bluuebunny/crossref_metadata_2025 huggingface dataset:
Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis
Authors: Pérez‐Baos S , Barrasa J I , Gratal P , Larrañaga‐Vera A , Prieto‐Potin I , Herrero‐Beaumont G , Largo R
Published: June 2017

Background and Purpose

Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation.

Experimental Approach

CA was induced in previously immunized rabbits, fed a high‐fat diet, by administering four intra‐articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg−1·day−1) for 2 weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP‐1‐derived macrophages were exposed to high lipid concentrations and then stimulated with IFNγ in the presence or absence of tofacitinib in order to study mediators of RCT.

Key Results

Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP‐binding cassette transporter (ABCA1) synthesis.

Conclusions and Implications

Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients.
The hydrophobic side chain of oseltamivir influences type A subtype selectivity of neuraminidase inhibitors
Authors: Lin Xiong , Qin‐Hua Chen , Peng Li , Chun‐Lei Li , Guang‐De Yang
Published: June 2017

Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure–activity relationships revealed that the C‐5 position amino group of oseltamivir was pointed to 150‐cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C‐5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC50 = 0.1 ± 0.04 μm, H3N2 IC50 = 0.26 ± 0.18 μm) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors.
Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon
Authors: Tostivint I. , Royer N. , Nicolas M. , Bourillon A. , Czerkiewicz I. , Becker P.‐H. , Muller F. , Benoist J.‐F.
Published: June 2017

Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in 2 genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon (HEC) has been reported in some patients as a non‐pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a HEC (HEC group) and 39 with a classical postnatal form (CC group). SLC3A1 and SLC7A9 were sequenced. All patients were fully genotyped, and the relationship between the genotype and clinical features was analyzed. We identified mutations in SLC3A1 in 80% of the HEC group and in only 49% of the CC group. The SLC3A1 p.Thr216Met mutation was found in 21% of the alleles in the HEC group but was never found in the CC group. Most of the mutations found in the HEC group were considered severe mutations in contrast with the CC group. Twenty‐five novel mutations were reported. This study shows a relationship between genotype and the clinical form of cystinuria, suggesting that only the patients with the most severe mutations presented with an HEC. These results emphasized the need for prenatal cystinuria screening using classical third‐trimester ultrasound scan and the early management of suspected newborns.
A habitat‐based approach to predict impacts of marine protected areas on fishers
Authors: Teixeira João B. , Moura Rodrigo L. , Mills Morena , Klein Carissa , Brown Christopher J. , Adams Vanessa M. , Grantham Hedley , Watts Matthew , Faria Deborah , Amado‐Filho Gilberto M. , Bastos Alex C. , Lourival Reinaldo , Possingham Hugh P.
Published: June 2017

Although marine protected areas can simultaneously contribute to biodiversity conservation and fisheries management, the global network is biased toward particular ecosystem types because they have been established primarily in an ad hoc fashion. The optimization of trade‐offs between biodiversity benefits and socioeconomic values increases success of protected areas and minimizes enforcement costs in the long run, but it is often neglected in marine spatial planning (MSP). Although the acquisition of spatially explicit socioeconomic data is perceived as a costly or secondary step in MSP, it is critical to account for lost opportunities by people whose activities will be restricted, especially fishers. We developed an easily reproduced habitat‐based approach to estimate the spatial distribution of opportunity cost to fishers in data‐poor regions. We assumed the most accessible areas have higher economic and conservation values than less accessible areas and their designation as no‐take zones represents a loss of fishing opportunities. We estimated potential distribution of fishing resources from bathymetric ranges and benthic habitat distribution and the relative importance of the different resources for each port of total catches, revenues, and stakeholder perception. In our model, we combined different cost layers to produce a comprehensive cost layer so that we could evaluate of trade‐offs. Our approach directly supports conservation planning, can be applied generally, and is expected to facilitate stakeholder input and community acceptance of conservation.
Towards “cognitively complex” problem‐solving: Six models of public service reform
Authors: McCourt Willy
Published: June 2017

This article proposes “cognitively complex problem‐solving” as a refinement of the recent problem‐solving approach to public service reform, and as an addition to existing political and institutional explanations for the frequent failure of reform. It substantiates the new problem‐solving model by identifying and selectively reviewing six models of reform that have been practised in developing countries over the past half‐century: public administration, decentralization, pay and employment reform, New Public Management, integrity and corruption reforms and “bottom‐up” reforms. A short case study of Myanmar is presented to illustrate the problem‐solving approach in practice.
Who bears the burden of bribery? Evidence from public service delivery in Kenya
Authors: Mbate Michael
Published: June 2017

This article empirically examines how an individual's economic, social and political capital affects their propensity to make bribe payments in exchange for public services. Using an individual‐level survey on bribes, the econometric results suggest that the burden of bribery is borne by the poor, but substantially decreases when institutions that constrain bureaucratic corruption are strong and effective. The results also show that the incidence of bribery decreases when social capital is high but increases when political networks are prevalent. These findings support the need to combine anti‐corruption reforms with poverty reduction strategies and social policies in order to foster equity in public services provision in Kenya.
The impact of higher education expansion on intergenerational mobility
Authors: Li Zhi , Zhong Hai
Published: June 2017

The persistent correlations between parents and children's outcomes have long been investigated. From a policy perspective, it is important to understand the underlying causes of those correlations. Educational policy changes may have significant impacts on intergenerational mobility. The last several decades have witnessed a remarkable expansion of higher education around the world. In this paper, we examine the effect of higher education expansion on intergenerational mobility in China. We find that the higher education expansion in China has weakened the advantage of cadres’ children in higher education participation, and has strengthened the intergenerational educational correlation. One explanation for these results might be that, along with the process of economic reform started in 1979, the cadre selection mechanism has placed more and more weight on candidate's education and abilities.
Prenatal, perinatal and neonatal risk factors for perinatal arterial ischaemic stroke: a systematic review and meta‐analysis
Authors: Li C. , Miao J. K. , Xu Y. , Hua Y. Y. , Ma Q. , Zhou L. L. , Liu H. J. , Chen Q. X.
Published: June 2017

The aim of the present study was to perform a meta‐analysis of published data to determine the significance of clinical factors and exposures to the risk of perinatal arterial ischaemic stroke (PAIS) and provide guidance for clinical diagnosis and treatment. A comprehensive literature search of the PubMed, Embase, MEDLINE and Cochrane Library databases for relevant observational studies (cohort/case−control) from March 1984 to March 2016 was undertaken. Two review authors independently examined the full text records to determine which studies met the inclusion criteria and evaluated risk factors for PAIS. Risk ratios, odds ratios and 95% confidence intervals were estimated. A total of 11 studies were included in the analyses. Intrapartum fever >38°C, pre‐eclampsia, oligohydramnios, primiparity, forceps delivery, vacuum delivery, fetal heart rate abnormalities, abnormal cardiotocography tracing, cord abnormalities, birth asphyxia, emergency caesarean section, tight nuchal cord, meconium‐stained amniotic fluid, umbilical arterial pH <7.10, Apgar score at 5 min <7, resuscitation at birth, hypoglycaemia, male gender and small for gestational age were identified as risk factors for PAIS. This systemic review and meta‐analysis provides a preliminary evidence‐based assessment of the risk factors for PAIS. Patients with any of the risk factors identified in this analysis should be given careful consideration to ensure the prevention of PAIS. Future studies focusing on the combined effects of multiple prenatal, perinatal and neonatal risk factors for PAIS are warranted.
Congenital unilateral facial nerve paralysis in a Warmblood filly
Authors: Schön S. , Wehrli Eser M. , Kircher P. R. , Sydler T. , Augsburger H. , Ohlerth S. , Beckmann K. , Fürst A. E.
Published: June 2017

A 17‐month‐old Warmblood filly was referred to our clinic for evaluation of congenital facial nerve (FN) paralysis. Clinical examination revealed a right‐sided facial paralysis with mild masticatory muscle atrophy, mild dysphagia and exposure keratitis. Apart from the FN deficits, neurological examination of the remaining cranial nerves showed no abnormalities. Magnetic resonance imaging (MRI) examination using a 3.0 Tesla scanner showed that in comparison to the left FN, the intracranial section of the right FN between the pons and internal acoustic canal was thinner, whereas it appeared indistinct and thickened within the internal acoustic canal and facial canal. Signs of meningitis or encephalitis were not present on MRI. Cerebrospinal fluid analysis showed mild pleocytosis. The owner of the filly requested euthanasia due to the guarded prognosis. At necropsy, the intracranial section of the right FN was macroscopically thinner than the left side and within the facial canal, a 5 mm tissue stump could be identified with an absent extracranial part of the right FN. Histological examination of the brain stem showed different architecture of the left and right motor nuclei of the FN: in the left nucleus, motor neurons of a normal size and well stainable Nissl bodies were present, whereas in the right nucleus, neurons with Nissl bodies were decreased in number and size. Further, a cytoplasmic rich cell population with a nucleus size compatible with normal neurons was present. These cells were suspected to be atrophic neurons. The tissue stump within the facial canal was histologically identified as connective tissue. Unilateral malformation of the FN has not previously been described in the horse. This filly showed a right‐sided, intracranial hypoplasia accompanied by an extracranial aplasia of the FN causing complete, congenital facial nerve paralysis, which corresponded to a difference in the architecture of the affected motor nucleus of the FN.
Aryepiglottic lymphoma in a 19‐year‐old Paint gelding treated with excision and adjunctive radiotherapy
Authors: Pezzanite L. M. , Leary D. M. , LaRue S. M. , Hackett E. S.
Published: June 2017

This case report describes the diagnosis and treatment of an aryepiglottic tumour in a 19‐year‐old Paint gelding. Diagnostic work‐up included physical examination, endoscopic evaluation of the upper airway, and histopathology of the mass following removal. Treatment consisted of surgical excision of the aryepiglottic mass under endoscopic guidance followed by a 100 Gy dose of radiation delivered with strontium‐90 plesiotherapy to the surgical bed at 72 h post‐operatively. The radiation applicator was passed through the left nostril and the application area was confirmed via endoscopic evaluation. Histopathology, including immunohistochemistry, confirmed that the aryepiglottic tumour was T cell lymphoma. Recheck examination, including physical examination and upper airway endoscopy, was performed 1, 3 and 6 months following treatment and local recurrence was not observed. Local control with minimal morbidity can be achieved with surgical excision of equine lymphoma followed by strontium‐90 plesiotherapy.
Comprehensive mathematical model of oxidative phosphorylation valid for physiological and pathological conditions
Authors: Heiske Margit , Letellier Thierry , Klipp Edda
Published: June 2017

We developed a mathematical model of oxidative phosphorylation (OXPHOS) that allows for a precise description of mitochondrial function with respect to the respiratory flux and the ATP production. The model reproduced flux–force relationships under various experimental conditions (state 3 and 4, uncoupling, and shortage of respiratory substrate) as well as time courses, exhibiting correct P/O ratios. The model was able to reproduce experimental threshold curves for perturbations of the respiratory chain complexes, the F1F0‐ATP synthase, the ADP/ATP carrier, the phosphate/OH carrier, and the proton leak. Thus, the model is well suited to study complex interactions within the OXPHOS system, especially with respect to physiological adaptations or pathological modifications, influencing substrate and product affinities or maximal catalytic rates. Moreover, it could be a useful tool to study the role of OXPHOS and its capacity to compensate or enhance physiopathologies of the mitochondrial and cellular energy metabolism.
Progress in Nd3+, Er3+, and Yb3+ doped laser glasses at Shanghai Institute of Optics and Fine Mechanics
Authors: Zhang Liyan , Hu Lili , Jiang Shibin
Published: June 2017

This paper reviews the progress made on Nd3+, Er3+, and Yb3+ doped laser glasses at SIOM, China. Key properties of Nd: phosphate and Nd: fluorophosphate (FP) laser glasses are presented and compared with the commercial laser glasses from Hoya and Schott. Also reviewed are properties of four types of Er: phosphate glasses. The development of a continuous, large‐scale melting platform producing high‐quality Nd: phosphate laser glass at SIOM is briefly described. Our study on the Stark splitting of Yb3+: 2F7/2 level indicates that mixed‐glass formers can significantly improve the Stark splitting, resulting enhancement of lasing performance of Yb: phosphate glass.
Vaccine candidate discovery for the next generation of malaria vaccines
Authors: Tuju James , Kamuyu Gathoni , Murungi Linda M. , Osier Faith H. A.
Published: June 2017

Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre‐ to post‐genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody‐guided vaccine design spanned both eras but currently benefits from technological advances facilitating high‐throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen‐specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines.
Interferon‐β regulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis
Authors: Pennell Leesa M. , Fish Eleanor N.
Published: June 2017

CD11c+ dendritic cells (DCs) exert a critical role as antigen‐presenting cells in regulating pathogenic T cells in multiple sclerosis (MS). To determine whether the therapeutic benefit of interferon‐β (IFN‐β) treatment for MS is in part influenced by IFN regulation of DC function, we examined the immunophenotype of DCs derived from IFN‐β+/+ and IFN‐β−/− mice using a myelin oligodendrocyte glycoprotein (MOG) peptide‐induced mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our earlier work identified that IFN‐β−/− mice exhibit earlier onset and more rapid progression of neurological impairment compared with IFN‐β+/+ mice. In this study we show that lipopolysaccharide‐/MOG peptide‐stimulated IFN‐β−/− DCs secrete cytokines associated with pathological T helper type 17 rather than regulatory T‐cell polarization and exhibit increased CD80 and MHCII expression when compared with stimulated IFN‐β+/+ DCs. IFN‐β−/− DCs from mice immunized to develop EAE induce greater proliferation of MOG‐transgenic CD4+ T cells and promote interleukin‐17 production by these T cells. Adoptive transfer of MOG peptide‐primed IFN‐β−/− DCs into IFN‐β+/+ and IFN‐β−/− mice immunized to develop EAE resulted in their rapid migration into the central nervous system of recipient mice, before onset of disease, which we attribute to failed signal transducer and activator of transcription 1‐mediated inhibition of CCR7. Taken together, our data support immunoregulatory roles for IFN‐β in the activation and migration of DCs during EAE.
Views of mental health consumers about being involved in nursing handover on acute inpatient units
Authors: Olasoji Michael , Plummer Virginia , Reed Fiona , Jacob Sini , Shaw Liam , Shanti Michelle , Cross Wendy
Published: June 2017

The involvement of consumers in handover with nurses has been identified as reducing miscommunication and a reduction in adverse events in generalist nursing settings. Mental health (MH) care is complex, and handover practices need to fit with the philosophy of recovery‐focussed practice. Recovery‐focussed practice recognizes the person at the centre of care as an expert in their own treatment and decision‐making. The aim of the present study was to explore the views of consumers with a mental illness, without prior involvement in nursing handover, about their need to be involved in nursing handover on an acute mental health inpatient unit. Using an exploratory descriptive, qualitative design (n = 11), participants who were receiving care in an acute inpatient unit were recruited using purposive convenience sampling. Data were collected using semistructured interviews and analysed using thematic analysis. Participants' diagnoses were schizophrenia (n = 6), bipolar affective disorder (n = 4), and depression (n = 1). Two themes emerged from the interviews: (i) behind closed doors; and (ii) being involved. Several subthemes were also identified. The first theme, behind closed doors, had two subthemes: (i) it is about us; and (ii) knowing their thoughts. The second theme had three subthemes: (i) clarifying issues; (ii) setting expectations; and (iii) when and how. Nursing handover on the acute inpatient unit offers a good opportunity for consumers to take an active role in the delivery of nursing care. There is a need to rethink the way nursing handover occurs to include consumers.
High‐temperature strength and plastic deformation behavior of niobium diboride consolidated by spark plasma sintering
Authors: Demirskyi Dmytro , Solodkyi Ievgen , Nishimura Toshiyuki , Sakka Yoshio , Vasylkiv Oleg
Published: June 2017

Bulk niobium diboride ceramics were consolidated by spark plasma sintering (SPS) at 1900°C. SPS resulted in dense specimens with a density of 98% of the theoretical density and a mean grain size of 6 μm. During the SPS consolidation, the hexagonal boron nitride (h‐BN) was formed from B2O3 on the powder particle surface and residual adsorbed nitrogen in the raw diboride powder. The room‐temperature strength of these NbB2 bulks was 420 MPa. The flexural strength of the NbB2 ceramics remained unchanged up to 1600°C. At 1700°C an increase in strength to 450 MPa was observed, which was accompanied by the disappearance of the secondary h‐BN phase. Finally, at 1800°C signs of plastic deformation were observed. Fractographic analysis revealed a number of etching pits and steplike surfaces suggestive of high‐temperature deformation. The temperature dependence of the flexural strength of NbB2 bulks prepared by SPS was compared with data for monolithic TiB2, HfB2 and ZrB2. Our analysis suggested that the thermal stresses accumulated during SPS consolidation may lead to additional strengthening at elevated temperatures.
A framework approach for unravelling the impact of multiple factors influencing flooding
Authors: Gai L. , Baartman J.E.M. , Mendoza‐Carranza M. , Wang F. , Ritsema C.J. , Geissen V.
Published: June 2017

To have a better understanding of the influence of topographic, climatic, and, especially, anthropogenic factors on hydrological discharge and flooding, this study proposes a new framework approach using a set of methods to answer the questions why, where, when, and how flooding occurs. Including conditional inference tree (CIT), cross‐correlation, and double‐mass curves analysis, the approach is demonstrated in an application to the Wei River Basin, China. From the CIT analysis, dam construction period was identified as the most important factor (why), and the sub‐catchment farthest upstream contributed the most to the flooding of the downstream floodplain (where). We then analysed the effect of the periods of dam construction on the time lag change (when) and the precipitation–discharge relationship (how) using cross‐correlation analysis and double‐mass curves analysis, respectively. The results suggested that the dam construction delayed the precipitation for 0.4 days on average compared to before the dam construction period, and the discharge at the outlet of the basin was reduced by 44%. This framework approach is promising as it can quantitatively evaluate the importance of multiple factors on multiple years of flooding, while many studies evaluate single flooding events.
THESEUS1 positively modulates plant defense responses against Botrytis cinerea through GUANINE EXCHANGE FACTOR4 signaling
Authors: Qu Shaofeng , Zhang Xi , Song Yutong , Lin Jinxing , Shan Xiaoyi
Published: June 2017

The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses. THESEUS1 (THE1) acts as a sensor of cell wall integrity that controls cell elongation during plant growth. However, no specific role for THE1 in plant defense responses has been reported. Here, we found that THE1 interacts with GUANINE EXCHANGE FACTOR4 (GEF4) and that both proteins play regulatory roles in plant resistance to the necrotrophic fungus Botrytis cinerea. Genetic analysis showed that THE1 and GEF4 function in the same genetic pathway to mediate plant defense responses. In addition, using transcriptome analysis, we identified various genes (such as defense‐related, secondary metabolite‐related, and transcription factor genes) that are likely downstream targets in the THE1‐GEF4 signaling pathway. Our results suggest that THE1 functions as an upstream regulator of GEF4 signaling to positively regulate defense responses against B. cinerea in Arabidopsis.
Unmet belongingness needs but not high belongingness needs alone predict adverse well‐being: A response surface modeling approach
Authors: Verhagen Maaike , Lodder Gerine M. A. , Baumeister Roy F.
Published: June 2017

Objective

Previous work has linked high levels of belongingness needs to low well‐being, suggesting that high desire for social connection causes problems. Against that view, we hypothesized that problems stem especially from unmet belongingness needs. To examine this, discrepancies between belongingness needs and relationship satisfaction were measured.

Method

A total of 1,342 adolescents (Mage = 13.94 years, 48.6% boys) completed questionnaires about belongingness needs, relationship satisfaction, loneliness, depressive symptoms, and self‐esteem. A combination of polynomial regression analyses with response surface modeling examined the effects of both fulfilled and unmet belongingness needs on well‐being.

Results

Fulfilled belongingness needs did not affect adolescents' well‐being. However, larger discrepancies between high belongingness needs and low relationship satisfaction were related to higher loneliness, more depressive symptoms, and lower self‐esteem. Thus, well‐being was most strongly affected among adolescents reporting an unmet need to belong.

Conclusions

We add to the current knowledge by emphasizing that especially belongingness needs that exceed relationship satisfaction, regardless of the actual levels of both, contribute to actual health outcomes. Thus, high need to belong is not detrimental per se, but only in combination with low relationship satisfaction. Implications for clinical practice could be to prevent unmet belongingness needs to ultimately alleviate negative affect and self‐esteem.
Melanoma‐associated GRM3 variants dysregulate melanosome trafficking and cAMP signaling
Authors: Neto Ana , Ceol Craig J.
Published: June 2017

Large‐scale sequencing studies have revealed several genes that are recurrently mutated in melanomas. To annotate the melanoma genome, we have expressed tumor‐associated variants of these genes in zebrafish and characterized their effects on melanocyte development and function. Here, we describe expression of tumor‐associated variants of the recurrently mutated metabotropic glutamate receptor 3 (GRM3) gene. Unlike wild‐type GRM3, tumor‐associated GRM3 variants disrupted trafficking of melanosomes, causing their aggregation in the cell body. Melanosomes are trafficked in a cAMP‐dependent manner, and drugs that directly or indirectly increased cAMP levels were able to suppress melanosome aggregation in mutant GRM3‐expressing melanocytes. Our data show that oncogenic GRM3 variants dysregulate cAMP signaling, a heretofore unknown role for these oncogenes. cAMP signaling has been implicated in melanoma progression and drug resistance, and our data show that oncogenic properties of GRM3 could be mediated, at least in part, by alterations in cAMP signaling.
Dormancy cycles in buried seeds of three perennial Xyris (Xyridaceae) species from the Brazilian campo rupestre
Authors: Oliveira T. G. S. , Diamantino I. P. , Garcia Q. S.
Published: June 2017

Dormancy cycles are an important mechanism for avoiding seed germination under unfavourable periods for seedling establishment. This mechanism has been scarcely studied in tropical species. Here, we studied three tropical and perennial species of Xyris, X. asperula, X. subsetigera and X. trachyphylla, to investigate in situ longevity and the existence of seasonal seed dormancy cycles.

Seeds of three species of Xyris were buried in their natural habitat, with samples exhumed bimonthly for 18 months. Germination of exhumed seeds was assessed under a 12‐h photoperiod over a broad range of temperatures. Seeds of X. trachyphylla were also subjected to treatments to overcome secondary dormancy.

Seeds of all species are able to form a persistent seed bank and exhibit seasonal changes in germinability. Secondary dormancy was acquired during the rainy summer and was overcome during the subsequent dry season (autumn/winter). Desiccation partially overcomes secondary dormancy in X. trachyphylla seeds.

Soil seed bank persistence and synchronisation of seed germination under favourable conditions for seedling establishment contribute to the persistence and regeneration of X. asperula, X. subsetigera and X. trachyphylla in their natural environment.
Influence of inspiratory resistive loading on expiratory muscle fatigue in healthy humans
Authors: Peters Carli M. , Welch Joseph F. , Dominelli Paolo B. , Molgat‐Seon Yannick , Romer Lee M. , McKenzie Donald C. , Sheel A. William
Published: June 2017

New Findings

What is the central question of this study?

This study is the first to measure objectively both inspiratory and expiratory muscle fatigue after inspiratory resistive loading to determine whether the expiratory muscles are activated to the point of fatigue when specifically loading the inspiratory muscles.

What is the main finding and its importance?

The absence of abdominal muscle fatigue suggests that future studies attempting to understand the neural and circulatory consequences of diaphragm fatigue can use inspiratory resistive loading without considering the confounding effects of abdominal muscle fatigue.

Expiratory resistive loading elicits inspiratory as well as expiratory muscle fatigue, suggesting parallel coactivation of the inspiratory muscles during expiration. It is unknown whether the expiratory muscles are likewise coactivated to the point of fatigue during inspiratory resistive loading (IRL). The purpose of this study was to determine whether IRL elicits expiratory as well as inspiratory muscle fatigue. Healthy male subjects (n = 9) underwent isocapnic IRL (60% maximal inspiratory pressure, 15 breaths min−1, 0.7 inspiratory duty cycle) to task failure. Abdominal and diaphragm contractile function was assessed at baseline and at 3, 15 and 30 min post‐IRL by measuring gastric twitch pressure (Pga,tw) and transdiaphragmatic twitch pressure (Pdi,tw) in response to potentiated magnetic stimulation of the thoracic and phrenic nerves, respectively. Fatigue was defined as a significant reduction from baseline in Pga,tw or Pdi,tw. Throughout IRL, there was a time‐dependent increase in cardiac frequency and mean arterial blood pressure, suggesting activation of the respiratory muscle metaboreflex. The Pdi,tw was significantly lower than baseline (34.3 ± 9.6 cmH2O) at 3 (23.2 ± 5.7 cmH2O, P < 0.001), 15 (24.2 ± 5.1 cmH2O, P < 0.001) and 30 min post‐IRL (26.3 ± 6.0 cmH2O, P < 0.001). The Pga,tw was not significantly different from baseline (37.6 ± 17.1 cmH2O) at 3 (36.5 ± 14.6 cmH2O), 15 (33.7 ± 12.4 cmH2O) and 30 min post‐IRL (32.9 ± 11.3 cmH2O). Inspiratory resistive loading elicits objective evidence of diaphragm, but not abdominal, muscle fatigue. Agonist–antagonist interactions for the respiratory muscles appear to be more important during expiratory versus inspiratory loading.
Down syndrome and Moyamoya disease: unusual cause of stroke
Authors: Tavares Bello Carlos , Barreiros Catarina , Gil Inês , Vasconcelos Carlos
Published: June 2017

Down syndrome is a frequent clinical entity, being considered one of the most frequent chromosomal aberrations. It is characterised by a typical clinical phenotype and is associated with a heterogeneous group of organ and system-specific abnormalities. The cardiovascular system is commonly affected and if so, it may be associated with an increased morbidity and mortality. Cerebrovascular events in patients with Down syndrome are multifactorial, being possibly related to congenital heart disease, vascular malformations and traditional cardiovascular risk factors. Moyamoya disease is a rare chronic occlusive vascular disease causing stenosis of the distal portion of the internal carotid artery, which has been associated with Down syndrome. The authors report the case of a 26-year-old woman with Down syndrome who presented with an acute stroke secondary to Moyamoya disease. The case is noteworthy for the rarity of this clinicopathological entity, and serves as a reminder for the possible association between these two conditions.
The relationship between bicycle commuting and perceived stress: a cross-sectional study
Authors: Avila-Palencia Ione , de Nazelle Audrey , Cole-Hunter Tom , Donaire-Gonzalez David , Jerrett Michael , Rodriguez Daniel A , Nieuwenhuijsen Mark J
Published: June 2017

Introduction

Active commuting — walking and bicycling for travel to and/or from work or educational addresses — may facilitate daily, routine physical activity. Several studies have investigated the relationship between active commuting and commuting stress; however, there are no studies examining the relationship between solely bicycle commuting and perceived stress, or studies that account for environmental determinants of bicycle commuting and stress. The current study evaluated the relationship between bicycle commuting, among working or studying adults in a dense urban setting, and perceived stress.

Methods

A cross-sectional study was performed with 788 adults who regularly travelled to work or study locations (excluding those who only commuted on foot) in Barcelona, Spain. Participants responded to a comprehensive telephone survey concerning their travel behaviour from June 2011 through to May 2012. Participants were categorised as either bicycle commuters or non-bicycle commuters, and (based on the Perceived Stress Scale, PSS-4) as either stressed or non-stressed. Multivariate Poisson regression with robust variance models of stress status based on exposures with bicycle commuting were estimated and adjusted for potential confounders.

Results

Bicycle commuters had significantly lower risk of being stressed than non-bicycle commuters (Relative Risk; RR (95% CI)=0.73 (0.60 to 0.89), p=0.001). Bicycle commuters who bicycled 4 days per week (RR (95% CI)=0.42 (0.24 to 0.73), p=0.002) and those who bicycled 5 or more days per week (RR (95% CI)=0.57 (0.42 to 0.77), p<0.001) had lower risk of being stressed than those who bicycled less than 4 days. This relationship remained statistically significant after adjusting for individual and environmental confounders and when using different cut-offs of perceived stress.

Conclusions

Stress reduction may be an important consequence of routine bicycle use and should be considered by decision makers as another potential benefit of its promotion.
Does depression increase the risk of stroke in patients with rheumatoid arthritis? A population-based cohort study
Authors: Tsai Tzung-Yi , Lu Ming-Chi , Livneh Hanoch , Chiu Shan-Yun , Lai Ning-Sheng , Guo How-Ran
Published: June 2017

Objectives

Comorbid depression is common and undertreated in patients with rheumatoid arthritis (RA). It remains uncertain whether comorbid depression provoked the risk of poor clinical outcome, stroke in particular, among patients with RA. This work aimed to determine if depression onset during the treatment process increases stroke risk for patients with RA as compared with those with (1) neither RA nor depression, (2) RA only and (3) depression only.

Design

A nationwide, population-based cohort study.

Setting

Taiwan's Longitudinal Health Insurance Database.

Participants

We identified 8045 subjects with a newly diagnosed RA between 1997 and 2010, together with 32 600 subjects without RA matched by age, gender and index date. All subjects were further divided into four groups based on whether they were diagnosed with comorbid depression during the follow-up period.

Main outcome measure

The incidence rate and HR for incident stroke were estimated by the end of 2012 using Cox proportional hazard regression.

Results

We discovered that patients with RA with the comorbid depression exhibited the highest risk of stroke, with an adjusted HR of 2.18 (95% CI 1.87 to 2.54). Those with RA only or those with depression only still had the higher risk of stroke by 43% and 57% as compared with subjects without either condition. Multivariate analysis showed RA subjects who were male or older, incurred the onset of depression, or had comorbidities such as hypertension, diabetes as well as heart disease, had a greater risk of stroke.

Conclusions

This study cleared up the significant association between RA and the subsequent risk of stroke, and further highlighted that the onset of depression within the treatment process may increase stroke risk for RA subjects. Findings could assist healthcare providers to pinpoint individuals with RA with a higher predisposition of stroke, which could facilitate the provision of appropriate rehabilitation.
Assessing the impact of colonoscopy complications on use of colonoscopy among primary care physicians and other connected physicians: an observational study of older Americans
Authors: Keating Nancy L , James O’Malley A , Onnela Jukka-Pekka , Landon Bruce E
Published: June 2017

Objectives

Psychological biases can distort treatment decision-making. The availability heuristic is one such bias, wherein events that are recent, vivid or easily imagined are readily ‘available’ to memory and are therefore judged more likely to occur than expected based on epidemiological data. We assessed if the occurrence of a serious colonoscopy complication for a primary care physician’s patient influenced colonoscopy rates for the physician’s other patients.

Design

Longitudinal study with time-varying exposure variables.

Setting/participants

Individuals living in 51 hospital referral regions across the USA identified based on enrolment in fee-for-service Medicare during 2005–2010. We assigned patients to a primary care physician based on office visits during the prior 2 years.

Exposures

For each physician in each month, we calculated the proportion of patients assigned to them who had a colonoscopy. We identified two serious complications of which the primary care provider would very likely be aware: gastrointestinal bleed or perforation leading to hospitalisation or death within 14 days of colonoscopy.

Main outcome measures

We employed Poisson regression models including physician fixed effects to assess the change in number of colonoscopies in the four quarters following an adverse colonoscopy event.

Results

We identified 5 360 191 patients assigned to 30 704 physicians. 4864 physicians (16%) had at least one patient with an adverse event. The estimated change in the quarterly number of colonoscopies among physicians’ patients was significantly lower in quarter 2 following an adverse colonoscopy event (change=−2.1% (95% CI −3.4 to −0.8%)), before returning to the rate expected in the absence of an adverse event.

Conclusions

Having a patient experience a serious adverse colonoscopy event was associated with a small and temporary decline in colonoscopy rates among a physician’s other patients. This finding provides empirical evidence for the influence of notable adverse events on care, possibly due to the availability heuristic.
Effect of e-cigarette advertisements and antismoking messages on explicit and implicit attitudes towards tobacco and e-cigarette smoking in 18–65-year-olds: a randomised controlled study protocol
Authors: Booth Paula , Albery Ian P , Frings Daniel
Published: June 2017

Introduction

Since the advent of e-cigarettes, e-cigarette advertising has escalated and companies are able to use marketing strategies that are not permissible for tobacco products. Research into the effect of e-cigarette advertising on attitudes towards tobacco and e-cigarettes is in its infancy. To date, no research has compared indirect (implicit) measures of attitude towards e-cigarettes with direct (explicit) measures. Furthermore, little consideration has been given to how viewing online advertisements may have an effect on attitudes towards e-cigarettes or how positive attitudes to e-cigarettes may undermine antismoking public health messages. The objectives of this study are to investigate (1) the relationship between explicit and implicit attitudes towards tobacco and e-cigarettes, (2) the effect of e-cigarette advertising on these attitudes and (3) the effect of these attitudes on the efficacy of antismoking health messages.

Methods and analysis

In experiment 1 an analysis of covariance will be conducted to determine whether viewing an e-cigarette advertisement, compared with a neutral image, has an effect on implicit or explicit attitudes towards tobacco and e-cigarettes, and if these attitudes differ between smokers, vapers and non-smokers aged 18 - 25 years. In experiment 2, moderation analysis will be conducted to assess whether attitudes towards e-cigarettes moderate the psychological efficacy of antismoking health messages in participants aged 18–65 years. In each experiment, attitudes will be measured preintervention and postintervention and 1 week later (n=150) in participants who are smokers (n=50), vapers (n=50) or non-smokers (n=50).

Ethics and dissemination

Approval for this study has been given by the London South Bank University’s (LSBU) Research Ethics Committee. The findings of these studies will be submitted for publication and disseminated via conferences. The results will be integrated into course provision for practitioners training at LSBU.
Formal consensus to identify clinically important changes in management resulting from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway
Authors: Pufulete Maria , Brierley Rachel C , Bucciarelli-Ducci Chiara , Greenwood John P , Dorman Stephen , Anderson Richard A , Harris Jessica , McAlindon Elisa , Rogers Chris A , Reeves Barnaby C
Published: June 2017

Objective

To define important changes in management arising from the use of cardiovascular magnetic resonance (CMR) in patients who activate the primary percutaneous coronary intervention (PPCI) pathway.

Design

Formal consensus study using literature review and cardiologist expert opinion to formulate consensus statements and setting up a consensus panel to review the statements (by completing a web-based survey, attending a face-to-face meeting to discuss survey results and modify the survey to reflect group discussion and completing the modified survey to determine which statements were in consensus).

Participants

Formulation of consensus statements: four cardiologists (two CMR and two interventional) and six non-clinical researchers. Formal consensus: seven cardiologists (two CMR and three interventional, one echocardiography and one heart failure). Forty-nine additional cardiologists completed the modified survey.

Results

Thirty-seven draft statements describing changes in management following CMR were generated; these were condensed into 12 statements and reviewed through the formal consensus process. Three of 12 statements were classified in consensus in the first survey; these related to the role of CMR in identifying the cause of out-of-hospital cardiac arrest, providing a definitive diagnosis in patients found to have unobstructed arteries on angiography and identifying patients with left ventricular thrombus. Two additional statements were in consensus in the modified survey, relating to the ability of CMR to identify patients who have a poor prognosis after PPCI and assess ischaemia and viability in patients with multivessel disease.

Conclusion

There was consensus that CMR leads to clinically important changes in management in five subgroups of patients who activate the PPCI pathway.
The Bipolar Illness Onset study: research protocol for the BIO cohort study
Authors: Kessing Lars Vedel , Munkholm Klaus , Faurholt-Jepsen Maria , Miskowiak Kamilla Woznica , Nielsen Lars Bo , Frikke-Schmidt Ruth , Ekstrøm Claus , Winther Ole , Pedersen Bente Klarlund , Poulsen Henrik Enghusen , McIntyre Roger S , Kapczinski Flavio , Gattaz Wagner F , Bardram Jakob , Frost Mads , Mayora Oscar , Knudsen Gitte Moos , Phillips Mary , Vinberg Maj
Published: June 2017

Introduction

Bipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%–2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5–10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.

The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder.

Methods and analysis

The study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period.

Ethics and dissemination

The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers.

Trial registration number

NCT02888262.