bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long‐acting glucagon‐like peptide‐1 receptor agonists have direct access to and effects on pro‐opiomelanocortin/cocaine‐ and amphetamine‐stimulated transcript neurons in the mouse hypothalamus
Authors: Knudsen Lotte Bjerre , Secher Anna , Hecksher‐Sørensen Jacob , Pyke Charles 
Published: April 2016

AbstractLiraglutide is a glucagon‐like peptide‐1 receptor (GLP‐1R) agonist marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide reduces bodyweight, and has recently also been approved for the obesity indication. Acutely, GLP‐1 markedly reduces gastric emptying, and this effect was previously believed to at least partly explain the effect on bodyweight loss. However, recent studies in both humans and animals have shown that GLP‐1R agonists, such as liraglutide, that lead to pharmacological concentrations for 24 h/day only have a minor effect on gastric emptying; such an effect is unlikely to have lasting effects on appetite reduction. Liraglutide has been shown to have direct effects in the arcuate nucleus of the rodent brain, activating pro‐opiomelanocortin neurons and increasing levels of the cocaine‐ and amphetamine‐stimulated transcript neuropeptide messenger ribonucleic acid, which correlate nicely to clinical studies where liraglutide was shown to increase feelings of satiety. However, despite the lack of a GLP‐1R on agouti‐related peptide/neuropeptide Y neurons, liraglutide also was able to prevent a hunger associated increase in agouti‐related peptide and neuropeptide Y neuropeptide messenger ribonucleic acid, again with a strong correlation to clinical studies that document reduced hunger feelings in patients while taking liraglutide. Studies using fluorescent labeled liraglutide, as well as other GLP‐1R agonists, and analysis using single‐plane illumination microscopy show that such medium‐sized peptide‐based compounds can directly access not only circumventricular organs of the brain, but also directly access discrete regions in the hypothalamus. The direct effects of long‐acting GLP‐1R agonists in the hypothalamus are likely to be an important new pathway in understanding GLP‐1R agonist mediated weight loss.
Sequence variation in nuclear ribosomal small subunit, internal transcribed spacer and large subunit regions of Rhizophagus irregularis and Gigaspora margarita is high and isolate‐dependent
Authors: Thiéry Odile , Vasar Martti , Jairus Teele , Davison John , Roux Christophe , Kivistik Paula‐Ann , Metspalu Andres , Milani Lili , Saks Ülle , Moora Mari , Zobel Martin , Öpik Maarja 
Published: April 2016

AbstractArbuscular mycorrhizal (AM) fungi are known to exhibit high intra‐organism genetic variation. However, information about intra‐ vs. interspecific variation among the genes commonly used in diversity surveys is limited. Here, the nuclear small subunit (SSU) rRNA gene, internal transcribed spacer (ITS) region and large subunit (LSU) rRNA gene portions were sequenced from 3 to 5 individual spores from each of two isolates of Rhizophagus irregularis and Gigaspora margarita. A total of 1482 Sanger sequences (0.5 Mb) from 239 clones were obtained, spanning ~4370 bp of the ribosomal operon when concatenated. Intrasporal and intra‐isolate sequence variation was high for all three regions even though variant numbers were not exhausted by sequencing 12–40 clones per isolate. Intra‐isolate nucleotide variation levels followed the expected order of ITS > LSU > SSU, but the values were strongly dependent on isolate identity. Single nucleotide polymorphism (SNP) densities over 4 SNP/kb in the ribosomal operon were detected in all four isolates. Automated operational taxonomic unit picking within the sequence set of known identity overestimated species richness with almost all cut‐off levels, markers and isolates. Average intraspecific sequence similarity values were 99%, 96% and 94% for amplicons in SSU, LSU and ITS, respectively. The suitability of the central part of the SSU as a marker for AM fungal community surveys was further supported by its level of nucleotide variation, which is similar to that of the ITS region; its alignability across the entire phylum; its appropriate length for next‐generation sequencing; and its ease of amplification in single‐step PCR.
Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage
Authors: Nowicka-Sans Beata , Protack Tricia , Lin Zeyu , Li Zhufang , Zhang Sharon , Sun Yongnian , Samanta Himadri , Terry Brian , Liu Zheng , Chen Yan , Sin Ny , Sit Sing-Yuen , Swidorski Jacob J. , Chen Jie , Venables Brian L. , Healy Matthew , Meanwell Nicholas A. , Cockett Mark , Hanumegowda Umesh , Regueiro-Ren Alicia , Krystal Mark , Dicker Ira B. 
Published: April 2016

ABSTRACT

BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC
50
], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (
n
= 87) of
gag/pr
recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC
50
of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC
50
s similar to those for the wild-type virus. A 5.4-fold reduction in EC
50
occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an
in vitro
measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally,
in vitro
combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent
in vitro
anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat.
Clinical Efficacy of Polymyxin Monotherapy versus Nonvalidated Polymyxin Combination Therapy versus Validated Polymyxin Combination Therapy in Extensively Drug-Resistant Gram-Negative Bacillus Infections
Authors: Cai Bingxuan , Cai Yiying , Liew Yi Xin , Chua Nathalie Grace , Teo Jocelyn Qi-Min , Lim Tze-Peng , Kurup Asok , Ee Pui Lai Rachel , Tan Thuan Tong , Lee Winnie , Kwa Andrea Lay-Hoon 
Published: April 2016

ABSTRACT

Polymyxins have emerged as a last-resort treatment of extensively drug-resistant (XDR) Gram-negative
Bacillus
(GNB) infections, which present a growing threat. Individualized polymyxin-based antibiotic combinations selected on the basis of the results of
in vitro
combination testing may be required to optimize therapy. A retrospective cohort study of hospitalized patients receiving polymyxins for XDR GNB infections from 2009 to 2014 was conducted to compare the treatment outcomes between patients receiving polymyxin monotherapy (MT), nonvalidated polymyxin combination therapy (NVCT), and
in vitro
combination testing-validated polymyxin combination therapy (VCT). The primary and secondary outcomes were infection-related mortality and microbiological eradication, respectively. Adverse drug reactions (ADRs) between treatment groups were assessed. A total of 291 patients (patients receiving MT,
n
= 58; patients receiving NVCT,
n
= 203; patients receiving VCT,
n
= 30) were included. The overall infection-related mortality rate was 23.0% (67 patients). In the multivariable analysis, treatment of XDR GNB infections with MT (adjusted odds ratio [aOR], 8.49; 95% confidence interval [CI], 1.56 to 46.05) and NVCT (aOR, 5.75; 95% CI, 1.25 to 25.73) was associated with an increased risk of infection-related mortality compared to that with treatment with VCT. A higher Acute Physiological and Chronic Health Evaluation II (APACHE II) score (aOR, 1.14; 95% CI 1.07 to 1.21) and a higher Charlson comorbidity index (aOR, 1.28; 95% CI, 1.11 to 1.47) were also independently associated with an increased risk of infection-related mortality. No increase in the incidence of ADRs was observed in the VCT group. The use of an individualized antibiotic combination which was selected on the basis of the results of
in vitro
combination testing was associated with significantly lower rates of infection-related mortality in patients with XDR GNB infections. Future prospective randomized studies will be required to validate these findings.
Methodological issues in the design and evaluation of supported communication for aphasia training: a cluster-controlled feasibility study
Authors: Horton Simon , Clark Allan , Barton Garry , Lane Kathleen , Pomeroy Valerie M 
Published: April 2016

ObjectiveTo assess the feasibility and acceptability of training stroke service staff to provide supported communication for people with moderate–severe aphasia in the acute phase; assess the suitability of outcome measures; collect data to inform sample size and Health Economic evaluation in a definitive trial.DesignPhase II cluster-controlled, observer-blinded feasibility study.SettingsIn-patient stroke rehabilitation units in the UK matched for bed numbers and staffing were assigned to control and intervention conditions.Participants70 stroke rehabilitation staff from all professional groups, excluding doctors, were recruited. 20 patients with moderate-severe aphasia were recruited.InterventionSupported communication for aphasia training, adapted to the stroke unit context versus usual care. Training was supplemented by a staff learning log, refresher sessions and provision of communication resources.Main outcome measuresFeasibility of recruitment and acceptability of the intervention and of measures required to assess outcomes and Health Economic evaluation in a definitive trial. Staff outcomes: Measure of Support in Conversation; patient outcomes: Stroke and Aphasia Quality of Life Scale; Communicative Access Measure for Stroke; Therapy Outcome Measures for aphasia; EQ-5D-3L was used to assess health outcomes.ResultsFeasibility of staff recruitment was demonstrated. Training in the intervention was carried out with 28 staff and was found to be acceptable in qualitative reports. 20 patients consented to take part, 6 withdrew. 18 underwent all measures at baseline; 16 at discharge; and 14 at 6-month follow-up. Of 175 patients screened 71% were deemed to be ineligible, either lacking capacity or too unwell to participate. Poor completion rates impacted on assessment of patient outcomes. We were able to collect sufficient data at baseline, discharge and follow-up for economic evaluation.ConclusionsThe feasibility study informed components of the intervention and implementation in day-to-day practice. Modifications to the design are needed before a definitive cluster-randomised trial can be undertaken.Trial registration numberISRCTN37002304; Results.
Effect of milk fat to protein ratio on genetic variance for milk yield in Thai tropical Holstein cattle
Authors: Puangdee S. , Duangjinda M. , Boonkum W. , Buaban S. , Katawatin S. 
Published: April 2016

The objective of this research was to investigate the optimum fat to protein ratio (FPR) in Thai tropical Holstein dairy cattle. First parity data consisting of 20 492 milk yields (MY) records for 24 891 cows for the period 2001 and 2011, were used in the analysis. The analysis used a random regression test-day animal model of third-order Legendre polynomials through the creation of a covariance function based on different FPRs. Variance components were estimated using the Bayesian method via the Gibbs sampling. The estimated heritability of MY in relation to FPR ranged from 0.19 to 0.27 with the pattern being similar to the genetic variances. Genetic correlations of MY at different FPRs were high at consecutive FPRs and then declined to negative in response to greater differences in FPR. Based on the results, it is concluded that the optimum FPR is in the range of 0.9 to 1.9, corresponding to the genetically controlled energy balance for MY in tropical Holsteins.
Transfer of Bursaphelenchus okinawaensis (Nematoda: Aphelenchoididae) associated with Monochamus maruokai (Coleoptera: Cerambycidae) into M. alternatus (Coleoptera: Cerambycidae) and Psacothea hilaris (Coleoptera: Cerambycidae)
Authors: Maehara Noritoshi , Kanzaki Natsumi 
Published: April 2016

We examined the transfer ofBursaphelenchus okinawaensisassociated withMonochamus maruokaiintoM. alternatusandPsacothea hilarisusing a simple nematode loading method in order:i) to clarify the effects of cerambycid beetles on the formation of dauer juveniles ofB. okinawaensis; andii) to clarify whether dauer juveniles transfer to cerambycid beetles other thanM. maruokai. Dauer juveniles appeared at a high percentage withoutM. alternatusorP. hilarisand these beetles did not have any positive effects on their formation. Dauer juveniles transferred to the adults ofM. alternatusandP. hilaris. We concluded that dauer juveniles ofB. okinawaensisform readily without its vector beetles and may be able to transfer to many kinds of cerambycid beetles, although the numbers carried by a beetle are small.
The role of macrophage polarization on bipolar disorder: Identifying new therapeutic targets
Authors: Ascoli Bruna M , Géa Luiza P , Colombo Rafael , Barbé-Tuana Florência M , Kapczinski Flávio , Rosa Adriane Ribeiro 
Published: April 2016

Objective: Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research. Method: This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity. Results: Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic–pituitary–adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood–brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism. Conclusions: This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders.
The combined impact of professional role identity and public service motivation on decision-making in dilemma situations
Authors: Schott Carina , van Kleef Daphne D. , Steen Trui P.S. 
Published: April 2016

Working in the public sector implies the need to make decisions in the face of dilemmas. As consistent decision-making is highly desirable for organizational performance, the question arises: what do public service professionals base their decisions on? This study aims to increase our understanding of whether public service motivation and professional role identity are useful concepts by which to predict what decisions public service professionals will make in complex situations. Using survey data, this research investigates the impact of these two concepts on the decision-making of veterinary inspectors working at the Dutch Food and Consumer Product Safety Authority. The results support the hypothesis that decision-making is influenced by the way in which veterinary inspectors interpret their professional role. Public service motivation, in contrast, seems to have neither a direct nor a moderating effect on decision-making in the context of dilemma situations. Points for practitioners Two important conclusions of this study are of interest for managers working with professionals. Our findings should urge them to consider the different views that employees have about their job when teams are formed or when specific combinations of tasks are assigned. For example, attention should be paid to the question of which mixture of professional role identities is most suitable to accomplish organizational objectives. Second, the construct of public service motivation can be used by human resource managers to assess whether public professionals are motivated to provide public services. However, the results also indicate that the operationalization of public service motivation needs to be adapted to the professional context of public service providers.
Adherence to guidelines regarding total hip replacement for fractured neck of femur
Authors: Fishlock A , Scarsbrook C , Marsh R 
Published: April 2016

Introduction In 2011 the National Institute for Health and Care Excellence (NICE) published guidelines suggesting that clinicians offer total hip replacement (THR) to patients with displaced intracapsular hip fractures who could walk independently outside with no aids or one stick, who are not cognitively impaired and are ASA (American Society of Anesthesiologists) grade ≤2. They also stated that best practice is operating within 36 hours of presentation. This audit aimed to determine whether Scarborough Hospital was following these guidelines and compared the results with the national average. Methods Two years of data (January 2012 – December 2013) were collected retrospectively from Scarborough Hospital’s hip fracture database on all patients presenting with an intracapsular hip fracture. Data were analysed to determine whether patients who had a THR fulfilled NICE criteria. Furthermore, patients with hemiarthroplasties who were eligible for THRs were identified. Finally, the time to surgery was calculated to examine whether patients receiving THRs waited longer than patients receiving hemiarthroplasties. Results In 2012, 48.6% of all eligible patients received a THR while in 2013 the figure was 55.9%. These percentages are much higher than the national average. However, 36 (53.7%) of the 67 patients who received a THR did not fulfil all the NICE criteria, mainly owing to high ASA grade. The mean time from presentation to theatre for THR was 8 hours and 37 minutes longer for THR patients than for hemiarthroplasty in 2012. This difference was reduced to 2 hours and 12 minutes in 2013. Conclusions Small general hospitals can meet and even exceed the standards regarding treatment strategies for hip factures. However, there is still room for improvement. Departmental training may be useful in achieving this aim. The anaesthetic team should be involved at the earliest opportunity, to help optimise patients preoperatively and determine whether patients listed for THR with higher ASA grades are suitable for this surgery.
Changes of sedimentation in the Drużno Lake based on geoarchaeological data from the Teutonic fortress in Elbląg, North Poland
Authors: Nitychoruk Jerzy , Szymanek Marcin , Bińka Krzysztof , Kasprzycka Maria , Zbucki Łukasz 
Published: April 2016

Abstract
The wooden structures unearthed in 2012 during archaeological excavation in the courtyard of the Museum of Archaeology and History in Elbląg have been dated using the dendrochronological method to the period between 1245 and 1302, which allows them to be considered to be parts of a Teutonic fortress. The remains of the wooden building located directly on the prehistoric lacustrine sediments created a unique opportunity to reconstruct the near-shore sedimentation of the Drużno Lake. Geological, malacological and palynological methods were applied during the investigation. The results, compared with the ranges of both the Drużno Lake and the Vistula Lagoon, known from previous studies of the region, allowed the correlation of a phase of a deep lake with the “Roman Period”. Rapid shallowing of the lake occurred in the “Migration Period”. The final disappearance of the lake in the area of modern Elbląg occurred in the early Middle Ages.
Are psychologists and psychiatrists assessing work capacity part of the problem or solution? / Jesu li psiholozi i psihijatri koji ocjenjuju radnu sposobnost dio problema ili rješenja problema?
Authors: Lalić Hrvoje 
Published: April 2016

Abstract
The aim of this case study was to emphasise the importance of coordination between the members of occupational medicine teams who assess work capacity in persons whose jobs may involve responsibility for other people’s safety and health. We have picked out four cases - three visiting nurses and one applicant for driving and firearms licence extension - where psychiatrists/psychologists and occupational health specialist disagreed in their assessment entirely. These cases illustrate how psychologists and psychiatrists tend to support patients’ wishes to either remain at their workplace or take disability retirement, whereas occupational health specialists take a different, less easy course, relying on the medical condition of the patient, specific job requirements, and broader implications for public safety. It appears that this is not a problem only in Croatia, but in a number of developed countries as well. This problem calls for additional training of all members of a work capacity assessment team.
Simple graph-theoretical model for flavonoid binding to P-glycoprotein / Jednostavan graf-teorijski model vezivanja flavonoida za P-glikoprotein / Jednostavan graf-teorijski model vezivanja flavonoida za P-glikoprotein
Authors: Miličević Ante , Raos Nenad 
Published: April 2016

Abstract
Three sets of flavonoid derivatives (N=32, 40, and 74) and logarithms of their dissociation constants (log Kd) that describe flavonoid affinity toward P-glycoprotein were modelled using six connectivity indices. The best results were obtained with the zero-order valence molecular connectivity index (0χv) for all three sets. Standard errors of the calibration models were around 0.3, and of the constants from the test sets even a little lower, 0.22 and 0.24. Despite using only one descriptor, our model proved better in internal (cross-validation) and especially in external (test set) statistics than much more demanding methods used in previous 3D QSAR modelling.