that membrane lipids play an important role in the regulation of insulin secretion. β‐cells release insulin in a pulsatile fashion. Signalling lipids integrate the nutrient and neurohormonal inputs to fine‐tune, shape and co‐ordinate the pulsatility. An important group of signalling lipids are phosphoinositides and their downstream messengers. This MiniReview will discuss new insights into lipid signalling dynamics in β‐cells obtained from live‐cell imaging experiments with fluorescent translocation biosensors. The plasma membrane concentration of several phosphoinositides and of their downstream messengers changes rapidly upon nutrient or neurohormonal stimulation. Glucose induces the most complex spatio‐temporal patterns, typically involving oscillations of messenger concentrations, which sometimes are locally restricted. The tightly controlled levels of lipid messengers can mediate specific binding of downstream effectors to the plasma membrane, contributing to the appropriate regulation of insulin secretion.
Cerebral Amyloid Angiopathy, Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA
Authors: Esiri Margaret , Chance Steven , Joachim Catharine , Warden Donald , Smallwood Aidan , Sloan Carolyn , Christie Sharon , Wilcock Gordon , Smith A. David
Published: December 2014

Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.
Endothelial Cells and Human Cerebral Small Vessel Disease
Authors: Hainsworth Atticus H. , Oommen Asho T. , Bridges Leslie R.
Published: December 2014

Brain endothelial cells have unique properties in terms of barrier function, local molecular signaling, regulation of local cerebral blood flow (CBF) and interactions with other members of the neurovascular unit. In cerebral small vessel disease (arteriolosclerosis;SVD), the endothelial cells in small arteries survive, even when mural pathology is advanced and myocytes are severely depleted. Here, we review aspects of altered endothelial functions that have been implicated inSVD: localCBFdysregulation, endothelial activation and blood–brain barrier (BBB) dysfunction. ReducedCBFis reported in the diffuse white matter lesions that are a neuroradiological signature ofSVD. This may reflect an underlying deficit in localCBFregulation (possibly via the nitric oxide/cGMPsignaling pathway). While many laboratories have observed an association of symptomaticSVDwith serum markers of endothelial activation, it is apparent that the origin of these circulating markers need not be brain endothelium. Our own neuropathology studies did not confirm local endothelial activation in small vessels exhibitingSVD. LocalBBBfailure has been proposed as a cause ofSVDand associated parenchymal lesions. Some groups find that computational analyses of magnetic resonance imaging (MRI) scans, following systemic injection of a gadolinium‐based contrast agent, suggest that extravasation into brain parenchyma is heightened in people withSVD. Our recent histochemical studies of donated brain tissue, using immunolabeling for large plasma proteins [fibrinogen, immunoglobulinG(IgG)], do not support an association ofSVDwith recent plasma protein extravasation. It is possible that a trigger leakage episode, or a size‐selective loosening of theBBB, participates inSVDpathology.
Making sense of ‘lower’ and ‘upper’ stem‐group Euarthropoda, with comments on the strict use of the name Arthropoda von Siebold, 1848
Authors: Ortega‐Hernández Javier
Published: December 2014

The ever‐increasing number of studies that address the origin and evolution of Euarthropoda – whose extant representatives include chelicerates, myriapods, crustaceans and hexapods – are gradually reaching a consensus with regard to the overall phylogenetic relationships of some of the earliest representatives of this phylum. The stem‐lineage of Euarthropoda includes numerous forms that reflect the major morphological transition from a lobopodian‐type to a completely arthrodized body organization. Several methods of classification that aim to reflect such a complex evolutionary history have been proposed as a consequence of this taxonomic diversity. Unfortunately, this has also led to a saturation of nomenclatural schemes, often in conflict with each other, some of which are incompatible with cladistic‐based methodologies. Here, I review the convoluted terminology associated with the classification of stem‐group Euarthropoda, and propose a synapomorphy‐based distinction that allows ‘lower stem‐Euarthropoda’ (e.g. lobopodians, radiodontans) to be separated from ‘upper stem‐Euarthropoda’ (e.g. fuxianhuiids, Cambrian bivalved forms) in terms of the structural organization of the head region and other aspects of overall body architecture. The step‐wise acquisition of morphological features associated with the origins of the crown‐group indicate that the node defining upper stem‐Euarthropoda is phylogenetically stable, and supported by numerous synapomorphic characters; these include the presence of a deutocerebral first appendage pair, multisegmented head region with one or more pairs of post‐ocular differentiated limbs, complete body arthrodization, posterior‐facing mouth associated with the hypostome/labrum complex, and post‐oral biramous arthropodized appendages. The name ‘Deuteropoda’ nov. is proposed for the scion (monophyletic group including the crown‐group and an extension of the stem‐group) that comprises upper stem‐Euarthropoda and Euarthropoda. A brief account of common terminological inaccuracies in recent palaeontological studies evinces the utility of Deuteropoda nov. as a reference point for discussing aspects of early euarthropod phylogeny.
Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1‐deficient mice
Authors: Morioka Takamitsu , Miyoshi‐Imamura Tomoko , Blyth Benjamin J. , Kaminishi Mutsumi , Kokubo Toshiaki , Nishimura Mayumi , Kito Seiji , Tokairin Yutaka , Tani Shusuke , Murakami‐Murofushi Kimiko , Yoshimi Naoki , Shimada Yoshiya , Kakinuma Shizuko
Published: December 2014

Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long‐term chronic inflammation is also a key risk factor, responsible for colitis‐associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation‐induced colon carcinogenesis in DNA mismatch repair‐proficient and repair‐deficient mice. Male and female Mlh1−/− and Mlh1+/+ mice were irradiated with 2 Gy X‐rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X‐rays and/or DSS treatment in Mlh1+/+ mice. Colon tumors developed after DSS treatment alone in Mlh1−/− mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well‐to‐moderately differentiated adenocarcinomas with tumor‐infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β‐catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis‐associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency.
Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin
Authors: Tsukigawa Kenji , Liao Long , Nakamura Hideaki , Fang Jun , Greish Khaled , Otagiri Masaki , Maeda Hiroshi
Published: December 2014

Previously, we prepared a pirarubicin (THP)‐encapsulated micellar drug using styrene–maleic acid copolymer (SMA) as the drug carrier, in which active THP was non‐covalently encapsulated. We have now developed covalently conjugated SMA‐THP (SMA‐THP conjugate) for further investigation toward clinical development, because covalently linked polymer–drug conjugates are known to be more stable in circulation than drug‐encapsulated micelles. The SMA‐THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA‐THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor‐targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one‐fifth of the maximum tolerable dose). Although SMA‐THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor‐targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA‐THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor‐targeting properties in vivo.
Molecular targeted therapy against B cells in multiple sclerosis
Authors: Miyazaki Yusei , Niino Masaaki
Published: December 2014

B cells have been implicated in the pathology of multiple sclerosis (MS) since the initial observation in the 1940s and 50s of increased immunoglobulin concentrations in the cerebrospinal fluid of MS patients. Until recently, B cells have been considered to participate in MS pathology through the secretion of antibodies specific to central nervous system antigens. However, the successful targeting of B cells with anti‐CD20 monoclonal antibodies without affecting immunoglobulin levels suggests that B cells have antibody‐independent functions in immune regulation in MS. Furthermore, the recent identification of B cell‐rich follicle‐like structures in the meninges of patients with secondary progressive MS indicates that B cells also have pathogenic roles within the central nervous system, where they contribute to disease progression by inducing cortical injury. These observations suggest that B cells are key players in the pathogenesis of MS, and are therefore attractive targets for therapeutic intervention. In addition to CD20, several other molecules and pathways related to B cell function are being evaluated as therapeutic targets in other autoimmune diseases. Furthermore, based on the increased understanding of the molecular mechanisms underlying B cell effector function, particularly those involved in MS, therapeutic strategies for specifically inhibiting the pro‐inflammatory activity of B cells while preserving or even enhancing their role in protective immune response are under active investigation. Here, we review recent advances in molecular targeted therapies against B cells for MS, and discuss perspectives for future therapies targeting B cells and related molecules.
Molecular targeted therapy against the blood–brain barrier in multiple sclerosis
Authors: Kanda Takashi
Published: December 2014

Previous therapeutic strategies for multiple sclerosis (MS) include the non‐selective suppression of systemic immunity (immunosuppressive agents, such as glucocorticoids, mitoxantrone and azathioprine) and immunomodulation (type I interferons or intravenous immunoglobulin). The recent development of two pivotal drugs, fingolimod and natalizumab, has resulted in a third category of MS treatment, namely the sequestration of pathogenic T cells. Natalizumab, a humanized monoclonal antibody that binds to the α4‐integrin molecule on the surface of circulating lymphocytes and thus blocks very late antigen‐4/vascular cell adhesion molecule‐1 interactions at the blood–brain barrier (BBB), is now widely accepted as a potent tool for treating relapsing–remitting MS. This drug is epoch‐making, as it is the first agent to confirm the efficacy of merely inhibiting the transfer of T cells across the BBB in the treatment of MS; however, the risk of a potentially fatal central nervous system opportunistic infection, progressive multifocal leukoencephalopathy, should always be kept in mind. Because the onset of progressive multifocal leukoencephalopathy might be partly due to the almost total blockage of T cells, including those participating in immune surveillance, the development of novel therapies that selectively inhibit only the entrance of pathogenic T cells is now eagerly awaited. In addition to the blockade of mononuclear cell intrusion, restoring the integrity of the BBB might quickly terminate the process of local inflammation. In addition, manipulating the BBB to enhance the transfer of useful molecules, including a variety of growth factors, could facilitate axonal regeneration. Therefore, the BBB is a promising target of future therapeutic strategies in MS.
Poor mental health in severely obese patients is not explained by the presence of comorbidities
Authors: Somerville R. , McKenzie K. , Eslami S. , Breen C. , O'Shea D. , Wall P.
Published: December 2014

The prevalence of obesity, especially severe obesity where body mass index (BMI) exceeds 40 kg m−2 and where the physical risks are greatest, is increasing. However, little is known about the impact of severe obesity on psychological well‐being and self‐rated health (SRH). We aimed to investigate this relationship in patients attending an Irish weight management clinic. SRH was measured with a single‐item inventory (excellent = 1, poor = 5). Well‐being was measured with the validated World Health Organization‐Five Well‐being Index (WHO‐5), in which scores <13 indicate poor well‐being. Previous studies of the Irish population have reported mean SRH = 2.56 (males) and 2.53 (females) and mean well‐being = 16.96. One hundred eighty‐two (46.8%) completed questionnaires were returned. The sample was representative of the clinic population with a mean age of 47.1, mean baseline BMI of 51.9 kg m−2 and 64.3% females. Mean SRH was 3.73 in males and 3.30 in females; mean well‐being was 10.27 in males and 10.52 in females. In the final multivariable models, number of medications, depression and obstructive sleep apnoea, WHO‐5 and current BMI were significant predictors of SRH, and secondary level education, social support and mindfulness scores were significant predictors of psychological well‐being. Number of medications was not significant. The results suggest that the poor psychological well‐being seen is not explained by the presence of comorbidities and that social support and mindfulness may be important targets for improving psychological well‐being. Improving psychological well‐being in addition to weight loss and effective management of comorbidities may be important for improving SRH.
Effects of Causal Structure on Decisions About Where to Intervene on Causal Systems
Authors: Edwards Brian J. , Burnett Russell C. , Keil Frank C.
Published: December 2014

We investigated how people design interventions to affect the outcomes of causal systems. We propose that the abstract structural properties of a causal system, in addition to people's content and mechanism knowledge, influence decisions about how to intervene. In Experiment 1, participants preferred to intervene at specific locations (immediate causes, root causes) in a causal chain regardless of which content variables occupied those positions. In Experiment 2, participants were more likely to intervene on root causes versus immediate causes when they were presented with a long‐term goal versus a short‐term goal. These results show that the structural properties of a causal system can guide the design of interventions.
How the Eyes Tell Lies: Social Gaze During a Preference Task
Authors: Foulsham Tom , Lock Maria
Published: December 2014

Social attention is thought to require detecting the eyes of others and following their gaze. To be effective, observers must also be able to infer the person's thoughts and feelings about what he or she is looking at, but this has only rarely been investigated in laboratory studies. In this study, participants' eye movements were recorded while they chose which of four patterns they preferred. New observers were subsequently able to reliably guess the preference response by watching a replay of the fixations. Moreover, when asked to mislead the person guessing, participants changed their looking behavior and guessing success was reduced. In a second experiment, naïve participants could also guess the preference of the original observers but were unable to identify trials which were lies. These results confirm that people can spontaneously use the gaze of others to infer their judgments, but also that these inferences are open to deception.
MicroRNA‐103a inhibits gastric cancer cell proliferation, migration and invasion by targeting c‐Myb
Authors: Liang Jinlong , Liu Xianfeng , Xue Hongpeng , Qiu Bing , Wei Bin , Sun Kan
Published: December 2014

Objectives

There have been no previous reports concerning functions of miR‐103a in gastric cancer (GC) cells. Thus the aim of the study was to investigate its expression and role in development of this tumour.

Materials and methods

Real‐time RT‐PCR was performed to detect expression of miR‐103a in GC cell lines and clinical cancer specimens. To further understand its role, we restored expression of miR‐103a in MGC‐803 cell line by transfection with miR‐103a mimics or inhibitors. Effects of miR‐103a on cell proliferation, migration and invasion on targets were also determined.

Results

miR‐103a was down‐regulated in both GC cell lines and clinical cancer specimens. Meanwhile, its level was closely associated with pM or pTNM stage of GC. Overexpression of miR‐103a markedly suppressed proliferation, migration, and invasion of GC cells, while its inhibition significantly accelerated cell proliferation, migration and invasion. Moreover, c‐Myb was identified to be a functional downstream target of miR‐103a, ectopic expression of which partially reversed suppression of cell proliferation and invasion.

Conclusions

Thus our observations suggest that miR‐103a functioned as a tumour suppressor by targeting c‐Myb. These findings indicate that miR‐103a might play a significant role in pathogenesis of GC.
MicroRNA expression and its clinical implications in Ewing's sarcoma
Authors: Li Zheng , Yu Xin , Shen Jianxiong , Wu William Ka Kei , Chan Matthew T.V.
Published: December 2014

Ewing's sarcoma (EWS) is the second most common primary bone cancer, and is a predominant childhood malignant disease. Due to limited understanding of its pathogenesis and frequent occurrence of resistance to conventional types of treatment, its management remains difficult, and mortality is frequent. Development of EWS is a multistep process involving genetic and epigenetic alterations of protein‐coding proto‐oncogenes and tumour‐suppressor genes. MicroRNAs (miRNAs) have recently been discovered as a new category of non‐protein coding; small RNA molecules that regulate gene expression at the post‐transcriptional level. Substantial numbers of deregulated miRNAs have been documented in EWS and their biological significance has been confirmed in multiple functional experiments. Several studies have confirmed involvement of miRNAs in various steps of EWS pathogenesis, from occurrence to metastasis. Functionally, miRNA dysregulation may promote cell‐cycle progression, confer resistance to apoptosis, and enhance invasiveness and metastasis. These miRNAs have opened a novel field in cancer research with potential clinical utilization for screening, diagnosis, prognostics and prediction of response to treatment. Elucidating biological aspects of miRNA dysregulation may help better understand pathogenesis of EWS and promote development of miRNA directed‐therapeutics against it.
Predictors of poor outcome among older liver transplant recipients
Authors: Sonny Abraham , Kelly Dympna , Hammel Jeffrey P. , Albeldawi Mazen , Zein Nizar , Cywinski Jacek B.
Published: December 2014

With the increasing age of recipients undergoing orthotopic liver transplant (OLT), there is need for better risk stratification among them. Our study aims to identify predictors of poor outcome among OLT recipients ≥60 yr of age. All patients who underwent OLT at Cleveland Clinic from January 2004 to April 2010 were included. Baseline patient characteristics and post‐OLT outcomes (mortality, graft failure, length of stay, and major post‐OLT cardiovascular events) were obtained from prospectively collected institutional registry. Among patients ≥60 yr of age, multivariate regression modeling was performed to identify independent predictors of poor outcome. Of the 738 patients included, 223 (30.2%) were ≥60 yr. Hepatic encephalopathy, platelet counts <45 000/μL, total serum bilirubin >3.5 mg/dL, and serum albumin <2.65 mg/dL independently predicted poor short‐term outcomes. The presence of pre‐OLT coronary artery disease and arrhythmia were independent predictors of poor long‐term outcomes. Cardiac causes represented the second most common cause of mortality among the elderly cohort. Despite that, this carefully selected cohort of older OLT recipients had outcomes that were comparable with the younger recipients. Thus, our results show the need for better pre‐OLT evaluation and optimization, and for closer post‐OLT surveillance, of cardiovascular disease among the elderly.
Habitat type shapes long‐term plant biodiversity budgets in two densely populated regions in north‐western Europe
Authors: Hautekèete Nina‐Coralie , Frachon Léa , Luczak Christophe , Toussaint Benoît , Van Landuyt Wouter , Van Rossum Fabienne , Piquot Yves
Published: December 2014

Aim

At a global scale, biodiversity changes are mainly driven by extinction, resulting in an overall decrease in species richness. At regional and local scales, although immigration often (over)compensates for local extinction, biodiversity changes have no clear trends. We tested the hypotheses that (1) at both regional and local scales, biodiversity changes result from the differential dynamics of local extinction and immigration, ultimately leading to increases in biodiversity following periods of transient surplus or deficit and (2) habitats are differentially affected by human activities, resulting in contrasting trends and dynamics that together shape the regional biodiversity budget.

Location

Northern France and Belgian Flanders, north‐western Europe.

Methods

We analysed changes in plant species richness over one century in two adjacent and densely populated regions. Because local to regional changes are expected to be driven by species–environment interactions, and because species ecology and environmental change are largely embodied by the habitat, we assessed biodiversity budgets according to the type of habitat.

Results

We observed major changes in species composition at the regional scale with about one of every five to six species becoming regionally extinct or newly naturalized. Immigration offset or exceeded losses, with local extinctions generally preceding gains. Overall, regional dynamics were driven by contrasting changes in a few habitat types, with either local extinction or immigration predominating. Transient biodiversity surpluses or deficits were observed at the regional scale and in certain habitat types.

Main conclusions

Including habitat types bridges the gap between regional and local studies and provides a more accurate assessment of the biodiversity budget: integrating habitat type into regional analyses or meta‐analyses can lead future research towards the understanding of the determinisms of biodiversity change across spatial scales.
Habitat availability for amphibians and extinction threat: a global analysis
Authors: Ficetola Gentile Francesco , Rondinini Carlo , Bonardi Anna , Baisero Daniele , Padoa‐Schioppa Emilio
Published: December 2014

Aim

Habitat loss and degradation are the factors threatening the largest number of amphibian species. However, quantitative measures of habitat availability only exist for a small subset of them. We evaluated the relationships between habitat availability, extinction risk and drivers of threat for the world's amphibians. We developed deductive habitat suitability models to estimate the extent of suitable habitat and the proportion of suitable habitat (PSH) inside the geographic range of each species, covering species and areas for which little or no high‐resolution distribution data are available.

Location

Global.

Methods

We used information on habitat preferences to develop habitat suitability models at 300‐m resolution, by integrating range maps with land cover and elevation. Model performance was assessed by comparing model output with point localities where species were recorded. We then used habitat availability as a surrogate of area of occupancy. Using the IUCN criteria, we identified species having narrow area of occupancy, for which extinction risk is likely underestimated.

Results

We developed models for 5363 amphibians. Validation success of models was high (94%), being better for forest specialists and generalists than for open habitat specialists. Generalists had proportionally more habitat than forest or open habitat specialists. The PSH was lower for species having small geographical ranges, currently listed as threatened, and for which habitat loss is recognized as a threat. Differences in habitat availability among biogeographical realms were strong. We identified 61 forest species for which the extinction risk may be higher that currently assessed in the Red List, due to limited extent of suitable habitat.

Main conclusions

Habitat models can accurately predict amphibian distribution at fine scale and allow describing biogeographical patterns of habitat availability. The strong relationship between amount of suitable habitat and extinction threat may help the conservation assessment in species for which limited information is currently available.
Short‐ and long‐term effects of gestational diabetes mellitus on healthcare cost: a cross‐sectional comparative study in the ATLANTIC DIP cohort
Authors: Danyliv A. , Gillespie P. , O'Neill C. , Noctor E. , O'Dea A. , Tierney M. , McGuire B. , Glynn L. G. , Dunne F.
Published: December 2014

Aims

This paper examines the association between gestational diabetes mellitus and costs of care during pregnancy and 2–5 years post pregnancy.

Methods

Healthcare utilization during pregnancy was measured for a sample of 658 women drawn from the Atlantic Diabetes in Pregnancy (ATLANTIC DIP) network. Healthcare utilization 2–5 years post pregnancy was assessed for a subsample of 348 women via a postal questionnaire. A vector of unit costs was applied to healthcare activity to calculate the costs of care at both time points. Differences in cost for women with gestational diabetes mellitus compared with those with normal glucose tolerance during the pregnancy were examined using univariate and multivariate regression analyses.

Results

Gestational diabetes mellitus was independently associated with an additional €817.60 during pregnancy (€1192.1 in the gestational diabetes mellitus group, €511.6 in the normal glucose tolerance group), in the form of additional delivery and neonatal care costs, and an additional €680.50 in annual healthcare costs 2–5 years after the index pregnancy (€6252.4 in the gestational diabetes mellitus group, €5434.8 in the normal glucose tolerance group).

Conclusions

These results suggest that gestational diabetes mellitus is associated with increased costs of care during and post pregnancy. They provide indication of the associated cost that can be avoided or reduced by the screening, prevention and management of gestational diabetes mellitus in pregnancy. These estimates are useful for further studies that examine the cost and cost‐effectiveness of such programmes.
New insights on chromatin modifiers and histone post‐translational modifications in renal cell tumours
Authors: Vieira‐Coimbra Márcia , Henrique Rui , Jerónimo Carmen
Published: December 2014

Renal cell tumours (RCTs) are the most common neoplasms affecting the kidney. They are clinically, pathologically and genetically heterogeneous, comprises four major histological subtypes [clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (chRCC), which are malignant tumours, and oncocytoma, a benign tumour], as well as an increasing number of less common entities. Epigenetics has emerged as an important field in oncology due to the critical role it plays in neoplastic transformation and progression. Among epigenetic mechanisms, the modulation of chromatin packaging through covalent modifications is fundamental for gene transcription regulation and its deregulation is involved in carcinogenesis. Recently, deregulation of chromatin machinery in RCTs has increasingly acknowledged as an important mechanism for renal neoplastic transformation. The aim of this review is to summarize the most relevant alterations in histone post‐translational modifications and chromatin modifiers, which have been implicated in renal tumorigenesis. The recognition of those modifications might provide new biomarkers for diagnosis and prognostication as well as novel targets for personalized therapeutic intervention.