bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review: the effects of autologous stem cell therapy for patients with liver disease
Authors: Moore J. K. , Stutchfield B. M. , Forbes S. J.
Published: February 2014

Background

As morbidity and mortality from liver disease continues to rise, new strategies are necessary. Liver transplantation is not only an expensive resource committing the patient to lifelong immunosuppression but also suitable donor organs are in short supply. Against this background, autologous stem cell therapy has emerged as a potential treatment option.

Aim

To evaluate if it is possible to make a judgement on the safety, feasibility and effect of autologous stem cell therapy for patients with liver disease.

Methods

MEDLINEandEMBASEwere searched up until July 2013 to identify studies where autologous stem cell therapy was administered to patients with liver disease.

Results

Of 1668 studies identified, 33 were eligible for inclusion evaluating a median sample size of 10 patients for a median follow‐up of 6 months. Although there was marked heterogeneity between studies with regards to type, dose and route of delivery of stem cell, the treatment was shown to be safe and feasible largely when a peripheral route of administration was used. Of the studies which also looked at biochemical outcome, statistically significant improvement in liver function tests was seen in 16 studies post‐treatment.

Conclusion

Although autologous stem cell therapy is a much needed possibility in the treatment of liver disease, further robust clinical trials and collaborative protocols are required.
Review article: advances in the management of patients with cirrhosis and portal hypertension‐related renal dysfunction
Authors: Leithead J. A. , Hayes P. C. , Ferguson J. W.
Published: February 2014

Background

In cirrhosis, portal hypertension is associated with a spectrum of renal dysfunction that has significant implications for morbidity and mortality.

Aim

To discuss recent progress in the patho‐physiological mechanisms and therapeutic options for portal hypertension‐related renal dysfunction.

Methods

A literature search using Pubmed was performed.

Results

Portal hypertension‐related renal dysfunction occurs in the setting of marked neuro‐humoral and circulatory derangement. A systemic inflammatory response is a pathogenetic factor in advanced disease. Such physiological changes render the individual vulnerable to further deterioration of renal function. Patients are primed to develop acute kidney injury when exposed to additional ‘hits’, such as sepsis. Recent progress has been made regarding our understanding of the aetiopathogenesis. However, treatment options once hepatorenal syndrome develops are limited, and prognosis remains poor. Various strategies to prevent acute kidney injury are suggested.

Conclusion

Prevention of acute kidney injury in high risk patients with cirrhosis and portal hypertension‐related renal dysfunction should be a clinical priority.
Model‐based clinical drug development in the past, present and future: a commentary
Authors: Kimko Holly , Pinheiro José
Published: February 2014

Clinical drug development remains a mostly empirical, costly enterprise, in which decision‐making is often based on qualitative assessment of risk, without properly leveraging all the relevant data collected throughout the development programme. Model‐based drug development (MBDD) has been proposed by regulatory agencies, academia and pharmaceutical companies as a paradigm to modernize drug research through the quantification of risk and combination of information from different sources across time. We present here a historical account of the use of MBDD in clinical drug development, the current challenges and further opportunities for its application in the pharmaceutical industry.
Beliefs about medicines in Dutch acenocoumarol and phenprocoumon users
Authors: Verhoef Talitha I. , Redekop W. Ken , Bouvy Marcel L. , Dorenbos Brenda , Karwar Zamiera , van Schie Rianne M. F. , de Boer Anthonius , Maitland‐van der Zee Anke‐Hilse ,   EU‐PACT group
Published: February 2014

Aims

Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs.

Methods

The Beliefs about Medicines Questionnaire was used to assess medication beliefs. The questionnaire was completed by new users of coumarins indicated for venous thromboembolism or atrial fibrillation. A necessity score and a concerns score were calculated for all patients. The analyses were repeated for users of antihypertensive drugs or statins (not using coumarins).

Results

Three hundred and twenty patients were included in the analysis of the beliefs about coumarins. The mean necessity score was 15.3, the concerns score 12.3 and the necessity–concerns differential 3.0. Patients with venous thromboembolism (n = 71) had higher necessity scores than patients with atrial fibrillation (n = 249; 16.8 vs. 14.9, P < 0.001). The mean necessity score in 493 users of other cardiovascular drugs was 16.1, the concerns score 13.5 and the necessity–concerns differential 2.6. The necessity score was higher in chronic cardiovascular drug users (n = 192) than in new users (n = 301; 17.9 vs. 14.9, P < 0.001).

Conclusions

Coumarin users score higher on the necessity scale than on the concerns scale, which is also the case in users of other cardiovascular drugs. Patients with atrial fibrillation have a less positive attitude towards these drugs than patients with venous thromboembolism, and could therefore benefit more from specific attention.
Assessing the safety features of electronic patient medication record systems used in community pharmacies in England
Authors: Ojeleye Oluwagbemileke , Avery Anthony J. , Boyd Matthew J.
Published: February 2014

Aims

To evaluate the ability of electronic patient medication record (ePMR) systems used in community pharmacies in England to detect and alert users about clinical hazards, errors and other safety problems.

Methods

Between September 2012 and November 2012, direct on‐site observational data about the performance of ePMR systems were collected from nine sites. Twenty‐eight scenarios were developed by consensus agreement between a general practitioner and two community pharmacists. Each scenario was entered into the ePMR system, and the results obtained from the assessment of six unique systems in nine sites, in terms of the presence or absence of an alert, were recorded onto a prespecified form.

Results

None of the systems produced the correct responses for all of the 28 scenarios tested. Only two systems provided an alert to penicillin sensitivity. No dose or frequency check was observed when processing a prescription for methotrexate. One system did not warn about nonsuitability of aspirin prescribed to a child of 14 years of age. In another system, it was not possible to record a patient's pregnancy status. None of the six systems provided any warning for diclofenac overdose, high initiation dose of morphine sulfate or significant dose increase. Only one of the systems did not produce any spurious alerts.

Conclusions

The performance of the ePMR systems tested was variable and suboptimal. The findings suggest the need for minimum specifications and standards for ePMR systems to ensure consistency of performance.
Citalopram and escitalopram plasma drug and metabolite concentrations: genome‐wide associations
Authors: Ji Yuan , Schaid Daniel J. , Desta Zeruesenay , Kubo Michiaki , Batzler Anthony J. , Snyder Karen , Mushiroda Taisei , Kamatani Naoyuki , Ogburn Evan , Hall‐Flavin Daniel , Flockhart David , Nakamura Yusuke , Mrazek David A. , Weinshilboum Richard M.
Published: February 2014

Aims

Citalopram (CT) and escitalopram (S‐CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome‐wide association study to identify genetic factors that contribute to variation in plasma concentrations ofCTorS‐CTand their metabolites inMDDpatients treated withCTorS‐CT.

Methods

Our genome‐wide association study was performed using samples from 435MDDpatients. Linear mixed models were used to account for within‐subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single‐nucleotide polymorphisms (SNPs) were modelled as additive allelic effects.

Results

Genome‐wide significant associations were observed forS‐CTconcentration withSNPsin or near theCYP2C19gene on chromosome 10 (rs1074145,P= 4.1 × 10−9) and withS‐didesmethylcitalopram concentration forSNPsnear theCYP2D6locus on chromosome 22 (rs1065852,P= 2.0 × 10−16), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect ofCYP2C19functional alleles, the analyses also identified novel loci that will require future replication and functional validation.

Conclusions

In vitroandin vivostudies have suggested that the biotransformation ofCTto monodesmethylcitalopram and didesmethylcitalopram is mediated byCYPisozymes. The results of our genome‐wide association study performed inMDDpatients treated withCTorS‐CThave confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels ofCTor its metabolites during the treatment ofMDDpatients with these selective serotonin reuptake inhibitors.
Applicability of Computational Systems Biology in Toxicology
Authors: Kongsbak Kristine , Hadrup Niels , Audouze Karine , Vinggaard Anne Marie
Published: February 2014

Systems biology as a research field has emerged within the last few decades. Systems biology, often defined as the antithesis of the reductionist approach, integrates information about individual components of a biological system. In integrative systems biology, large data sets from various sources and databases are used to model and predict effects of chemicals on, for instance, human health. In toxicology, computational systems biology enables identification of important pathways and molecules from large data sets; tasks that can be extremely laborious when performed by a classical literature search. However, computational systems biology offers more advantages than providing a high‐throughput literature search; it may form the basis for establishment of hypotheses on potential links between environmental chemicals and human diseases, which would be very difficult to establish experimentally. This is possible due to the existence of comprehensive databases containing information on networks of human protein–protein interactions and protein–disease associations. Experimentally determined targets of the specific chemical of interest can be fed into these networks to obtain additional information that can be used to establish hypotheses on links between the chemical and human diseases. Such information can also be applied for designing more intelligent animal/cell experiments that can test the established hypotheses. Here, we describe how and why to apply an integrative systems biology method in the hypothesis‐generating phase of toxicological research.
Hirsch, Brett D (2012) Digital humanities pedagogyhttp://openbookpublishers.com/ isbn 978‐1‐909254‐25‐1 426 pp £14.95
Authors: Dettori Giuliana
Published: February 2014

This interesting book, the target audience of which is teachers of digital humanities at university level, highlights the need to teach methodological approaches and not simply technological skills. Thus we nurture scholars who are culturally literate as well as digitally adept, and foster the development of critical thinking skills. If the content of this book is likely to be relevant to you, I recommend that you buy a copy for your own use.

Giuliana Dettori
Miller, Suzanne M & McVee, Mary B ed (2012) Multimodal composing in classroomsRoutledge (New York & London) isbn 978‐0‐415‐89747‐1 161 pp £27.99 http://www.routledge.com/books/details/9780415897471/
Authors: Dettori Giuliana
Published: February 2014

Multimodal composing in classrooms aims to encourage school teachers to change their view of literacy, through the analysis of experiences of multimodal literacies in a variety of learning contexts. Literacy entails not only reading and writing, but, working in different modes, effectively expressing oneself and understanding others’ expressions. Developing multimodal literacies is a powerful tool to foster learning and understanding and hence to improve school education. If what this book is about is likely to appeal to you, I recommend that you arrange to borrow a copy for a while.

Giuliana Dettori
Motteram, Gary ed (2013) Innovations in learning technology for English language teachingBritish Council (London) isbn 978‐0‐86355‐713‐2 197 pp £12 (free download) http://www.teachingenglish.org.uk/sites/teacheng/files/C607%20Information%20and%20Communication_WEB%20ONLY_FINAL.pdf
Authors: Laborda Jesús García
Published: February 2014

This reader‐friendly volume brings a lot of fresh ideas to teaching English as a foreign language. However, not only teachers of English may benefit from it—teachers of other subjects may do so as well, if they have a genuine interest in the use of new technologies in the classroom. The free availability is a plus, and I recommend you to download your own copy, even if the book does not at once seem directly relevant to you.

Jesús García Laborda
Nelson, Brian C & Erlandson, Benjamin E (2012) Design for learning in virtual worlds Routledge (New York & London) isbn 978‐0‐415‐88640‐6 215 pp £24.99 http://www.routledge.com/books/details/9780415886406/
Authors: Hedberg John G
Published: February 2014

Nelson and Erlandson have collated a summary of the work of early designers and researchers into virtual worlds for learning and assessment. While it is confined to those experiences already well known in the literature, it does provide a basic introduction for undergraduates. If it seems that this book could be relevant to you, I advise that you will probably find only parts of it of interest or use.

John G Hedberg
How Does China's New Labour Contract Law Affect Floating Workers?
Authors: Li Xiaoying , Freeman Richard B.
Published: February 2014

China's new Labour Contract Law took effect in January 2008 and required firms to give migrant workers written contracts, strengthened labour protections for workers and contained penalties for firms that did not follow the labour code. This article uses survey data of migrant workers in the Pearl River Delta before and after the law, and a retrospective question on when workers received their first labour contract to assess the effects of the law on labour outcomes. The evidence shows that the new law increased the percentage of migrant workers with written contracts, which in turn raised social insurance coverage, reduced the likelihood of wage arrears and raised the likelihood that workers had a union at their workplace.
Thematic analysis of the effectiveness of an inpatient mindfulness group for adults with intellectual disabilities
Authors: Yildiran Hatice , Holt Rachel R.
Published: February 2014

Accessible summary

Mindfulness helps people focus instead of worrying about the past or future.

We talked to six people who took part in a mindfulness group.

They all had intellectual disabilities and were in hospital for mental health problems.

They told us the group helped, and we hope that mindfulness can help other people too.

The study focused on the effectiveness of group mindfulness for people with intellectual disabilities in an assessment and treatment unit. Six participants with mild or moderate intellectual disabilities were interviewed using semi‐structured interviews. The interviews focused on identifying the benefits and difficulties of using mindfulness. The interviews were analysed using thematic analysis. Five themes were identified which were categorised into interpersonal (‘helping people’) and intrapersonal (‘focusing on one particular thing’; ‘improving skills’; get rid of all nasty bad stuff you want to get rid of’) benefits. The theme ‘bit too late to teach old dog new tricks’ captured the difficulties encountered. The themes highlighted that people with intellectual disabilities were able to form an understanding of mindfulness and were able to benefit from the intervention.
Challenges for opioid receptor nomenclature: IUPHAR Review 9
Authors: Cox Brian M , Christie Macdonald J , Devi Lakshmi , Toll Lawrence , Traynor John R
Published: February 2014

Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo‐ or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Acute desipramine restores presynaptic cortical defects in murine experimental autoimmune encephalomyelitis by suppressing central CCL5 overproduction
Authors: Di Prisco Silvia , Merega Elisa , Lanfranco Massimiliano , Casazza Simona , Uccelli Antonio , Pittaluga Anna
Published: February 2014

Background and Purpose

Altered glutamate exocytosis and cAMP production in cortical terminals of experimental autoimmune encephalomyelitis (EAE) mice occur at the early stage of disease (13 days post‐immunization, d.p.i.). Neuronal defects were paralleled by overexpression of the central chemokine CCL5 (also known as RANTES), suggesting it has a role in presynaptic impairments. We propose that drugs able to restore CCL5 content to physiological levels could also restore presynaptic defects. Because of its efficacy in controlling CCL5 overexpression, desipramine (DMI) appeared to be a suitable candidate to test our hypothesis.

Experimental Approach

Control and EAE mice at 13 d.p.i. were acutely or chronically administered DMI and monitored for behaviour and clinical scores. Noradrenaline and glutamate release, cAMP, CCL5 and TNF‐α production were quantified in cortical synaptosomes and homogenates. Peripheral cytokine production was also determined.

Key Results

Noradrenaline exocytosis and α2‐adrenoeceptor‐mediated activity were unmodified in EAE mice at 13 d.p.i. when compared with control. Acute, but not chronic, DMI reduced CCL5 levels in cortical homogenates of EAE mice at 13 d.p.i., but did not affect peripheral IL‐17 and TNF‐α contents or CCL5 plasma levels. Acute DMI caused a long‐lasting restoration of glutamate exocytosis, restored endogenous cAMP production and impeded the shift from inhibition to facilitation of the CCL5‐mediated control of glutamate exocytosis. Finally, DMI ameliorated anxiety‐related behaviour but not motor activity or severity of clinical signs.

Conclusions

We propose DMI as an add‐on therapy to normalize neuropsychiatric symptoms in multiple sclerosis patients at the early stage of the disease.
CO and CO‐releasing molecules (CO‐RMs) in acute gastrointestinal inflammation
Authors: Babu D , Motterlini R , Lefebvre R A
Published: February 2014

Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti‐inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO‐releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post‐operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6
Oxytocin inhibits the activity of acid‐sensing ion channels through the vasopressin, V1A receptor in primary sensory neurons
Authors: Qiu Fang , Qiu Chun‐Yu , Cai Huilan , Liu Ting‐Ting , Qu Zu‐Wei , Yang Zhifan , Li Jia‐Da , Zhou Qun‐Yong , Hu Wang‐Ping
Published: February 2014

Background and Purpose

A growing number of studies have demonstrated that oxytocin (OT) plays an analgesic role in modulation of nociception and pain. Most work to date has focused on the central mechanisms of OT analgesia, but little is known about whether peripheral mechanisms are also involved. Acid‐sensing ion channels (ASICs) are distributed in peripheral sensory neurons and participate in nociception. Here, we investigated the effects of OT on the activity of ASICs in dorsal root ganglion (DRG) neurons.

Experimental Approach

Electrophysiological experiments were performed on neurons from rat DRG. Nociceptive behaviour was induced by acetic acid in rats and mice lacking vasopressin, V1A receptors.

Key Results

OT inhibited the functional activity of native ASICs. Firstly, OT dose‐dependently decreased the amplitude of ASIC currents in DRG neurons. Secondly, OT inhibition of ASIC currents was mimicked by arginine vasopressin (AVP) and completely blocked by the V1A receptor antagonist SR49059, but not by the OT receptor antagonist L‐368899. Thirdly, OT altered acidosis‐evoked membrane excitability of DRG neurons and significantly decreased the amplitude of the depolarization and number of action potentials induced by acid stimuli. Finally, peripherally administered OT or AVP inhibited nociceptive responses to intraplantar injection of acetic acid in rats. Both OT and AVP also induced an analgesic effect on acidosis‐evoked pain in wild‐type mice, but not in V1A receptor knockout mice.

Conclusions and Implications

These results reveal a novel peripheral mechanism for the analgesic effect of OT involving the modulation of native ASICs in primary sensory neurons mediated by V1A receptors.
Orexin/hypocretin role in reward: implications for opioid and other addictions
Authors: Baimel Corey , Bartlett Selena E , Chiou Lih‐Chu , Lawrence Andrew J , Muschamp John W , Patkar Omkar , Tung Li‐Wei , Borgland Stephanie L
Published: February 2014

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti‐craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug‐induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid‐mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co‐express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the ‘anti‐reward’ effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction‐related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Transient receptor potential cation channels in visceral sensory pathways
Authors: Blackshaw L Ashley
Published: February 2014

The extensive literature on this subject is in direct contrast to the limited range of clinical uses for ligands of the transient receptor potential cation channels (TRPs) in diseases of the viscera. TRPV1 is the most spectacular example of this imbalance, as it is in other systems, but it is nonetheless the only TRP target that is currently targeted clinically in bladder sensory dysfunction. It is not clear why this discrepancy exists, but a likely answer is in the promiscuity of TRPs as sensors and transducers for environmental mechanical and chemical stimuli. This review first describes the different sensory pathways from the viscera, and on which nociceptive and non‐nociceptive neurones within these pathways TRPs are expressed. They not only fulfil roles as both mechano‐ and chemo‐sensors on visceral afferents, but also form an effector mechanism for cell activation after activation of GPCR and cytokine receptors. Their role may be markedly changed in diseased states, including chronic pain and inflammation. Pain presents the most obvious potential for further development of therapeutic interventions targeted at TRPs, but forms of inflammation are emerging as likely to benefit also. However, despite much basic research, we are still at the beginning of exploring such potential in visceral sensory pathways.

Linked Articles

This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐10
Developmental rodent models of fear and anxiety: from neurobiology to pharmacology
Authors: Ganella Despina E , Kim Jee Hyun
Published: February 2014

Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear‐related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic ‘unlearned’ fear are poorly understood, especially beyond the period of infancy. Models using ‘learned’ fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour‐shock preferences, and then switch to more adult‐like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (includingNMDA,GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders.

Linked Articles

This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue-20
Geographic variation in animal colour polymorphisms and its role in speciation
Authors: McLean Claire A. , Stuart‐Fox Devi
Published: February 2014

Polymorphic species, in which multiple variants coexist within a population, are often used as model systems in evolutionary biology. Recent research has been dominated by the hypothesis that polymorphism can be a precursor to speciation. To date, the majority of research regarding polymorphism and speciation has focused on whether polymorphism is maintained within a population or whether morphs within populations may diverge to form separate species (sympatric speciation); however, the geographical context of speciation in polymorphic systems is likely to be both diverse and complex. In this review, we draw attention to the geographic variation in morph composition and frequencies that characterises many, if not most polymorphic species. Recent theoretical and empirical developments suggest that such variation in the number, type and frequency of morphs present among populations can increase the probability of speciation. Thus, the geographical context of a polymorphism requires a greater research focus. Here, we review the prevalence, causes and evolutionary consequences of geographic variation in polymorphism in colour‐polymorphic animal species. The prevalence and nature of geographic variation in polymorphism suggests that polymorphism may be a precursor to and facilitate speciation more commonly than appreciated previously. We argue that a better understanding of the processes generating geographic variation in polymorphism is vital to understanding how polymorphism can promote speciation.
Epigenetic dysregulation in glioma
Authors: Kondo Yutaka , Katsushima Keisuke , Ohka Fumiharu , Natsume Atsushi , Shinjo Keiko
Published: February 2014

Given that treatment options for patients with glioblastoma are limited, much effort has been made to clarify the underlying mechanisms of gliomagenesis. Recent genome‐wide genomic and epigenomic analyses have revealed that mutations in epigenetic modifiers occur frequently in gliomas and that dysregulation of epigenetic mechanisms is closely associated with glioma formation. Given that epigenetic changes are reversible, understanding the epigenetic abnormalities that arise in gliomagenesis might be key to developing more effective treatment strategies for glioma. In this review, we focus on the recent advancements in epigenetic research with respect to gliomas, consider how epigenetic mechanisms dynamically regulate tumor cells, including the cancer stem cell population, and discuss perspectives and challenges for glioma treatment in the near future.
Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ
Authors: Osako Tomo , Iwase Takuji , Ushijima Masaru , Horii Rie , Fukami Yasuyoshi , Kimura Kiyomi , Matsuura Masaaki , Akiyama Futoshi
Published: February 2014

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole‐node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle‐biopsy diagnosis of DCIS who underwent SN biopsy using the one‐step nucleic acid amplification assay in the period 2009–2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro‐ and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro‐ and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS.
How Well Socially Wary Preschoolers Fare Over Time Depends on Their Parasympathetic Regulation and Socialization
Authors: Hastings Paul D. , Kahle Sarah , Nuselovici Jacob M.
Published: February 2014

Parasympathetic regulation and maternal overprotective parenting were examined in 101 children as moderators of links between preschool (M = 3.53 years) social wariness and childhood (M = 9.07 years) internalizing and anxiety problems, social skills, and scholastic performance. Across these three domains of functioning, more socially wary children were likely to manifest worse adjustment when they had low respiratory sinus arrhythmia (RSA) or highly overprotective mothers. Conversely, maternal overprotection appeared to confer benefits for preschoolers with low wariness and low RSA. These findings point to the importance of both internal self‐regulatory capacities and external support for autonomy and competence to understand and assist socially wary children and their families.
Local increase in IgE and class switch recombination to IgE in nasal polyps in chronic rhinosinusitis
Authors: Baba S. , Kondo K. , Toma‐Hirano M. , Kanaya K. , Suzukawa K. , Ushio M. , Suzukawa M. , Ohta K. , Yamasoba T.
Published: February 2014

Background

Chronic rhinosinusitis with nasal polyps is generally characterized by local Th2 inflammation and is categorized into two subtypes in Japan: eosinophilic chronic rhinosinusitis (similar to chronic rhinosinusitis with nasal polyps in western countries) and non‐eosinophilic chronic rhinosinusitis (characterized by Th1‐dominant inflammation).

Objective

To investigate local IgE production and class switch recombination to IgE in these two subtypes of chronic rhinosinusitis with nasal polyps.

Methods

The identity of IgE‐positive cells was determined using double‐immunofluorescent staining for IgE and cell‐type‐specific molecular markers. To investigate the local class switch recombination to IgE and IgE synthesis in the mucosa, we performed real‐time polymerase chain reaction to examine the mRNA expression of Th2 cytokines and class‐switch‐related molecules, including IL‐4, IL‐5, IL‐13, ε germline gene transcripts, IgE mature transcript, IgG mature transcript, RAG1, RAG2 and activation‐induced cytidine deaminase in eosinophilic polyps, non‐eosinophilic polyps and controls.

Results

The concentrations of total IgE and number of IgE‐positive cells were significantly higher in the eosinophilic polyps compared with control and non‐eosinophilic polyps. IgE‐positive cells were predominantly mast cells in eosinophilic polyps and significantly correlated with the number of FcεR1‐positive cells in the subepithelial layer. IL‐5 and IL‐13 mRNA and ε germline gene transcripts expression levels were significantly higher in eosinophilic polyps compared with control and non‐eosinophilic polyps. In contrast, the number of plasma cells and the expression of IgG mature transcripts were increased in non‐eosinophilic polyps compared with eosinophilic polyps. RAG2 mRNA was significantly increased in both eosinophilic and non‐eosinophilic polyps compared with control mucosa.

Conclusion and Clinical Relevance

The current study suggests local class switching to IgE, production of IgE and IgE localization to the surface of mast cells in eosinophilic chronic rhinosinusitis in the Japanese population. The difference in the IgE‐related profiles between eosinophilic chronic rhinosinusitis and non‐eosinophilic chronic rhinosinusitis suggests heterogeneity in the pathogenesis of chronic rhinosinusitis with nasal polyps.
Exposure to Helicobacter pylori infection in early childhood and the risk of allergic disease and atopic sensitization: a longitudinal birth cohort study
Authors: Amberbir A. , Medhin G. , Abegaz W. E. , Hanlon C. , Robinson K. , Fogarty A. , Britton J. , Venn A. , Davey G.
Published: February 2014

Background

An inverse relation between Helicobacter pylori infection and allergic disease has been reported by a range of independent epidemiological studies, but evidence from longitudinal studies is scarce.

Objective

We have investigated the effects of H. pylori infection on the incidence and prevalence of allergic diseases and sensitization in a low‐income birth cohort.

Methods

In 2005/2006, a population‐based birth cohort was established in Butajira, Ethiopia, and the 1006 singleton babies born were followed up at ages 1, 3, and 5. Symptoms of allergic disease were collected using the ISAAC questionnaire, allergen skin tests performed, and stool samples analysed for H. pylori antigen and geohelminths. Multiple logistic regression was used to determine the independent effects of H. pylori measured at age 3 on the incidence of each outcome between ages 3 and 5 years (in those without the outcome at age 3), controlling for potential confounders, and to additionally assess cross‐sectional associations.

Results

A total of 863 children were followed up to age 5. H. pylori infection was found in 25% of the children at both ages 3 and 5, in 21% at age 5 but not 3, and in 17% at age 3 but not at age 5. H. pylori infection at age 3 was significantly associated with a decreased risk of incident eczema between ages 3 and 5 (adjusted OR, 95% CI, 0.31; 0.10–0.94, P = 0.02). Cross‐sectionally at age 5, H. pylori infection was inversely associated with skin sensitization (adjusted OR, 95% CI, 0.26; 0.07–0.92, P = 0.02).

Conclusion and clinical relevance

These findings provide further evidence to suggest that early‐life exposure to H. pylori may play a protective role in the development of allergy.
Interferon (IFN)-γ-mediated inflammation and the kynurenine pathway in relation to bone mineral density: the Hordaland Health Study
Authors: Apalset E M , Gjesdal C G , Ueland P M , Midttun Ø , Ulvik A , Eide G E , Meyer K , Tell G S
Published: February 2014

The risk of osteoporosis increases in inflammatory disorders. In cell-mediated immune activation, interferon (IFN)-γ stimulates macrophage release of neopterin and increases the activity of indoleamine 2,3-dioxygenase (IDO), thereby stimulating tryptophan degradation along the kynurenine pathway. Plasma levels of neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Several kynurenine pathway metabolites (kynurenines) possess immunomodulatory properties. The aim of this study was to investigate associations between markers of IFN-γ-mediated inflammation and kynurenines with bone mineral density (BMD). The community-based Hordaland Health Study (HUSK), with middle-aged (46–49 years) and older (71–74 years) participants, was conducted from 1998 to 2000 (n = 5312). Hip BMD in relation to neopterin, KTR and kynurenines were investigated, using linear and logistic regression analyses. In the oldest group, neopterin (P ≤ 0·019) and KTR (P ≤ 0·001) were associated inversely with BMD after multiple adjustment. Comparing the highest to the lowest quartiles, the odds ratios of low BMD (being in the lowest quintile of BMD) in the oldest cohort were for neopterin 2·01 among men and 2·34 among women (P ≤ 0·007) and for KTR 1·80 for men and 2·04 for women (P ≤ 0·022). Xanthurenic acid was associated positively with BMD in all sex and age groups while 3-hydroxyanthranilic acid was associated positively with BMD among women only (P ≤ 0·010). In conclusion, we found an inverse association between BMD and markers of IFN-γ-mediated inflammation in the oldest participants. BMD was also associated with two kynurenines in both age groups. These results may support a role of cell-mediated inflammation in bone metabolism.
Multi-functional flow cytometry analysis of CD4+ T cells as an immune biomarker for latent tuberculosis status in patients treated with tumour necrosis factor (TNF) antagonists
Authors: Sauzullo I , Scrivo R , Mengoni F , Ermocida A , Coppola M , Valesini G , Vullo V , Mastroianni C M
Published: February 2014

Although monitoring tuberculosis (TB) infection during long-term treatment with tumour necrosis factor (TNF) antagonists is of great importance, no monitoring strategy has yet proved successful. Indeed, even the newly proposed interferon-gamma release assays (IGRAs) are known to produce dynamic changes in IFN-γ plasma levels, making them unreliable indicators of patients' pathological/clinical status. We used intracellular cytokine flow cytometry (ICCFC) to investigate the performance of multi-functional CD4+ T cells producing IFN-γ, interleukin (IL)-2 and/or TNF in response to Mycobacterium tuberculosis-specific antigens in subjects treated with TNF antagonists. Patients were classified into three groups based on their TB status before commencement of treatment and on IFN-γ level fluctuations evaluated by IGRA during a 36-month follow-up period. The cytokine profile of M. tuberculosis-specific CD4+ T cells showed that latent tuberculosis infection (LTBI) subjects had a higher frequency of double-positive IFN-γ+ IL-2+ CD4+ T cells and triple-positive IFN-γ+ IL-2+ TNF+ CD4+ T cells compared to those without LTBI, who showed IFN-γ-level fluctuations over time. In contrast, this latter group of patients showed similar proportions of cells producing IFN-γ alone, IL-2 alone and IL-2 in combination with TNF in response to M. tuberculosis-specific antigens. It therefore appears that patients with and without LTBI infection are characterized by different intracellular cytokine profiles. This is the first study evaluating ICCFC in patients treated with TNF antagonists, and suggests that multi-functional analysis of CD4+ T cells could be useful for ruling out TB infection in patients classified at screening as LTBI-negative but who show IGRA fluctuations under long-term TNF antagonist treatment.
Functional imaging in primary tumour‐induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor‐based functional scans: a series of nine patients
Authors: Jadhav Swati , Kasaliwal Rajeev , Lele Vikram , Rangarajan Venkatesh , Chandra Piyush , Shah Hina , Malhotra Gaurav , Jagtap Varsha S. , Budyal Sweta , Lila Anurag R. , Bandgar Tushar , Shah Nalini S.
Published: February 2014

Context

Localization of phosphatonin‐producing mesenchymal tumours in patients with primary tumour‐induced osteomalacia (pTIO) is challenging. Functional imaging plays an important role in the localization of these tumours.

Objective

We studied the relative performance of different functional imaging modalities (18F‐FDG PET/CT, 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT) in tumour localization in cases of pTIO.

Design and Methods

Retrospective chart evaluation of 16 patients with confirmed TIO treated from 2006 to 2013 was conducted in a tertiary care referral centre.

Results

Of 16, nine patients had pTIO. In these nine, the positivity rates of different functional imaging modalities were 50% for 18 F‐FDG PET/CT (four of eight patients), 100% for 99Tc‐HYNIC‐TOC SPECT/CT (six of six patients) and 100% for 68Ga‐DOTATATE PET/CT (seven of seven patients). Of nine patients, six were subjected to both the 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT and all of them showed coregistration on the two scans.

Conclusions

In patients with pTIO, the somatostatin receptor‐based functional scans performed better than 18F‐FDG PET/CT in tumour localization. Amongst the somatostatin receptor‐based scans, 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT performed equally well for localization of tumours.
Graves' disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently?
Authors: Weetman Anthony P.
Published: February 2014

Graves' disease and other disorders of thyroid function may occur following treatment with novel anticancer agents or during periods of lymphocyte recovery after lymphopenia. There are three main settings for such lymphocyte reconstitution: recovery after a bone marrow or haematopoietic stem cell transplant, alemtuzumab treatment and the use of highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection. The available evidence suggests that Graves' disease behaves as normal in most of these cases and should be treated conventionally, but it may follow a more favourable course in those receiving alemtuzumab or HAART. As spontaneous or drug‐induced remission may be more likely in these two settings, first‐line treatment should usually consist of an antithyroid drug.