bluuebunny/crossref_metadata_2025 huggingface dataset:
GM Crop Coexistence in Practice: Delivering Real Choices for Farmers and Consumers
Authors: Pearsall Daniel
Published: April 2016

The political context which frames the EU policy debate over farm‐level coexistence between genetically modified (GM) and non‐GM crops has progressively lost sight of the practical and commercial realities involved. Instead of providing the basis for farmers and consumers to exercise a meaningful choice in relation to approved GM and non‐GM products, the politically motivated use of disproportionate or unworkable coexistence measures has in itself become a further barrier to GM crop adoption in Europe. Yet coexistence is not a new concept in agriculture, and well‐established practices exist throughout the farm supply chain to produce, segregate, store and deliver harvested crops to specified levels of quality and purity. In each case, the level of market differentiation – not the degree of political prejudice – determines the nature and cost of the segregation procedures applied. This article argues that worldwide experience of managing GM crop coexistence in practice suggests that a supply chain‐based approach to managing GM crop coexistence – rather than Government prescription – offers the most effective solution to servicing differentiated market demands.
Corporate Strategy on GMOs under Alternative Futures: The Case of a Large Food Retailer in Italy
Authors: Passuello Francesca , Boccaletti Stefano
Published: April 2016

This article analyses the possible response strategies of a large Italian food retailer to alternative future scenarios for the segregation of GM and non‐GM products/ingredients in EU feed and food supply chains. Scenarios were developed by key EU feed‐food supply chain stakeholders during a 2‐day workshop held in Brussels in September 2014. Based on two major drivers, namely regulatory framework and perception of genetically modified organisms, stakeholders ended up with three scenarios: 1) Enabling regulatory framework, negative consumer's perception of GMOs; 2) Restrictive regulatory framework, positive consumer's perception of GMOs; 3) Restrictive regulatory framework, negative consumer's perception of GMOs. The retailer's strategy, which entails the certification of all the products sold under its private label as non‐GM, could be modified under different future scenarios. For example, with an increase in segregation costs due to a more restrictive regulatory framework and a positive perception of GMOs, the retailer may decide to differentiate private labels based on other safety/quality attributes or on the direct benefits for consumers of second generation quality‐enhanced GM products. If instead under a restrictive regulation the consumer's perception was still negative, the de facto ban of GMOs in the EU would probably cancel the retailer's exclusive reputational benefits from its voluntary non‐GM schemes, making this differentiation process unprofitable.
A Question of Segregation: ‘GM‐free’ Maize Bread in Portugal
Authors: Quedas Fátima , Ponte João , Trindade Carlos , Punt Maarten , Wesseler Justus
Published: April 2016

We describe the maize supply chain in Portugal for maize bread, a traditional bread type. As this bread is not labelled as ‘contains genetically modified organisms’ it should not contain more than 0.9 per cent genetically modified ingredients. On the basis of interviews we identify a general lack of documentation of the presence or absence of genetically modified ingredients along the complete supply chain (farmers, traders, mills and bakeries). Part of this deficiency is probably driven by a lack of awareness of the labelling rules at the end of the supply chain. A test of maize bread showed that more than 40 per cent of breads were indeed over the labelling threshold, and should be labelled. This includes GM maize that is not cultivated in the EU and enters the supply chain via international trade. We conclude that the realisation of coexistence and segregation requires involvement of the full supply chain, rather than just segregation at the start, if bread is to be sold with a GMO content below the 0.9 per cent threshold level. Alternatively, retailers can label their bread. This might be a cheaper solution and as a study from Switzerland shows may not result in adverse consumer reaction.
Detecting the movement and spawning activity of bigheaded carps with environmental DNA
Authors: Erickson Richard A. , Rees Christopher B. , Coulter Alison A. , Merkes Christopher M. , McCalla Sunnie G. , Touzinsky Katherine F. , Walleser Liza , Goforth Reuben R. , Amberg Jon J.
Published: April 2016

Bigheaded carps are invasive fishes threatening to invade the Great Lakes basin and establish spawning populations, and have been monitored using environmental DNA (eDNA). Not only does eDNA hold potential for detecting the presence of species, but may also allow for quantitative comparisons like relative abundance of species across time or space. We examined the relationships among bigheaded carp movement, hydrography, spawning and eDNA on the Wabash River, IN, USA. We found positive relationships between eDNA and movement and eDNA and hydrography. We did not find a relationship between eDNA and spawning activity in the form of drifting eggs. Our first finding demonstrates how eDNA may be used to monitor species abundance, whereas our second finding illustrates the need for additional research into eDNA methodologies. Current applications of eDNA are widespread, but the relatively new technology requires further refinement.
Diagnosis of hypersexual or compulsive sexual behavior can be made using ICD‐10 and DSM‐5 despite rejection of this diagnosis by the American Psychiatric Association
Authors: Krueger Richard B.
Published: April 2016

Commentary to: Should compulsive sexual behavior be considered an addiction?
The main signs of ageing in people with intellectual disability
Authors: Wark Stuart , Hussain Rafat , Edwards Helen
Published: April 2016

Objective

Investigations around ageing with an intellectual disability have increased substantially in the past three decades. A research gap continued to exist regarding the detection of ageing issues in this cohort of people, particularly in rural areas where access to specialist support continued to be limited. The purpose of this study was to identify the main signs of ageing in rural people with intellectual disabilities.

Design

A multi‐round Delphi design was used to examine what signs of ageing were observed by disability support staff, who assisted people with intellectual disability.

Setting

The project was conducted across nine of the ten rural regions (as defined by the government funding body) in New South Wales (NSW).

Participants

There were 31 participants representing 14 non‐government organisations. The group was composed of 26 women and 5 men, with a mean age of 47 years, who averaged 10‐year experience with people with intellectual disabilities.

Main Outcome Measures

The objective was to gain the direct input of rurally based disability workers to identify the main signs of ageing in people with intellectual disabilities.

Results

Thirty‐two specific signs of ageing, including emerging mental health issues, grief, loss of identity and aggression, were identified. A thematic analysis indicated two main categories: mental/emotional functioning and physical functioning.

Conclusions

When carers have the information and skills needed to identify the main signs of ageing, they can more accurately recognise and address potential problems in a timely manner. Such understandings have the potential to reduce premature admissions to residential aged‐care.
Childhood atopic dermatitis—Brain‐derived neurotrophic factor correlates with serum eosinophil cationic protein and disease severity
Authors: Fölster‐Holst R. , Papakonstantinou E. , Rüdrich U. , Buchner M. , Pite H. , Gehring M. , Kapp A. , Weidinger S. , Raap U.
Published: April 2016

Several studies have shown that neurotrophins including brain‐derived neurotrophic factor (BDNF) play a role in chronic inflammatory skin diseases such as atopic dermatitis (AD). BDNF is increased in the serum samples of adults with AD. Interestingly, eosinophils of these patients can release and produce BDNF. We analyzed BDNF serum levels with ELISA and their correlation with SCORAD score, eosinophil cationic protein (ECP), total IgE, IL‐4, IL‐13 and IL‐31 in children with AD (n = 56) compared to nonatopic healthy children (n = 25). In addition, we analyzed FLG loss‐of‐function mutations in 17 children with AD and their connection to BDNF. BDNF serum levels were significantly higher in children with AD. Further, BDNF correlated with disease activity, serum ECP, and total IgE serum levels in AD. There was no difference in BDNF levels of filaggrin‐positive or filaggrin‐negative children with AD, and there was no correlation of BDNF with IL‐31 and Th2 cytokines including IL‐4 and IL‐13. Together, our data add new insights into the pathophysiology of AD, suggesting that serum BDNF which correlates with disease severity contributes to the regulation of inflammation in an eosinophil‐, but not Th2‐dependent manner.
The Effect of an Interphase Interval on Electrically Induced Dorsiflexion Force and Fatigue in Subjects With an Upper Motor Neuron Lesion
Authors: Becher Meni , Springer Shmuel , Braun‐Benyamin Orit , Laufer Yocheved
Published: April 2016

The study objective was to investigate the effects of an interphase interval (IPI) interposed between the two phases of a biphasic symmetric pulse, on electrically induced contraction (EIC) forces and fatigue during stimulation of the ankle dorsiflexors in individuals with an upper motor neuron lesion (UMNL). The dorsiflexor muscles of 20 subjects with UMNL routinely using functional electrical stimulation to correct a foot drop during ambulation, were electrically stimulated with biphasic pulses (250 µs phase duration and 35 Hz pulse frequency) using nine IPI durations (ranging from 0 to 400 µs). The induced muscle force and fatigue were measured. A significant positive correlation was found between IPI duration and induced muscle force. Introducing a 250 µs IPI significantly decreased rate of muscle fatigue compared to stimulation with no IPI (P < 0.05). Thus, the introduction of an IPI may reduce the current intensity required to achieve a specific force during functional electrical stimulation in individuals with UMNL. Reduction in muscle fatigue may shorten the conditioning period necessary for first time users of functional electrical stimulation.
Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles
Authors: Allegretti J. R. , Kearney S. , Li N. , Bogart E. , Bullock K. , Gerber G. K. , Bry L. , Clish C. B. , Alm E. , Korzenik J. R.
Published: April 2016

Background

The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI.

Aim

To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes.

Methods

Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels.

Results

Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups.

Conclusions

Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence.
Meta‐analysis of erythrocyte polyunsaturated fatty acid biostatus in bipolar disorder
Authors: McNamara Robert K. , Welge Jeffrey A.
Published: April 2016

Objectives

Dietary deficiency in polyunsaturated fatty acids (PUFAs), including the omega‐3 fatty acids eicosapentaenoic acid (EPA; 20:5n‐3) and docosahexaenoic acid (DHA; 22:6n‐3), and excesses in omega‐6 fatty acids, including linoleic acid (LA; 18:2n‐6) and arachidonic acid (AA; 20:4n‐6), may be associated with the pathophysiology of bipolar disorder. In an effort to provide clarification regarding the relationship between PUFA biostatus and bipolar disorder, this meta‐analysis investigated studies comparing erythrocyte (red blood cell) membrane PUFA composition in patients with bipolar disorder and healthy controls.

Methods

A meta‐analysis was performed on case–control studies comparing erythrocyte PUFA (EPA, DHA, LA and AA) levels in patients with bipolar I disorder and healthy controls. Standardized effect sizes were calculated and combined using a random effects model.

Results

Six eligible case‐control studies comprising n = 118 bipolar I patients and n = 147 healthy controls were included in the analysis. Compared with healthy controls, patients with bipolar I disorder exhibited robust erythrocyte DHA deficits (p = 0.0008) and there was a trend for lower EPA (p = 0.086). There were no significant differences in LA (p = 0.42) or AA (p = 0.64).

Conclusions

Bipolar I disorder is associated with robust erythrocyte DHA deficits. These findings add to a growing body of evidence implicating omega‐3 PUFA deficiency in the pathophysiology of bipolar disorder.
Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats
Authors: Yokohira Masanao , Nakano‐Narusawa Yuko , Yamakawa Keiko , Hashimoto Nozomi , Yoshida Shota , Kanie Shohei , Imaida Katsumi
Published: April 2016

Fiber‐shaped particles of potassium octatitanate (tradename TISMO; chemical formula K2O·6TiO2), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment carried out over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co‐administration of the fibers with a known carcinogen. To detect the induction of malignant pleural mesotheliomas, two experiments were undertaken. In Experiment 1, four strains of mice, A/J, C3H, ICR, and C57BL, were examined for 52 weeks after experimental treatment with TISMO. In Experiment 2, the F344 rats were treated with TISMO alone, the lung carcinogen N‐bis (2‐hydroxypropyl) nitrosamine (DHPN) alone, both TISMO and DHPN, or left untreated and were then examined for 52 weeks. In this experiment, malignant lesion induction was expected in the co‐administration group. TISMO fibers were observed in the alveoli, indicating penetration through the visceral pleura in mice and rats. The histopathological detection of TISMO fibers in the liver and kidneys of mice and rats indicated migration of the fibers out of the pleural cavity. Atypical mesothelial cells with severe pleural proliferation were observed, but malignant mesotheliomas were not detected. Among the rats, there were no observed malignant alterations in the mesothelium induced by DHPN–TISMO co‐administration.
Equol inhibits prostate cancer growth through degradation of androgen receptor by S‐phase kinase‐associated protein 2
Authors: Itsumi Momoe , Shiota Masaki , Takeuchi Ario , Kashiwagi Eiji , Inokuchi Junichi , Tatsugami Katsunori , Kajioka Shunichi , Uchiumi Takeshi , Naito Seiji , Eto Masatoshi , Yokomizo Akira
Published: April 2016

Chemopreventive and potential therapeutic effects of soy isoflavones have been shown to be effective in numerous preclinical studies as well as clinical studies in prostate cancer. Although the inhibition of androgen receptor signaling has been supposed as one mechanism underlying their effects, the precise mechanism of androgen receptor inhibition remains unclear. Thus, this study aimed to clarify their mechanism. Among soy isoflavones, equol suppressed androgen receptor as well as prostate‐specific antigen expression most potently in androgen‐dependent LNCaP cells. However, the inhibitory effect on androgen receptor expression and activity was less prominent in castration‐resistant CxR and 22Rv1 cells. Consistently, cell proliferation was suppressed and cellular apoptosis was induced by equol in LNCaP cells, but less so in CxR and 22Rv1 cells. We revealed that the proteasome pathway through S‐phase kinase‐associated protein 2 (Skp2) was responsible for androgen receptor suppression. Taken together, soy isoflavones, especially equol, appear to be promising as chemopreventive and therapeutic agents for prostate cancer based on the fact that equol augments Skp2‐mediated androgen receptor degradation. Moreover, because Skp2 expression was indicated to be crucial for the effect of soy isoflavones, soy isoflavones may be applicable for precancerous and cancerous prostates.
B7‐H4 facilitates proliferation of esophageal squamous cell carcinoma cells through promoting interleukin‐6/signal transducer and activator of transcription 3 pathway activation
Authors: Chen Xinran , Wang Ling , Wang Wei , Zhao Lianmei , Shan Baoen
Published: April 2016

B7‐H4, one of the costimulatory molecules of the B7 family, has been found to be widely expressed in many kinds of tumor tissues and to play an important part in tumor progression and poor prognosis. However, the role of B7‐H4 in esophageal squamous cell carcinoma (ESCC) cells has not been elucidated. In this study, we found that, compared with normal esophageal tissue, B7‐H4 was highly expressed in three ESCC cell lines, Eca109, TE1, and TE13. B7‐H4 silenced cells suppressed cellular proliferation and colony formation. Additionally, compared with control cells, B7‐H4 silenced cells showed higher apoptosis rates, Bcl‐2 and Survivin upregulation, and BAX downregulation. Further study revealed that B7‐H4 silenced cells also showed reduction in interleukin‐6 (IL‐6) secretion, signal transducer and activator of transcription 3 (STAT3) activation, and p‐STAT3 translocation from cytoplasm to nucleus. Moreover, B7‐H4 depletion inhibited the IL‐6 secretion of control cells but not JAK2/STAT3 inhibitor FLLL32‐treated cells. Interleukin‐6 receptor antagonist tocilizumab did not block the p‐JAK2 or p‐STAT3 downregulation induced by B7‐H4 silence. It was suggested that B7‐H4 silence suppressed IL‐6 secretion through JAK2/STAT3 inactivation. Furthermore, cell proliferation and colony formation were downregulated by tocilizumab in control cells but not in B7‐H4 silenced cells, indicating that IL‐6 upregulation induced by B7‐H4 was necessary for cell growth. On the other hand, B7‐H4 expression was downregulated by tocilizumab. In all, our study provided the first evidence that B7‐H4 facilitated ESCC cell proliferation through promoting IL‐6/STAT3 positive loopback pathway activation.
A systematic literature review on the use of vacuum assisted closure for enterocutaneous fistula
Authors: Misky A. , Hotouras A. , Ribas Y. , Ramar S. , Bhan C.
Published: April 2016

Aim

Enterocutaneous fistula (ECF) is considered to be one of the most challenging complications a general surgeon can encounter. The current mainstay of treatment is surgical closure, associated with significant morbidity and mortality. Vacuum assisted closure (VAC) has been successfully used for closure of persistent abdominal wounds for a number of years. This study aims to investigate whether current literature supports the use of VAC for ECF.

Method

A PubMed search of the search terms ‘enterocutaneous fistula’ and ‘vacuum assisted closure/therapy’ was performed in December 2014. Results were restricted to articles involving human subjects with an available abstract and full text written between 1950 and 2014. The end‐points analysed included rate of fistula closure, duration of follow‐up, and morbidity and mortality where available.

Results

Ten studies (all level IV) including 151 patients were examined. In all except one, surgery was the underlying aetiology with median number of fistulae per patient of one. The median rate of closure with VAC was 64.6% (7.7–100%) with healing occurring within 58 (12–90) days. Follow‐up was only mentioned in three of the 10 studies, in which the patients were followed for 3, 20 and 28.5 months. No complications were reported in all but one of the studies, in which abdominal wall disruption and intestinal obstruction were identified in a minority of patients.

Conclusion

The included studies suggest that VAC therapy may be considered a safe treatment for ECF. The current evidence is generally of low level and characterized by heterogeneity. Definitive recommendations based on this information cannot therefore be made. Further studies are necessary to establish any proven benefit over standard surgical or conservative therapy.
Establishing a deceased donor program in north Indian region: lessons learnt
Authors: Gupta Vivek , Chandra Abhijit , Rahul  , Singh Manmeet , Shrivastava Peeyush Kumar , Singhai Atin , Ojha Bal Krishna , Chandra Girish , Khan Mohammed Parvez , Pandey Sant , Kant Ravi
Published: April 2016

Introduction

Living‐related donors are the source of almost all organ transplants in India. However, these donations fall far short of current needs, and there remains a huge disparity between demand and supply of organs. In the last five yr, a consistent increase in deceased donor transplant activity has been observed in some southern Indian states. This report describes our experience of establishing a new deceased donor program in the state of Uttar Pradesh in north India.

Methods

We describe our experience on counseling families of all brain‐dead patients admitted to our center from October 2013 to September 2014 and data on retrieving and transplanting organs.

Results

A total of 99 brain‐dead patients were identified, of which 67 were medically eligible as donors. Fourteen patients developed cardiac arrest before the counseling could begin. Only eight families agreed for multi‐organ donation.

Conclusion

Lack of consensus among the family members, mistrust of the medical system, fear of mutilation of the body, and delay in the funeral were identified as the main reasons behind negative consent. Conversely, mass media campaign, proper ICU care of brain‐dead patients, rapport with the family and streamlining all medico legal processes were associated with positive consent.
Inhibitory effects of heterotopic noxious counter‐stimulation on perception and brain activity related to Aβ‐fibre activation
Authors: Rustamov Nabi , Tessier Jessica , Provencher Benjamin , Lehmann Alexandre , Piché Mathieu
Published: April 2016

Heterotopic noxious counter‐stimulation (HNCS) inhibits pain and pain processes through cerebral and cerebrospinal mechanisms. However, it is unclear whether HNCS inhibits non‐nociceptive processes, which needs to be clarified for a better understanding of HNCS analgesia. The aim of this study was to examine the effects of HNCS on perception and scalp somatosensory evoked potentials (SEPs). Seventeen healthy volunteers participated in two counter‐balanced sessions, including non‐nociceptive (selective Aβ‐fibre activation) or nociceptive electrical stimulation, combined with HNCS. HNCS was produced by a 20‐min cold pressor test (left hand) adjusted individually to produce moderate pain (mean ± SEM: 42.5 ± 5.3 on a 0–100 scale, where 0 is no pain and 100 the worst pain imaginable). Non‐nociceptive electrical stimulation was adjusted individually at 80% of pain threshold and produced a tactile sensation in every subject. Nociceptive electrical stimulation was adjusted individually at 120% of RIII‐reflex threshold and produced moderate pain (45.3 ± 4.5). Shock sensation was significantly decreased by HNCS compared with baseline for non‐nociceptive (P < 0.001) and nociceptive (P < 0.001) stimulation. SEP peak‐to‐peak amplitude at Cz was significantly decreased by HNCS for non‐nociceptive (P < 0.01) and nociceptive (P < 0.05) stimulation. These results indicate that perception and brain activity related to Aβ‐fibre activation are inhibited by HNCS. The mechanisms of this effect remain to be investigated to clarify whether it involves inhibition of spinal wide‐dynamic‐range neurons by diffuse noxious inhibitory controls, supraspinal processes or both.
Dihydroorotate dehydrogenase depletion hampers mitochondrial function and osteogenic differentiation in osteoblasts
Authors: Fang JingXian , Yamaza Haruyoshi , Uchiumi Takeshi , Hoshino Yoshihiro , Masuda Keiji , Hirofuji Yuta , Wagener Frank A. D. T. G. , Kang Dongchon , Nonaka Kazuaki
Published: April 2016

Mutation of the dihydroorotate dehydrogenase (DHODH) gene is responsible for Miller syndrome, which is characterized by craniofacial malformations with limb abnormalities. We previously demonstrated that DHODH was involved in forming a mitochondrial supercomplex and that mutated DHODH led to protein instability, loss of enzyme activity, and increased levels of reactive oxygen species in HeLa cells. To explore the etiology of Miller syndrome in more detail, we investigated the effects of DHODH inhibition in the cells involved in skeletal structure. Dihydroorotate dehydrogenase in MC3T3‐E1 cells derived from mouse calvaria osteoblast precursor cells was knocked down by specific small interfering RNAs (siRNAs), and cell proliferation, ATP production, and expression of bone‐related genes were investigated in these cells. After depletion of DHODH using specific siRNAs, inhibition of cell proliferation and cell cycle arrest occurred in MC3T3‐E1 cells. In addition, ATP production was reduced in whole cells, especially in mitochondria. Furthermore, the levels of runt‐related transcription factor 2 (Runx2) and osteocalcin (Ocn) mRNAs were lower in DHODH siRNA‐treated cells compared with controls. These data suggest that depletion of DHODH affects the differentiation and maturation of osteoblasts. This study shows that mitochondrial dysfunction by DHODH depletion in osteoblasts can be directly linked to the abnormal bone formation in Miller syndrome.
Adenosine A1 receptor–mediated suppression of carbamazepine‐resistant seizure‐like events in human neocortical slices
Authors: Klaft Zin‐Juan , Hollnagel Jan‐Oliver , Salar Seda , Calişkan Gürsel , Schulz Steffen B. , Schneider Ulf C. , Horn Peter , Koch Arend , Holtkamp Martin , Gabriel Siegrun , Gerevich Zoltan , Heinemann Uwe
Published: April 2016

Objective

The need for alternative pharmacologic strategies in treatment of epilepsies is pressing for about 30% of patients with epilepsy who do not experience satisfactory seizure control with present treatments. In temporal lobe epilepsy (TLE) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of TLE patients. In this study we investigate purinergic modulation of drug‐resistant seizure‐like events (SLEs) in human temporal cortex slices.

Methods

Layer V/VI field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor SLEs induced by application of 8 mM [K+] and 50 μm bicuculline.

Results

Activating A1 receptors with a specific agonist completely suppressed SLEs in 73% of human temporal cortex slices. In the remaining slices, incidence of SLEs was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A1 agonist, in slices insensitive to a high dose of carbamazepine (50 μm). Also in these cases the A1 agonist was equally efficient. Moreover, ATP and adenosine blocked or modulated SLEs, an effect mediated not by P2 receptors but rather by adenosine A1 receptors.

Significance

Selective activation of A1 receptors mediates a strong anticonvulsant action in human neocortical slices from pharmacoresistant patients. We propose that our human slice model of seizure‐like activity is a feasible option for future studies investigating new antiepileptic drug (AED) candidates.
New directions in poly(ADP‐ribose) polymerase biology
Authors: Bock Florian J. , Chang Paul
Published: April 2016

Poly(ADP‐ribose) polymerases (PARPs) regulate the function of target proteins by modifying them with ADP‐ribose, a large and unique post‐translational modification. Humans express 17 PARPs; however, historically, much of the focus has been on PARP1 and its function in DNA damage repair. Recent work has uncovered an amazing diversity of function for these enzymes including the regulation of fundamental physiological processes in the cell and at the organismal level, as well as new roles in regulating cellular stress responses. In this review, we discuss recent advancements in our understanding of this important protein family, and technological developments that have been critical for moving the field forward. Finally, we discuss new directions that we feel are important areas of further scientific exploration.
Measuring Relative Sustainability of Regions Using Regional Sustainability Assessment Methodology
Authors: Smetana Sergiy , Tamásy Christine , Mathys Alexander , Heinz Volker
Published: April 2016

Scientists analyze sustainability at the regional level with a combination of multiple indicators which reflect different characteristics of regions without combining the results in a single comparative unit. Moreover, the assessment of interdependencies between different characteristics requires experts' analyses, which makes sustainability analysis subjective, time consuming, and limited in use. This article analyzes the relative sustainability of subnational level regions through the application of regional sustainability assessment methodology (RSAM) based on accounting of resources capital and its internal and external transfers. This approach allows for assessment of regional sustainability as a function of resource quantity, quality, and interchangeability. The comparison of the two case study regions presented in the paper indicates the difference between a more sustainable region and a region of “weak sustainability.” First, the article indicates the discussion of the relevant geographic, economic, and social literature for both sustainability assessment and regional comparison. This discussion is followed by a conceptual representation of proposed RSAM and its application to various regions. Next, the article covers the data used and applied methods to test the proposed methodology and compare the two case study regions. The article concludes with a discussion of findings and recommendations for further application and testing.
Refining peripheral blood smear review rules for neonatal inpatients in a South African academic laboratory
Authors: Vaughan J. , Alli N. , Mannaru K. , Sedick Q.
Published: April 2016

Introduction

Peripheral blood smear review (PBSR) is a labour‐intensive test, and skilled morphologists are in short supply. It is therefore helpful for laboratories to establish rules for PBSR to improve laboratory efficiency. Previously published guidelines in this regard are useful, but make few recommendations specific to neonates. Neonatal blood is characterized by several peculiarities which would be considered pathological if present in adults. Consequently, smear review rules (SRR) are often triggered in neonates without significant value being added on review. This study aimed to assess and fine‐tune the SRR triggered in neonatal samples in order to improve laboratory efficiency.

Methods

Full blood counts collected from 188 neonatal inpatients of the Chris Hani Baragwanath Academic Hospital in South Africa were retrospectively reviewed, the triggered rules documented, and the value added on PBSR determined.

Results

Smear review rules were triggered in 148 (78.7%) samples, with significant morphological abnormalities identified in 84 (54.4%), and a false‐positive rate of 34.0%. In patients with unhelpful review, the commonest rules triggered were the flags querying the presence of abnormal lymphocytes, blasts or nucleated red blood cells. When one or more of these flags were triggered in the absence of any other SRR, PBSR was always noncontributory. Disregarding these flags in the current cohort would reduce both the review and the false‐positive rates by >20% without increasing the false‐negative rate.

Conclusion

False‐positive smear review is common in neonates, and minor modifications to SRR can substantially reduce the smear review rate without increasing the false‐negative rate.
ADrosophilaheat shock response represents an exception rather than a rule amongst Diptera species
Authors: Zatsepina O. G. , Przhiboro A. A. , Yushenova I. A. , Shilova V. , Zelentsova E. S. , Shostak N. G. , Evgen'ev M. B. , Garbuz D. G.
Published: April 2016

Heat shock protein 70 (Hsp70) is the major player that underlies adaptive response to hyperthermia in all organisms studied to date. We investigated patterns of Hsp70 expression in larvae of dipteran species collected from natural populations of species belonging to four families from different evolutionary lineages of the order Diptera: Stratiomyidae, Tabanidae, Chironomidae and Ceratopogonidae. All investigated species showed a Hsp70 expression pattern that was different from the pattern inDrosophila. In contrast toDrosophila, all of the species in the families studied were characterized by high constitutive levels of Hsp70, which was more stable than that inDrosophila. When Stratiomyidae Hsp70 proteins were expressed inDrosophilacells, they became as short‐lived as the endogenous Hsp70. Interestingly, three species of Ceratopogonidae and a cold‐water species of Chironomidae exhibited high constitutive levels ofHsp70mRNA and high basal levels of Hsp70. Furthermore, two species of Tabanidae were characterized by significant constitutive levels of Hsp70 and highly stableHsp70mRNA. In most cases, heat‐resistant species were characterized by a higher basal level of Hsp70 than more thermosensitive species. These data suggest that different trends were realized during the evolution of the molecular mechanisms underlying the regulation of the responses ofHsp70genes to temperature fluctuations in the studied families.
New oral anticoagulants: appropriateness of prescribing in real‐world setting
Authors: Pattullo C. S. , Barras M. , Tai B. , McKean M. , Donovan P.
Published: April 2016

Background

The new oral anticoagulants (NOAC) have been extensively studied in the clinical trial setting; however, concerns remain about the safety of prescribing in the elderly and patients with renal impairment.

Aim

The aim of this study was to assess the appropriateness of NOAC prescribing in a real‐world setting in terms of patient selection and to compare patient demographics to those included in pivotal clinical trials.

Methods

One hundred and seventy‐six patients from three tertiary university teaching hospitals were identified over 3 months in 2014.

Results

Median age of the cohort was 74 years (interquartile range: 61–81 years), with a range of 23–96 years. Overall, 34% of the study population were prescribed a NOAC inappropriately. Of these, treatment was contraindicated in 40%, predominantly due to severe renal impairment, 22% were prescribed an excessively high dose, while 38% were under dosed. Although community‐initiated patients had poorer renal function (glomerular filtration rate 91.7 ± 55.7 vs 69.3 ± 38.9, P = 0.024), appropriateness of prescription was no different compared to hospital‐initiated patients (78% during admission cf. 61% prior, P = 0.061). Appropriate prescribing was better in patients with venous thromboembolism compared to AF (85% appropriate cf. 60%, P = 0.021).

Conclusion

Our findings imply that there remains considerable uncertainty about appropriate prescribing and dosing of NOAC, particularly in patients with impaired renal function. We recommend judicious prescribing and regular monitoring of renal function in patients at high risk of complications from NOAC therapy.
Microenvironmental cues for T‐cell acute lymphoblastic leukemia development
Authors: Passaro Diana , Quang Christine Tran , Ghysdael Jacques
Published: April 2016

Intensive chemotherapy regimens have led to a substantial improvement in the cure rate of patients suffering from T‐cell acute lymphoblastic leukemia (T‐ALL). Despite this progress, about 15% and 50% of pediatric and adult cases, respectively, show resistance to treatment or relapse with dismal prognosis, calling for further therapeutic investigations. T‐ALL is an heterogeneous disease, which presents intrinsic alterations leading to aberrant expression of transcription factors normally involved in hematopoietic stem/progenitor cell development and mutations in genes implicated in the regulation of cell cycle progression, apoptosis, and T‐cell development. Gene expression profiling allowed the classification of T‐ALL into defined molecular subgroups that mostly reflects the stage of their differentiation arrest. So far this knowledge has not translated into novel, targeted therapy. Recent evidence points to the importance of extrinsic signaling cues in controlling the ability of T‐ALL to home, survive, and proliferate, thus offering the perspective of new therapeutic options. This review summarizes the present understanding of the interactions between hematopoietic cells and bone marrow/thymic niches during normal hematopoiesis, describes the main signaling pathways implicated in this dialog, and finally highlights how malignant T cells rely on specific niches to maintain their ability to sustain and propagate leukemia.
Development of T‐cell tolerance utilizes both cell‐autonomous and cooperative presentation of self‐antigen
Authors: Perry Justin S. A. , Hsieh Chyi‐Song
Published: April 2016

The development of T‐cell self‐tolerance in the thymus is important for establishing immune homeostasis and preventing autoimmunity. Here, we review the components of T‐cell tolerance, which includes T‐cell receptor (TCR) self‐reactivity, costimulation, cytokines, and antigen presentation by a variety of antigen‐presenting cells (APCs) subsets. We discuss the current evidence on the process of regulatory T (Treg) cell and negative selection and the importance of TCR signaling. We then examine recent evidence showing unique roles for bone marrow (BM)‐derived APCs and medullary thymic epithelial cells (mTECs) on the conventional and Treg TCR repertoire, as well as emerging data on the role of B cells in tolerance. Finally, we review the accumulating data that suggest that cooperative antigen presentation is a prominent component of T ‐ell tolerance. With the development of tools to interrogate the function of individual APC subsets in the medulla, we have gained greater understanding of the complex cellular and molecular events that determine T‐cell tolerance.
T follicular regulatory cells
Authors: Sage Peter T. , Sharpe Arlene H.
Published: April 2016

Pathogen exposure elicits production of high‐affinity antibodies stimulated by T follicular helper (Tfh) cells in the germinal center reaction. Tfh cells provide both costimulation and stimulatory cytokines to B cells to facilitate affinity maturation, class switch recombination, and plasma cell differentiation within the germinal center. Under normal circumstances, the germinal center reaction results in antibodies that precisely target foreign pathogens while limiting autoimmunity and excessive inflammation. In order to have this degree of control, the immune system ensures Tfh‐mediated B‐cell help is regulated locally in the germinal center. The recently identified T follicular regulatory (Tfr) cell subset can migrate to the germinal center and inhibit Tfh‐mediated B‐cell activation and antibody production. Although many aspects of Tfr cell biology are still unclear, recent data have begun to delineate the specialized roles of Tfr cells in controlling the germinal center reaction. Here we discuss the current understanding of Tfr‐cell differentiation and function and how this knowledge is providing new insights into the dynamic regulation of germinal centers, and suggesting more efficacious vaccine strategies and ways to treat antibody‐mediated diseases.
Thymus: the next (re)generation
Authors: Chaudhry Mohammed S. , Velardi Enrico , Dudakov Jarrod A. , van den Brink Marcel R. M.
Published: April 2016

As the primary site of T‐cell development, the thymus plays a key role in the generation of a strong yet self‐tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin‐22 (IL‐22) in response to loss of double positive thymocytes and upregulation of IL‐23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way toward the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL‐7 and IL‐22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the preclinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.
Parallel and nonparallel behavioural evolution in response to parasitism and predation in Trinidadian guppies
Authors: Jacquin L. , Reader S. M. , Boniface A. , Mateluna J. , Patalas I. , Pérez‐Jvostov F. , Hendry A. P.
Published: April 2016

Natural enemies such as predators and parasites are known to shape intraspecific variability of behaviour and personality in natural populations, yet several key questions remain: (i) What is the relative importance of predation vs. parasitism in shaping intraspecific variation of behaviour across generations? (ii) What are the contributions of genetic and plastic effects to this behavioural divergence? (iii) And to what extent are responses to predation and parasitism repeatable across independent evolutionary lineages? We addressed these questions using Trinidadian guppies (Poecilia reticulata) (i) varying in their exposure to dangerous fish predators andGyrodactylusectoparasites for (ii) both wild‐caught F0 and laboratory‐reared F2 individuals and coming from (iii) multiple independent evolutionary lineages (i.e. independent drainages). Several key findings emerged. First, a population's history of predation and parasitism influenced behavioural profiles, but to different extent depending on the behaviour considered (activity, shoaling or boldness). Second, we had evidence for some genetic effects of predation regime on behaviour, with differences in activity of F2 laboratory‐reared individuals, but not for parasitism, which had only plastic effects on the boldness of wild‐caught F0 individuals. Third, the two lineages showed a mixture of parallel and nonparallel responses to predation/parasitism, with parallel responses being stronger for predation than for parasitism and for activity and boldness than for shoaling. These findings suggest that different sets of behaviours provide different pay‐offs in alternative predation/parasitism environments and that parasitism has more transient effects in shaping intraspecific variation of behaviour than does predation.
Characterization and viral susceptibility of a brain cell line from brown‐marbled grouper Epinephelus fuscoguttatus (Forsskål) with persistent betanodavirus infection
Authors: Wen C M
Published: April 2016

A continuous cell line designated BMGB (brown‐marbled grouper brain) was established from the brain tissues of the brown‐marbled grouper Epinephelus fuscoguttatus and characterized. BMGB cells were identified as astroglial progenitor cells because they expressed glial fibrillary acidic protein and keratin and were persistently infected by betanodavirus, as confirmed through immunocytochemistry, polymerase chain reaction and immunoblot analyses. Because few intact virions were present in the BMGB cell culture fluid, the cytopathic effect (CPE) was not observed when the culture fluid was inoculated with GBC1 cells. However, BMGB cells displayed typical CPE after infection with additional betanodavirus, megalocytivirus and chum salmon reovirus. BMGB cells showed low myxovirus resistance (Mx) protein expression, which increased following betanodavirus and reovirus infection. Because the cells contained several unusual or degraded viral proteins, the persistent infection of betanodavirus in the BMGB cells may have resulted from a mechanism that destroys the viral proteins rather than the result of Mx protein expression. Despite the persistent betanodavirus infection, BMGB cells proliferated in a manner similar to other normal tropic fish cells and supported the propagation of several piscine viruses; however, the yield was lower than that of normal cells. The BMGB cells will be useful for investigating virus and host cell interaction.
Prenatal diagnosis and physical model reconstruction of agnathia–otocephaly with limb deformities (absent ulna, fibula and digits) following maternal exposure to oxymetazoline in the first trimester
Authors: Menezes Gláucia Aparecida , Araujo Júnior Edward , Lopes Jorge , Belmonte Simone , Tonni Gabriele , Werner Heron
Published: April 2016

Agnathia–otocephaly or agnathia‐sinotia‐microstomy syndrome is the most severe malformation affecting the first branchial arch. It is a rare congenital anomaly characterized by absence of the lower jaw and abnormal ear positioning. Prenatal diagnosis is possible on conventional 2‐D ultrasound in the second trimester. Three‐dimensional ultrasound enhances detection of abnormal facial phenotype, especially in surface rendering mode. In addition, 3‐D volume datasets are used to produce a physical model of the anomaly. We present a case of second trimester ultrasound diagnosis of agnathia–otocephaly associated with limb deformities. A physical model produced using 3‐D ultrasound volume datasets facilitated better understanding of this congenital malformation, and improvement of parental counselling and management by the multispecialist team.