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1.  The next-generation nicotine vaccine: a novel and potent hybrid nanoparticle based nicotine vaccine 
Biomaterials  2016;106:228-239.
Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanoparticle-based nicotine vaccine (NanoNiccine) was developed in this study. NanoNiccine was composed of a poly(lactide-co-glycolide) acid (PLGA) core, keyhole limpet hemocyanin (KLH) as an adjuvant protein enclosed within the PLGA core, a lipid layer, and nicotine haptens conjugated to the outer surface of the lipid layer. In contrast to the traditional nicotine vaccine, NanoNiccine is not a nicotine-protein conjugate vaccine. Instead, the nicotine hapten and protein are separately located in the nanostructure to minimize antibody production towards KLH. The cellular uptake study demonstrated that NanoNiccine was ideal for internalization and processing by dendritic cells (DCs). Mice immunized with NanoNiccine produced much lower IgG level against KLH as compared to that immunized with the traditional nicotine-KLH (Nic-KLH) vaccine. In addition, NanoNiccine achieved up to a 400% higher titer of anti-nicotine IgG than the positive control, Nic-KLH. Additionally, the Th1/Th2 index of NanoNiccine suggested that the immune response induced by NanoNiccine was antibody response dominant. Furthermore, NanoNiccine was found to be safe in mice.
PMCID: PMC5018466  PMID: 27569868
Nicotine vaccine; hybrid nanoparticle; antibody; PLGA; KLH; dendritic cell
2.  Vole abundance and reindeer carcasses determine breeding activity of Arctic foxes in low Arctic Yamal, Russia 
BMC Ecology  2017;17:32.
High latitude ecosystems are at present changing rapidly under the influence of climate warming, and specialized Arctic species at the southern margin of the Arctic may be particularly affected. The Arctic fox (Vulpes lagopus), a small mammalian predator endemic to northern tundra areas, is able to exploit different resources in the context of varying tundra ecosystems. Although generally widespread, it is critically endangered in subarctic Fennoscandia, where a fading out of the characteristic lemming cycles and competition with abundant red foxes have been identified as main threats. We studied an Arctic fox population at the Erkuta Tundra Monitoring site in low Arctic Yamal (Russia) during 10 years in order to determine which resources support the breeding activity in this population. In the study area, lemmings have been rare during the last 15 years and red foxes are nearly absent, creating an interesting contrast to the situation in Fennoscandia.
Arctic fox was breeding in nine of the 10 years of the study. The number of active dens was on average 2.6 (range 0–6) per 100 km2 and increased with small rodent abundance. It was also higher after winters with many reindeer carcasses, which occurred when mortality was unusually high due to icy pastures following rain-on-snow events. Average litter size was 5.2 (SD = 2.1). Scat dissection suggested that small rodents (mostly Microtus spp.) were the most important prey category. Prey remains observed at dens show that birds, notably waterfowl, were also an important resource in summer.
The Arctic fox in southern Yamal, which is part of a species-rich low Arctic food web, seems at present able to cope with a state shift of the small rodent community from high amplitude cyclicity with lemming dominated peaks, to a vole community with low amplitude fluctuations. The estimated breeding parameters characterized the population as intermediate between the lemming fox and the coastal fox ecotype. Only continued ecosystem-based monitoring will reveal their fate in a changing tundra ecosystem.
Electronic supplementary material
The online version of this article (doi:10.1186/s12898-017-0142-z) contains supplementary material, which is available to authorized users.
PMCID: PMC5602845  PMID: 28915877
Food web; Numerical response; Reindeer carcasses; Small rodent community; Vole cycle; Diet; Vulpes lagopus
Lanthionine Synthetase Cyclase-Like 2 (LANCL2) is a novel therapeutic target for Crohn's disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/day. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/day for 14 days (n=10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical and continuous endpoints, including posture, in-cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2-4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/day for 14 days. One hour after oral administration of a single 80 mg/kg dose, BT-11 had a maximal concentration of 21 ng/ml; the half-life was 3 hr. These experimental results demonstrated that BT-11 is well-tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD.
PMCID: PMC5033715  PMID: 27230993
LANCL2; safety; toxicology; BT-11; rats
4.  Worldwide view of nephropathic cystinosis: results from a survey from 30 countries 
BMC Nephrology  2017;18:210.
Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN].
A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries.
A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5−/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis.
Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-017-0633-3) contains supplementary material, which is available to authorized users.
PMCID: PMC5496396  PMID: 28673276
Nephropathic cystinosis; Cysteamine; Developing nations
5.  Negatively Charged Carbon Nanohorn Supported Cationic Liposome Nanoparticles: A Novel Delivery Vehicle for Anti-Nicotine Vaccine 
Journal of biomedical nanotechnology  2015;11(12):2197-2210.
Tobacco addiction is the second-leading cause of death in the world. Due to the nature of nicotine (a small molecule), finding ways to combat nicotine’s deleterious effects has been a constant challenge to the society and the medical field. In the present work, a novel anti-nicotine vaccine based on nanohorn supported liposome nanoparticles (NsL NPs) was developed. The nano-vaccine was constructed by using negatively charged carbon nanohorns as a scaffold for the assembly of cationic liposomes, which allow the conjugation of hapten conjugated carrier proteins. The assembled bio-nanoparticles are stable. Mice were immunized subcutaneously with the nano-vaccine, which induced high titer and high affinity of nicotine specific antibodies in mice. Furthermore, no evidence of clinical signs or systemic toxicity followed multiple administrations of NsL-based anti-nicotine vaccine. These results suggest that NsL-based anti-nicotine vaccine is a promising candidate in treating nicotine dependence and could have potential to significantly contribute to smoking cessation.
PMCID: PMC5344192  PMID: 26510313
Nicotine; Nicotine Vaccine; Anti-Nicotine; Bionanoparticle; Carbon Nanohorn; Nano-Vaccine
6.  In vitro controlled release of antigen in dendritic cells using pH-sensitive liposome-polymeric hybrid nanoparticles 
Polymer  2015;80:171-179.
A hybrid nanoparticle (NP) consisting of a pH sensitive lipid shell and a poly(lactic-co-glycolic) acid (PLGA) core was constructed. This hybrid NP has a mean size of 120.1 ± 8.8 nm and positively charged surface (zeta potential of 14.2 ± 1.4 mV). The lipid shell of the hybrid NP was quickly disintegrated in buffer with a pH of 5.5, which resembles the acidic environment of endosomes in dendritic cell (DC). Less than 20% of the antigen enclosed in pH-sensitive hybrid NP was released into human serum at physiological pH within 24 h, but more than 40% of the enclosed antigen was released within 8 h after pH was adjusted to 5.5. Fast uptake of the pH sensitive hybrid NP by DC was also observed. It was found that pH sensitive hybrid NP displayed faster degradation and antigen release compared to regular hybrid NPs after uptake by DC.
PMCID: PMC4662652  PMID: 26622069
PLGA nanoparticle; pH-sensitive lipid; Vaccine
7.  Engineering the lipid layer of lipid-PLGA hybrid nanoparticles for enhanced in vitro cellular uptake and improved stability 
Acta biomaterialia  2015;28:149-159.
Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid-PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long- term storage. However, stabilized hybrid structures of high cholesterol content tended to fuse with each other during storage, resulting in significant size increase and lowered cellular uptake. Additional experiments demonstrated that PEGylation of NPs could effectively minimize fusion-caused size increase after long term storage, leading to improved cellular uptake, although excessive PEGylation will not be beneficial and led to reduced improvement.
Graphical Abstract
PMCID: PMC4648676  PMID: 26428192
PLGA; hybrid nanoparticle; lipid layer; cholesterol; delivery system
8.  Good‐bye to tropical alpine plant giants under warmer climates? Loss of range and genetic diversity in Lobelia rhynchopetalum  
Ecology and Evolution  2016;6(24):8931-8941.
The main aim of this paper is to address consequences of climate warming on loss of habitat and genetic diversity in the enigmatic tropical alpine giant rosette plants using the Ethiopian endemic Lobelia rhynchopetalum as a model. We modeled the habitat suitability of L. rhynchopetalum and assessed how its range is affected under two climate models and four emission scenarios. We used three statistical algorithms calibrated to represent two different complexity levels of the response. We analyzed genetic diversity using amplified fragment length polymorphisms and assessed the impact of the projected range loss. Under all model and scenario combinations and consistent across algorithms and complexity levels, this afro‐alpine flagship species faces massive range reduction. Only 3.4% of its habitat seems to remain suitable on average by 2,080, resulting in loss of 82% (CI 75%–87%) of its genetic diversity. The remaining suitable habitat is projected to be fragmented among and reduced to four mountain peaks, further deteriorating the probability of long‐term sustainability of viable populations. Because of the similar morphological and physiological traits developed through convergent evolution by tropical alpine giant rosette plants in response to diurnal freeze‐thaw cycles, they most likely respond to climate change in a similar way as our study species. We conclude that specialized high‐alpine giant rosette plants, such as L. rhynchopetalum, are likely to face very high risk of extinction following climate warming.
PMCID: PMC5192889  PMID: 28035281
afro‐alpine; climate change; giant rosette plants; Lobelia rhynchopetalum; loss of genetic diversity; model algorithms; model complexity; range loss; tropical alpine plants
9.  The role of sea ice for vascular plant dispersal in the Arctic 
Biology Letters  2016;12(9):20160264.
Sea ice has been suggested to be an important factor for dispersal of vascular plants in the Arctic. To assess its role for postglacial colonization in the North Atlantic region, we compiled data on the first Late Glacial to Holocene occurrence of vascular plant species in East Greenland, Iceland, the Faroe Islands and Svalbard. For each record, we reconstructed likely past dispersal events using data on species distributions and genetics. We compared these data to sea-ice reconstructions to evaluate the potential role of sea ice in these past colonization events and finally evaluated these results using a compilation of driftwood records as an independent source of evidence that sea ice can disperse biological material. Our results show that sea ice was, in general, more prevalent along the most likely dispersal routes at times of assumed first colonization than along other possible routes. Also, driftwood is frequently dispersed in regions that have sea ice today. Thus, sea ice may act as an important dispersal agent. Melting sea ice may hamper future dispersal of Arctic plants and thereby cause more genetic differentiation. It may also limit the northwards expansion of competing boreal species, and hence favour the persistence of Arctic species.
PMCID: PMC5046916  PMID: 27651529
Arctic; climate change; plant colonization; plant dispersal; driftwood; sea ice
10.  Geographical Area and Life History Traits Influence Diet in an Arctic Marine Predator 
PLoS ONE  2016;11(5):e0155980.
Global changes are thought to affect most Arctic species, yet some populations are more at risk. Today, the Barents Sea ecoregion is suffering the strongest sea ice retreat ever measured; and these changes are suspected to modify food access and thus diet of several species. Biochemical diet tracers enable investigation of diet in species such as polar bears (Ursus maritimus). We examined individual diet variation of female polar bears in Svalbard, Norway, and related it to year, season (spring and autumn), sampling area and breeding status (solitary, with cubs of the year or yearlings). Sampling areas were split according to their ice cover: North-West (less sea ice cover), South-East (larger amplitude in sea ice extent) and North-East/South-West (NESW) as bears from that zone are more mobile among all regions of Svalbard. We measured fatty acid (FA) composition in adipose tissue and carbon (δ13C) and nitrogen (δ15N) stable isotopes in plasma and red blood cells. Females feeding in the North-West area had lower δ15N values than those from the NESW. In South-East females, δ13C values were lower in autumn compared to spring and females seemed less selective in their diet as depicted by large variances in stable isotope values. Considering the differences in FA composition and stable isotope values, we suggest that females from the North-West and South-East could ingest a higher proportion of avian prey. With regard to breeding status, solitary females had higher δ15N values and smaller variance in their stable isotopic values than females with cubs, suggesting that solitary females were more selective and prey on higher trophic level species (i.e. seals). Overall, our results indicate that prey availability for Svalbard polar bears varies according to geographical area and prey selectivity differs according to breeding status. Our findings suggest that complex changes in sea ice and prey availability will interact to affect Svalbard polar bear feeding patterns and associated nutrition.
PMCID: PMC4873193  PMID: 27196700
11.  Changing Arctic snow cover: A review of recent developments and assessment of future needs for observations, modelling, and impacts 
Ambio  2016;45(5):516-537.
Snow is a critically important and rapidly changing feature of the Arctic. However, snow-cover and snowpack conditions change through time pose challenges for measuring and prediction of snow. Plausible scenarios of how Arctic snow cover will respond to changing Arctic climate are important for impact assessments and adaptation strategies. Although much progress has been made in understanding and predicting snow-cover changes and their multiple consequences, many uncertainties remain. In this paper, we review advances in snow monitoring and modelling, and the impact of snow changes on ecosystems and society in Arctic regions. Interdisciplinary activities are required to resolve the current limitations on measuring and modelling snow characteristics through the cold season and at different spatial scales to assure human well-being, economic stability, and improve the ability to predict manage and adapt to natural hazards in the Arctic region.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-016-0770-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4980315  PMID: 26984258
Climate change; Ecosystem services; Human health; Societal costs; Indigenous; Snow
12.  Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons 
The Journal of Neuroscience  2015;35(37):12917-12931.
The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR−/− mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.
SIGNIFICANCE STATEMENT Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects.
PMCID: PMC4571610  PMID: 26377476
depression; dopamine; dynorphin; GIRK; kappa opioid receptor; stress
13.  Integrating and rationalizing public healthcare services as a source of cost containment in times of economic crises 
Serious concern has been raised about the sustainability of public health care systems of European Nations and ultimately about the health of European citizens, as a result of the economic crisis that has distressed Europe since 2008. The severe economic crisis of the Euro zone, which is still afflicting Europe in 2016, has in fact threatened to equally impact public health services of nations presenting either a weak or a strong domestic growth.
On behalf of the European Paediatric Association, the Union of National European Societies and Associations, the authors of the Commentary debates the relationship between the effects of economic instability and health, through the report on an article recently published in the Italian Journal of Pediatrics, which emphasized the importance of integrating existing public health care services, otherwise independently provided by public hospitals, and Primary Care Paediatric networks. The interconnections between the effects of economic instability and health are briefly commented, following the observation that these two factors are not yet fully understood, and that the definition of proper solutions to be applied in circumstances, where health is negatively impacted by periods of economic distress, is still open for discussion.
Furthermore it is noted that the pressure to “deliver more for less” often seems to be the driving force forging the political strategic decisions in the area of pediatric healthcare, rather than social, cultural, and economic sensitivity and competences. Thus, the delivery of appropriate pediatric healthcare seems not to be related exclusively to motivations aimed to the benefit of children, but more often to other intervening factors, including economic, and political rationales.
The conclusions emphasize that local European experiences suggest that positive and cost effective healthcare programs are possible, and they could serve as a model in the development of effective cross-border regional program, not weakening the quality of services provided to children.
PMCID: PMC4765240  PMID: 26911573
Public healthcare; Economy; Cost containment; Pediatrics; Children
14.  How does stress-induced activation of the kappa opioid system increase addiction risk? 
Biological psychiatry  2014;76(10):760-762.
PMCID: PMC4684190  PMID: 25442057
15.  Kappa Opioid Receptor Activation Potentiates the Cocaine-Induced Increase in Evoked Dopamine Release Recorded In Vivo in the Mouse Nucleus Accumbens 
Neuropsychopharmacology  2014;39(13):3036-3048.
Behavioral stressors increase addiction risk in humans and increase the rewarding valence of drugs of abuse including cocaine, nicotine and ethanol in animal models. Prior studies have established that this potentiation of drug reward was mediated by stress-induced release of the endogenous dynorphin opioids and subsequent kappa opioid receptor (KOR) activation. In this study, we used in vivo fast scan cyclic voltammetry to test the hypothesis that KOR activation before cocaine administration might potentiate the evoked release of dopamine from ventral tegmental (VTA) synaptic inputs to the nucleus accumbens (NAc) and thereby increase the rewarding valence of cocaine. The KOR agonist U50488 inhibited dopamine release evoked by either medial forebrain bundle (MFB) or pedunculopontine tegmental nucleus (PPTg) activation of VTA inputs to the shell or core of the mouse NAc. Cocaine administration increased the dopamine response recorded in either the shell or core evoked by either MFB or PPTg stimulation. Administration of U50488 15 min before cocaine blocked the conditioned place preference (CPP) to cocaine, but only significantly reduced the effect of cocaine on the dopamine response evoked by PPTg stimulation to NAc core. In contrast, administration of U50488 60 min before cocaine significantly potentiated cocaine CPP and significantly increased the effects of cocaine on the dopamine response evoked by either MFB or PPTg stimulation, recorded in either NAc shell or core. Results of this study support the concept that stress-induced activation of KOR by endogenous dynorphin opioids may enhance the rewarding valence of drugs of abuse by potentiating the evoked dopamine response.
PMCID: PMC4229575  PMID: 24971603
16.  Expect the unexpected: patients’ and families’ expectations and experiences of new clinical procedures 
Early stage clinical innovation often occurs ‘under the radar’ of governance systems for established procedures. Previously impossible or unavailable techniques still being developed involve additional uncertainty and unknown risks and benefits compared with standard procedures. Patient and family expectations, perceptions and experiences of these new procedures and their possible impacts on aspects of patient safety are under‐researched.
To explore patient and family expectations and experiences of undergoing new clinical procedures.
A large UK Hospital NHS Foundation Trust with a range of clinically innovative specialties.
We interviewed 15 patients who received new clinical procedures in a variety of medical and surgical specialties. Qualitative interviews were used to facilitate in‐depth exploration of patient and family views and experiences. Topics included patient and family access to and expectations of the procedure, informed decision making regarding acceptance of new procedures and post‐procedure experiences.
Some patients sought out specific interventions, while others accepted new treatment options that clinicians proposed. Most participants reported that explanations about the procedure and risks were clear, and there were opportunities to ask questions prior to the procedure. Most participants also regarded their procedures as successful. However, post‐procedure information follow‐up was often reported as lacking and some outcomes were considerably problematic and raised patient safety issues.
The importance of patients’ and family views in evaluating health care are increasingly recognized. We discuss the implications of our findings for informed decision making and post‐intervention follow‐up.
PMCID: PMC5060887  PMID: 23614706
innovation; new clinical procedures; patient involvement; patient safety
18.  The role of patients and their relatives in ‘speaking up’ about their own safety – a qualitative study of acute illness 
Poor recognition of and response to acute illness in hospitalized patients continues to cause significant harm despite the implementation of safety strategies such as early warning scores. Patients and their relatives may be able to contribute to their own safety by speaking up about changes in condition, but little is known about the factors that influence this. This study examined the experiences and views of patients and their relatives to determine the potential for involvement in promoting their own safety.
This data set is drawn from a wider ethnographic study of the management of the acutely ill patient in hospital. Thirteen patients and seven relatives from two medical settings in two UK NHS Trusts were interviewed. Thematic analysis identified factors likely to influence patients' and their relatives' ability to contribute to the management of deterioration.
All patients interviewed had experienced their acute illness within the context of a long‐term health problem. Speaking up was influenced by the ability to recognize changes in clinical condition, self‐monitoring, confidence and trust, and culture and system of health care. When patients or relatives did raise concerns, health‐care staff had a mediating effect on their comfort with and the effectiveness of speaking up.
Safety strategies based on patient involvement must take account of the complexities of acute illness. Those that promote partnership may be more acceptable to patients, their families and staff than those that promote challenging behaviour and may ultimately prove to be most safe and effective.
PMCID: PMC5060780  PMID: 23332029
acute illness; patient involvement; patient safety
19.  Evaluation of Opioid Modulation in Major Depressive Disorder 
Neuropsychopharmacology  2015;40(6):1448-1455.
Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a μ-opioid partial agonist, buprenorphine (BUP), and a potent μ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist–antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.
PMCID: PMC4397403  PMID: 25518754
20.  Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent μ-Receptor Antagonist 
A novel clinical study design was used to evaluate the blockade of a selective short-acting μ-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with μ-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2). Complete blockade persisted with samidorphan for 24 hours for pupil miosis and 48 hours for the drug liking visual analog scale. Samidorphan effects persisted beyond measurable samidorphan exposure (t½ = 7 hours). Samidorphan was associated with complete blockade of remifentanil, and the duration supports daily administration. This study used a novel approach with multiple administrations of remifentanil to successfully demonstrate a durable effect with samidorphan and a rapid and potent blockade of physiological and subjective μ-opioid effects.
PMCID: PMC4415969  PMID: 25928699
remifentanil; samidorphan; opioid blockade; pharmacodynamic; pupillometry
21.  Whole genome bisulfite sequencing of cell-free DNA and its cellular contributors uncovers placenta hypomethylated domains 
Genome Biology  2015;16(1):78.
Circulating cell-free fetal DNA has enabled non-invasive prenatal fetal aneuploidy testing without direct discrimination of the maternal and fetal DNA. Testing may be improved by specifically enriching the sample material for fetal DNA. DNA methylation may allow for such a separation of DNA; however, this depends on knowledge of the methylomes of circulating cell-free DNA and its cellular contributors.
We perform whole genome bisulfite sequencing on a set of unmatched samples including circulating cell-free DNA from non-pregnant and pregnant female donors and genomic DNA from maternal buffy coat and placenta samples. We find CpG cytosines within longer fragments are more likely to be methylated. Comparison of the methylomes of placenta and non-pregnant circulating cell-free DNA reveal many of the 51,259 identified differentially methylated regions are located in domains exhibiting consistent placenta hypomethylation across millions of consecutive bases. We find these placenta hypomethylated domains are consistently located within regions exhibiting low CpG and gene density. Differentially methylated regions identified when comparing placenta to non-pregnant circulating cell-free DNA are recapitulated in pregnant circulating cell-free DNA, confirming the ability to detect differential methylation in circulating cell-free DNA mixtures.
We generate methylome maps for four sample types at single-base resolution, identify a link between DNA methylation and fragment length in circulating cell-free DNA, identify differentially methylated regions between sample groups, and uncover the presence of megabase-size placenta hypomethylated domains.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0645-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4427941  PMID: 25886572
22.  Rough-Legged Buzzards, Arctic Foxes and Red Foxes in a Tundra Ecosystem without Rodents 
PLoS ONE  2015;10(2):e0118740.
Small rodents with multi-annual population cycles strongly influence the dynamics of food webs, and in particular predator-prey interactions, across most of the tundra biome. Rodents are however absent from some arctic islands, and studies on performance of arctic predators under such circumstances may be very instructive since rodent cycles have been predicted to collapse in a warming Arctic. Here we document for the first time how three normally rodent-dependent predator species—rough-legged buzzard, arctic fox and red fox – perform in a low-arctic ecosystem with no rodents. During six years (in 2006-2008 and 2011-2013) we studied diet and breeding performance of these predators in the rodent-free Kolguev Island in Arctic Russia. The rough-legged buzzards, previously known to be a small rodent specialist, have only during the last two decades become established on Kolguev Island. The buzzards successfully breed on the island at stable low density, but with high productivity based on goslings and willow ptarmigan as their main prey – altogether representing a novel ecological situation for this species. Breeding density of arctic fox varied from year to year, but with stable productivity based on mainly geese as prey. The density dynamic of the arctic fox appeared to be correlated with the date of spring arrival of the geese. Red foxes breed regularly on the island but in very low numbers that appear to have been unchanged over a long period – a situation that resemble what has been recently documented from Arctic America. Our study suggests that the three predators found breeding on Kolguev Island possess capacities for shifting to changing circumstances in low-arctic ecosystem as long as other small - medium sized terrestrial herbivores are present in good numbers.
PMCID: PMC4333295  PMID: 25692786
23.  Implications of the Circumpolar Genetic Structure of Polar Bears for Their Conservation in a Rapidly Warming Arctic 
PLoS ONE  2015;10(1):e112021.
We provide an expansive analysis of polar bear (Ursus maritimus) circumpolar genetic variation during the last two decades of decline in their sea-ice habitat. We sought to evaluate whether their genetic diversity and structure have changed over this period of habitat decline, how their current genetic patterns compare with past patterns, and how genetic demography changed with ancient fluctuations in climate. Characterizing their circumpolar genetic structure using microsatellite data, we defined four clusters that largely correspond to current ecological and oceanographic factors: Eastern Polar Basin, Western Polar Basin, Canadian Archipelago and Southern Canada. We document evidence for recent (ca. last 1–3 generations) directional gene flow from Southern Canada and the Eastern Polar Basin towards the Canadian Archipelago, an area hypothesized to be a future refugium for polar bears as climate-induced habitat decline continues. Our data provide empirical evidence in support of this hypothesis. The direction of current gene flow differs from earlier patterns of gene flow in the Holocene. From analyses of mitochondrial DNA, the Canadian Archipelago cluster and the Barents Sea subpopulation within the Eastern Polar Basin cluster did not show signals of population expansion, suggesting these areas may have served also as past interglacial refugia. Mismatch analyses of mitochondrial DNA data from polar and the paraphyletic brown bear (U. arctos) uncovered offset signals in timing of population expansion between the two species, that are attributed to differential demographic responses to past climate cycling. Mitogenomic structure of polar bears was shallow and developed recently, in contrast to the multiple clades of brown bears. We found no genetic signatures of recent hybridization between the species in our large, circumpolar sample, suggesting that recently observed hybrids represent localized events. Documenting changes in subpopulation connectivity will allow polar nations to proactively adjust conservation actions to continuing decline in sea-ice habitat.
PMCID: PMC4285400  PMID: 25562525
24.  Long-distance plant dispersal to North Atlantic islands: colonization routes and founder effect 
AoB Plants  2015;7:plv036.
Our study provides new knowledge of two processes that are important for plant adaptation in a changing environment: 1) long-distance dispersal patterns, and 2) genetic founder effect on islands. Although the theoretical framework for the genetic founder effect on islands was proposed in 1973, we are the first to quantify it in relation to island size, dispersal distance, and plant traits. In addition, our genetic results are mainly coherent with post-glacial colonisation rather than in situ glacial survival, and should therefore bring a final end to the 140-year-long glacial survival-tabula rasa debate among northern biologists.
Long-distance dispersal (LDD) processes influence the founder effect on islands. We use genetic data for 25 Atlantic species and similarities among regional floras to analyse colonization, and test whether the genetic founder effect on five islands is associated with dispersal distance, island size and species traits. Most species colonized postglacially via multiple dispersal events from several source regions situated 280 to >3000 km away, and often not from the closest ones. A strong founder effect was observed for insect-pollinated mixed maters, and it increased with dispersal distance and decreased with island size in accordance with the theory of island biogeography. Only a minor founder effect was observed for wind-pollinated outcrossing species. Colonization patterns were largely congruent, indicating that despite the importance of stochasticity, LDD is mainly determined by common factors, probably dispersal vectors. Our findings caution against a priori assuming a single, close source region in biogeographic analyses.
PMCID: PMC4432000  PMID: 25876627
Amplified fragment length polymorphism (AFLP); dispersal vector; founder effect; genetic diversity; islands; long-distance dispersal (LDD); postglacial; species traits

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