bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzymatic Modification of Rice Bran Polysaccharides by Enzymes from Grifola Frondosa: Natural Killer Cell Cytotoxicity and Antioxidant Activity
Authors: Liu Shiyao , Zhuang Xuhui , Zhang Xiaolin , Han Wei , Liu Yuchun , Sun Dongmei , Guo Weiqun
Published: June 2018

Rice bran polysaccharides (RBPSs) are the major active constituents of rice bran (RB). In this study, we utilized intracellular enzymes from Grifola frondosa to modify RBPSs, which were extracted from RB using ultrasound. To enhance the effect on natural killer (NK) cell cytotoxicity of modified polysaccharides (mRBPSs) generated from RBPSs, an orthogonal test (L9[3]4) was employed to optimize the modification conditions. Based on the results of a single‐factor test, the enzyme to polysaccharide ratio, reaction temperature, reaction pH, and reaction time were the main factors affecting mRBPSs‐enhanced NK‐cell cytotoxicity. The best conditions were determined to be an enzyme to polysaccharide ratio of 1:5, a reaction temperature of 40 °C, a reaction pH of 4, and a reaction time of 4 hr. By optimizing the conditions, the NK‐cell cytotoxicity induced by mRBPSs6 was the highest, increasing by 12.01% ± 0.08%. Gas chromatographic analysis revealed that mRBPSs6 consists of rhamnose, arabinose, xylose, mannose, glucose, and galactose at a molar ratio of 7:21:6:5:53:48, which was 8:13:8:5:44:44 before modification. High‐performance liquid chromatography results indicated molecular weights for the RBPSs of approximately 106 Da, which decreased to 104 to 105 Da after modification. Antioxidant activity tests revealed high capacity of mRBPSs6 for scavenging 1,1‐diphenyl‐2‐picrylhydrazyl radicals and hydroxyl free radicals at 1.0 mg/mL.

Practical Application

Rice bran polysaccharides (RBPSs) contain compounds with many biological activities. However, these polysaccharides difficult to absorb due to high molecular weights and unexposed active sites, which are the main factors that limit their use in functional foods. The results of this study demonstrate that modification of RBPSs using intracellular enzymes from an edible fungus alters the molecular weights and monosaccharide composition of RBPSs. In addition, immune and antioxidant activities of RBPSs were increased. The findings provide a new and beneficial application for rice bran.
Reconstructing phylogeny from reduced‐representation genome sequencing data without assembly or alignment
Authors: Fan Huan , Ives Anthony R. , Surget‐Groba Yann
Published: June 2018

Reduced‐representation genome sequencing such as RADseq aids the analysis of genomes by reducing the quantity of data, thereby lowering both sequencing costs and computational burdens. RADseq was initially designed for studying genetic variation across genomes at the population level, but has also proved to be suitable for interspecific phylogeny reconstruction. RADseq data pose challenges for standard phylogenomic methods, however, due to incomplete coverage of the genome and large amounts of missing data. Alignment‐free methods are both efficient and accurate for phylogenetic reconstructions with whole genomes and are especially practical for nonmodel organisms; nonetheless, alignment‐free methods have not been applied with reduced genome sequencing data. Here, we test a full‐genome assembly‐ and alignment‐free method, AAF, in application to RADseq data and propose two procedures for reads selection to remove reads from restriction sites that were not found in taxa being compared. We validate these methods using both simulations and real data sets. Reads selection improved the accuracy of phylogenetic construction in every simulated scenario and the two real data sets, making AAF as good or better than a comparable alignment‐based method, even though AAF had much lower computational burdens. We also investigated the sources of missing data in RADseq and their effects on phylogeny reconstruction using AAF. The AAF pipeline modified for RADseq or other reduced‐representation sequencing data, phyloRAD, is available on github (https://github.com/fanhuan/phyloRAD).
Assessment of skin temperature during regional anaesthesia—What the anaesthesiologist should know
Authors: Hermanns H. , Werdehausen R. , Hollmann M. W. , Stevens M. F.
Published: June 2018

Body temperature homeostasis is accurately regulated by complex feedback‐driven neuronal mechanisms, which involve a multitude of thermoregulatory pathways. Thus, core temperature is constantly maintained within a narrow range. As one of the most effective regulatory systems skin temperature is dependent on skin blood flow. Skin blood flow in turn is highly dependent on sympathetic activity. Regional anaesthesia leads to blockade not only of somatosensory and motor nerve fibres but also of sympathetic fibres. As a consequence, vasoconstrictor tonic activity is abrogated and a vasodilation leads to an increase in skin blood flow and temperature. The aim of this review was to summarize the general physiology of thermoregulation and skin temperature as well as the alterations during regional anaesthesia. The main focus was the usefulness of measuring skin temperature as an indicator of regional anaesthesia success. According to the available literature, assessment of skin temperature can indeed serve to predict success of regional anaesthesia. Hence, it is important to realize that relevant and reliable temperature increase is only seen in the most distal body parts, ie fingers and toes. More proximally, temperature changes are frequently small and inconsistent, which means that assessment of block levels is not possible by temperature measurement. Furthermore, relevant skin temperature increases will only be observed in patients, which are initially vasoconstricted. In conclusion, measurement of skin temperature represents a reliable and feasible diagnostic tool to assess and predict the success or failure of regional anaesthesia procedures, especially in patients in which sensory testing is impossible.
Effects of gamma radiation on the survival of four species of thrips (Thysanoptera: Thripidae)
Authors: Nicholas Adrian , Lidbetter Fiona , Eagleton Fah , Spohr Lorraine , Harris Anne , Barchia Idris
Published: June 2018

The survival of four species of thrips (Frankliniella occidentalis, Frankliniella schultzei, Thrips tabaci and Thrips imaginis) exposed to gamma irradiation at doses of 0, 200, 300, 400 and 500 Gray was investigated. The aim of the work was to identify a generic dose of gamma radiation capable of killing or sterilising thrips infesting horticultural produce to prevent movement to, and colonisation of host plants in noninfested regions or countries. To simulate naturally occurring thrips populations, mixed life‐stages were irradiated, and the effects compared with a nonirradiated control. The eggs of F. occidentalis and T. tabaci were more tolerant to irradiation than those of F. schultzei and Thrips imaginis, but none of the F. occidentalis or T. tabaci eggs developed beyond first stage larvae when irradiated at a target dose of 200 Gy. In mixed life‐stage tests, all species had a similar tolerance to gamma irradiation. At a target dose of 200 Gy, all species were sterilised and no further offspring were produced. Based on these results, a minimum generic dose of 200 Gy would be sufficient to control these species of thrips in fresh horticultural produce destined for export to thrips‐sensitive regions. A target dose of 250 Gy will provide a further margin of safety, until large‐scale confirmatory trials are completed.
The presence of atrial fibrillation in Takotsubo cardiomyopathy is predictive of mortality: Systematic review and meta‐analysis
Authors: Prasitlumkum Narut , Kittipibul Veraprapas , Limpruttidham Nath , Rattanawong Pattara , Chongsathidkiet Pakawat , Boondarikpornpant Thosaporn
Published: June 2018

Introduction

Atrial fibrillation (AF) is known as the most common arrhythmia and an independent risk factor for mortality. Recent studies suggest that AF is associated with morbidity and mortality in Takotsubo cardiomyopathy (TTC). However, a systematic review and meta‐analysis of the literature have not been done. We assessed the association between AF in patients with TTC and mortality by a systematic review of the literature and a meta‐analysis.

Methods

We comprehensively searched the databases of MEDLINE and EMBASE from inception to January 2018. Included studies were published prospective or retrospective cohort studies that compared all‐cause mortality in TTC with AF versus without AF. Data from each study were combined using the random‐effects, generic inverse variance method of DerSimonian and Laird to calculate risk ratios and 95% confidence intervals.

Results

Five studies from August 2008 to October 2017 were included in this meta‐analysis involving 2,321 subjects with TTC (243 with AF and 2,078 without AF). The presence of AF was associated with all‐cause mortality (pooled odds ratio = 2.19, 95% confidence interval: 1.57–3.06, p < 0.001, I 2 = 0%).

Conclusion

Atrial fibrillation increased all‐cause mortality by double among patients with TTC compared to without it. Our study suggests that the presence of AF in TTC is prognostic for all‐cause mortality.
Aromatherapy: Activating olfactory calcium‐sensing receptors impairs renal hemodynamics via sympathetic nerve‐mediated vasoconstriction
Authors: Lee Shih‐Pin , Wu Wei‐Yi , Hsiao Jong‐Kai , Zhou Jia‐Hao , Chang Hao‐Hsiang , Chien Chiang‐Ting
Published: June 2018

Aim

This study determines whether the activation of olfactory calcium‐sensing receptor initiates a sympathetic activation‐dependent neurovascular reflex subsequently contributing to renal hemodynamic depression.

Methods

Immunohistochemistry and nose‐loading calcium‐sensitive dye were used to explore the location and function of calcium‐sensing receptor on the olfactory sensory neuron. The renal sympathetic nervous activity, renal hemodynamics and the microcirculation of kidney, liver and intestine were evaluated after liquid‐phase intranasal administrations of saline, lidocaine, calcium‐sensing receptor agonists and antagonist in sham and bilateral renal denervated rats. Real‐time renal glomerular filtration rate was measured by a magnetic resonance renography.

Results

Calcium‐sensing receptors were expressed on the cilia the olfactory sensory neuron and their activation depolarized olfactory sensory neuron and induced the calcium influx in the terminal side on olfactory glomeruli. Activating olfactory calcium‐sensing receptors significantly increased arterial blood pressure and renal sympathetic nervous activities and subsequently decreased renal blood flow, renal, hepatic and enteral microcirculation. Cotreatments with calcium‐sensing receptor antagonist or lidocaine inhibited these physiological alterations. The renal hemodynamic depressions by olfactory calcium‐sensing receptor activation were significantly blocked by bilateral renal denervation. The intranasal manganese administration decreased the glomerular filtration rate.

Conclusion

Calcium‐sensing receptor acts as a functional chemosensory receptor on olfactory sensory neuron, and its activation causes the global sympathetic enhancement contributing to systematic vasoconstriction and subsequently depresses renal blood flow and glomerular filtration rate. These data implicate a possibly clinical aspect that several environmental stimuli may activate olfactory calcium‐sensing receptors to evoke a sympathetic nervous system‐mediated neurovascular reflex to depress renal hemodynamics.
Letter: unlikely liver bedfellows—alpha‐1 antitrypsin deficiency and granulomatosis with polyangiitis
Authors: Farshad S. , Imam Z. H. , Tobi M.
Published: June 2018

Linked Content

This article is linked to Townsend et al and Turner papers. To view these articles visit https://doi.org/10.1111/apt.14537 and https://doi.org/10.1111/apt.14809.
Editorial: real‐life data confirm efficacy of elbasvir/grazoprevir in HCV patients with severe kidney disease
Authors: Rumi M. G. , Occhipinti V.
Published: June 2018

Linked Content

This article is linked to Flamm et al and Flamm papers. To view these articles visit https://doi.org/10.1111/apt.14635 and https://doi.org/10.1111/apt.14826.
Letter: unlikely liver bedfellows—alpha‐1 antitrypsin deficiency and granulomatosis with polyangiitis. Author's reply
Authors: Turner A. M.
Published: June 2018

Linked Content

This article is linked to Townsend et al and Farshad et al papers. To view these articles visit https://doi.org/10.1111/apt.14537 and https://doi.org/10.1111/apt.14675.
Letter: impact of HBV genotypes and PC/BCP mutations on serum HBsAg levels in Chinese HBeAg‐negative patients
Authors: Chen E.‐Q. , Wang M.‐L. , Wu D.‐B. , Liao J. , Tang H.
Published: June 2018

Linked Content

This article is linked to Kuhnhenn et al papers. To view these articles visit https://doi.org/10.1111/apt.14636 and https://doi/org/10.1111/apt.14836.
Letter: impact of HBV genotypes and PC/BCP mutations on serum HBsAg levels in Chinese HBeAg negative patients—Authors′ reply
Authors: Kuhnhenn L. , Jiang B. , Kubesch A. , Zeuzem S. , Sarrazin C. , Hildt E. , Peffer K.‐H.
Published: June 2018

Linked Content

This article is linked to Kuhnhenn et al and Chen et al papers. To view these articles visit https://doi.org/10.1111/apt.14636 and https://doi.org/10.1111/apt.14815.
Offset Analgesia and The Impact of Treatment with Oxycodone and Venlafaxine: A Placebo‐Controlled, Randomized Trial in Healthy Volunteers
Authors: Olesen Anne E. , Nissen Thomas D. , Nilsson Matias , Lelic Dina , Brock Christina , Christrup Lona L. , Drewes Asbjørn M.
Published: June 2018

Offset analgesia (OA) is a pain‐modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a discrete decrease in stimulus temperature. The role of the opioidergic, serotonergic and noradrenergic systems on OA remains unclear. The aim of this study was to evaluate whether OA is modulated by an opioid (oxycodone) and a serotonin and noradrenaline reuptake inhibitor (venlafaxine) in terms of psychophysical assessments. In this randomized, double‐blinded, placebo‐controlled cross‐over study, 20 healthy male participants (mean age: 24.6 ± 2.5 years) received 10 mg oxycodone, 37.5 mg venlafaxine or placebo twice daily for 5 days in three periods. OA was induced by noxious thermal stimulation on the forearm at baseline and last day of treatment. A control session of constant stimulus intensity was included for comparison. OA magnitude was unaffected by oxycodone and venlafaxine (p = 0.20 and p = 0.90, respectively). Oxycodone affected the control paradigm where a decreased rating of pain intensity was observed compared to placebo (p = 0.001). OA could not be modulated by oxycodone or venlafaxine and may be a robust phenomenon in healthy volunteers and not suitable for exploring pharmacological mechanisms of analgesia in human beings.
Advances in understanding iron metabolism and its crosstalk with erythropoiesis
Authors: Camaschella Clara , Pagani Alessia
Published: June 2018

Recent years have witnessed impressive advances in our understanding of iron metabolism. A number of studies of iron disorders and of their animal models have provided landmark insights into the mechanisms of iron trafficking, distribution and homeostatic regulation, the latter essential to prevent both iron deficiency and iron excess. Our perception of iron metabolism has been completely changed by an improved definition of cellular and systemic iron homeostasis, of the molecular pathogenesis of iron disorders, the fine tuning of the iron hormone hepcidin by activators and inhibitors and the dissection of the components of the hepcidin regulatory pathway. Important for haematology, the crosstalk of erythropoiesis, the most important iron consumer, and the hepcidin pathway has been at least partially clarified. Novel potential biomarkers are available and novel therapeutic targets for iron‐related disorders have been tested in murine models. These preclinical studies provided proofs of principle and are laying the ground for clinical trials. Understanding iron control in tissues other than erythropoiesis remains a challenge for the future.
Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia
Authors: Hannemann Anke , Rees David C. , Brewin John N. , Noe Andreas , Low Ben , Gibson John S.
Published: June 2018

Phosphatidylserine (PS) exposure increases as red cells age, and is an important signal for the removal of senescent cells from the circulation. PS exposure is elevated in red cells from sickle cell anaemia (SCA) patients and is thought to enhance haemolysis and vaso‐occlusion. Although precise conditions leading to its externalisation are unclear, high intracellular Ca2+ has been implicated. Red cells from SCA patients are also exposed to an increased oxidative challenge, and we postulated that this stimulates PS exposure, through increased Ca2+ levels. We tested four different ways of generating oxidative stress: hypoxanthine and xanthine oxidase, phenazine methosulphate, nitrite and tert‐butyl hydroperoxide, together with thiol modification with N‐ethylmaleimide (NEM), dithiothreitol and hypochlorous acid (HOCl), in red cells permeabilised to Ca2+ using bromo‐A23187. Unexpectedly, our findings showed that the four oxidants significantly reduced Ca2+‐induced PS exposure (by 40–60%) with no appreciable effect on Ca2+ affinity. By contrast, NEM markedly increased PS exposure (by about 400%) and slightly but significantly increased the affinity for Ca2+. Dithiothreitol modestly reduced PS exposure (by 25%) and HOCl had no effect. These findings emphasise the importance of thiol modification for PS exposure in sickle cells but suggest that increased oxidant stress alone is not important.
Climate reconstruction for the Entre‐Douro‐e‐Minho region (NWPortugal) betweenAD1626 andAD1820: synthesis of viticulture data and foraminiferal evidence
Authors: Moreno João , Fatela Francisco , Gonçalves Mário A. , Leorri Eduardo , Trigo Ricardo M. , Moreno Filipa , Gómez‐Navarro Juan J. , Brázdil Rudolf , Ferreira Manuel J.
Published: June 2018

This work presents two novel climate‐related time series for the northwest of Portugal. The first is anAD1626–1820 triennial‐resolved wine production series, based on the Benedictine accounts from six monasteries of the Entre‐Douro‐e‐Minho (EDM) region. The second, anAD1654–2010 benthic foraminiferal record from the Caminha salt marsh, located in the lower estuary of the Minho River. The series were analysed together for the common period to outline how both palaeoclimatic proxies respond to the most likely natural environmental drivers of temporal variability, solar forcing included. Singular spectral analysis revealed a common significant multidecadal periodicity agreeing with recognized long‐term changes in solar activity, i.e. the Lower Gleissberg cycle (50–80 years). The application of wavelet analysis allowed the detection of high coherence at this time scale (centred atc. 64 years) between marsh foraminifera and both total solar irradiance and the North Atlantic Oscillation index. This relationship persists throughout thec. AD1730–1875 period. The continuous wavelet transform results for wine production were inconclusive. As the time‐span analysed is recognized as one of high socio‐economic and political distress, the main human‐driven impacts on wine production, particularly in the two periods of greatly reduced solar activity – the Maunder and Dalton Minima – are reviewed in the light of the available historical records. In addition to a documented climate‐related agricultural crisis in Portugal, damage and losses to wine production may have been triggered by several local and international conflicts in which the country was involved. But to what extent the two influences contributed to the wine production variations observed in theEDMregion during both periods remains an open question.
Driftwood in the Eemian interglacial lacustrine unit from the Faroe Islands and its possible source areas: palaeobotanical and ichnological analysis
Authors: Pokorný Richard , Koutecký Vít , Björck Svante , Krmíček Lukáš , Árting Uni E. , Štofik Marcel
Published: June 2018

The coastal cliffs in Klaksvík (Borðoyar Bay) are the only known locality with Eemian sediments in the Faroe Islands. Previous studies carried out there focused on the sedimentology, tephra chemistry, paleoecology including aquatic environment, or the age of the deposits. In the lacustrine, clayey to silty gyttja we collected scattered wood fragments, identified asLarixsp.,Pinussp.,Taxussp. and Betulaceae? In addition, these wood remains contain numerous trace fossils, made by marine wood‐boring bivalves (Teredolites longissimus), which together with a discussion about the areal extent of the identified tree species leads us to conclude that they are non‐native, i.e. driftwood. Northern Siberia is usually regarded as the most likely source area for driftwood in the eastern North Atlantic region. We combined the approximate transport distance from the areal extent of the wood with the main directions of marine currents in the relevant section of the North Atlantic. Adding the known average marine current velocities during the penultimate interglacial resulted in 130–200 days for transport from North America and 350–1100 days from Siberia. Comparing this with the maximal buoyancy period for the identified tree species, we conclude that the Faroese driftwood may originate not only from Siberia, but also from the eastern coast of North America, especially from the region around the Great Lakes, as well as from western Europe.
Forest disturbance and seasonal food availability influence a conditional seed dispersal mutualism
Authors: Aliyu Babale , Thia Joshua A. , Moltchanova Elena , Forget Pierre‐Michel , Chapman Hazel M.
Published: June 2018

The interaction between granivorous scatterhoarding mammals and plants is a conditional mutualism: scatterhoarders consume seeds (acting as predators), but the movement of seed by scatterhoarders may contribute to dispersal (acting as mutualists). Understanding the ecological factors that shape this relationship is highly relevant in anthropogenically disturbed tropical forests where large‐bodied frugivores are extirpated. In such forests, large‐seeded trees that once depended on these frugivores for dispersal may now only have scatterhoarders as prospective dispersers. We studied Carapa oreophila (Meliaceae) in an Afromontane forest, to test the hypotheses that the proportion of seeds immediately consumed or hoarded (dispersed) would vary over a disturbance gradient. Temporal replication also afforded exploration of how habitat effects might vary with food availability. Using a Bayesian framework, we demonstrate that seeds were more likely to be hoarded in less disturbed forest, irrespective of temporal variation in food abundance. In contrast, forest disturbance only appeared to increase seed predation in temporal replicates that coincided with sustained food availability. These results highlight the potential variability in the dynamics between plants and scatterhoarders over fine temporal scales, elucidating possible ecological scenarios where scatterhoarders might act as mutualists (contributing positively to plant recruitment). Our study also fills important knowledge gaps about the importance of scatterhoarders as dispersers in tropical forests depleted of large‐bodied frugivores, particularly in Africa where scatterhoarding mutualisms have not been extensively studied.
Survival analysis of multiple peptide vaccination for the selection of correlated peptides in urological cancers
Authors: Noguchi Masanori , Koga Noriko , Moriya Fukuko , Suekane Shigetaka , Yutani Shigeru , Yamada Akira , Shichijo Shigeki , Kakuma Tatuyuki , Itoh Kyogo
Published: June 2018

Peptide‐based cancer vaccines are able to induce strong immune responses, but their clinical results are unsatisfactory. To determine clinically correlated peptides, we analyzed survival data from urological cancer patients treated by personalized peptide vaccination (PPV), in which different multiple peptides were used for individual patients based on human leukocyte antigen (HLA) type and pre‐existing immunity. Survival data were obtained from a database of 265 urological cancer patients treated in 5 clinical PPV trials comprising 154 patients with castration‐resistant prostate cancer (CRPC) and 111 patients with advanced urothelial cancer (UC). Expression of tumor‐associated antigens (TAA) was evaluated in 10 prostate cancer tissues, 4 metastatic lymph nodes from prostate cancer, and 10 UC tissues using immunohistochemical staining. Clinical efficacy of individual peptides for overall survival was evaluated by the Cox proportional hazards regression model. All TAA coding candidate peptides used in PPV treatment were expressed in tumor cells from prostate cancer and UC samples except for p56Lck in both, and prostate‐specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate‐specific membrane antigen (PSMA) in the UC samples. Patients with the following peptides had a significantly longer survival than patients without the peptides (hazard ratio <1.0, 95% confidence intervals <1.0 and P < .05): SART3‐109, PTHrP‐102, HNPRL‐140, SART3‐302 and Lck‐90 in CRPC patients, and EGF‐R‐800, Lck‐486, PSMA‐624, CypB‐129 and SART3‐734 in advanced UC patients, respectively. Correlated peptides selected using both survival data and pre‐existing immunity for PPV treatment may enhance the clinical benefits for urological cancer patients.
Victimization Disparities Between Heterosexual and Sexual Minority Youth From Ages 9 to 15
Authors: Martin‐Storey Alexa , Fish Jessica
Published: June 2018

Mental health disparities between heterosexual and sexual minority youth are partly explained by the higher rates of victimization experienced by sexual minority youth. The onset and progression of these victimization disparities, however, are poorly understood. Using multirater longitudinal data, trajectories of victimization starting at age 9 were compared among youth who did and did not report same‐sex attraction at age 15 (N = 310). Self and teacher, but not primary caregivers, reported victimization was significantly higher among sexual minority youth starting at age 9, but did not vary across time. The findings underscore the importance of understanding homophobic experiences of sexual minority youth during late childhood and early adolescence in order to inform prevention programs.
The JAK1/JAK2‐ inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release
Authors: Hermans Maud A. W. , Schrijver Benjamin , van Holten‐Neelen Conny C.P.A. , Gerth van Wijk Roy , van Hagen P. Martin , van Daele Paul L.A. , Dik Willem A.
Published: June 2018

Background

Mastocytosis is characterized by the accumulation of aberrant mast cells (MC). Patients suffering from mastocytosis suffer from a wide range of symptoms due to increased levels of MC mediators. It would therefore be of great benefit to inhibit MC mediator release. However, to date there are few drugs available that are known to effectively lower MC mediator levels. The evidence for the involvement of the janus kinase 2 (JAK2)—signal transducer and activation of transcription 5 (STAT5) signalling pathway in MC activation is slowly accumulating. Interference with the JAK2‐STAT5 pathway might inhibit MC mediator release. Ruxolitinib, a JAK1/JAK2 inhibitor, indeed decreases symptoms like pruritus and fatigue in patients with myeloproliferative neoplasms. Yet, detailed studies on how ruxolitinib affects human mast cell activity are lacking.

Objective

To investigate the effect of JAK1/2‐inhibition with ruxolitinib in the human mast cell lines LAD2 and HMC1.

Methods

LAD2 and HMC1 were stimulated with substance P, codeine or the calcium ionophore A23817. The effect of ruxolitinib on mast cell degranulation (via measurement of β‐hexosaminidase, histamine release and CD63 membrane expression) and IL‐6, IL‐13, MCP‐1 and TNF‐α production was investigated. The involvement of STAT5 activation was explored using the selective STAT5 inhibitor pimozide.

Results

Ruxolitinib effectively inhibited codeine‐ and substance P‐induced degranulation in a concentration‐dependent manner. Ruxolitinib also significantly inhibited the production of IL‐6, TNF‐α and MCP‐1 as induced by A23817 and substance P. Selective STAT5 inhibition with pimozide resulted in diminished degranulation and inhibition of cytokine production as induced by A23817 and substance P.

Conclusions & clinical relevance

This study demonstrates that the JAK1/JAK2 inhibitor ruxolitinib can inhibit MCactivity, possibly through prevention of STAT5 activation. This renders the JAK‐STAT pathway as an interesting target for therapy to release symptom burden in mastocytosis and many other MC mediator‐related diseases.
Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation
Authors: Pilch Jacek , Koppolu Agnieszka A. , Walczak Anna , Murcia Pienkowski Victor A. , Biernacka Anna , Skiba Paweł , Machnik‐Broncel Joanna , Gasperowicz Piotr , Kosińska Joanna , Rydzanicz Małgorzata , Emich‐Widera Ewa , Płoski Rafał
Published: June 2018

The HNRNPH2‐associated disease (mental retardation, X‐linked, syndromic, Bain type [MRXSB, MIM #300986]) is caused by de novo mutations in the X‐linked HNRNPH2 gene. MRXSB has been described in six female patients with dysmorphy, developmental delay, intellectual disability, autism, hypotonia and seizures. The reported HNRNPH2 mutations were clustered in the small domain encoding nuclear localization signal; in particular, the p.Arg206Trp was found in four independent de novo events. HNRNPH1 is a conserved autosomal paralogue of HNRNPH2 with a similar function in regulation of pre‐mRNAs splicing but so far it has not been associated with human disease. We describe a boy with a disease similar to MRXSB in whom a novel de novo mutation c.616C>T (p.Arg206Trp) in HNRNPH1 was found (ie, the exact paralogue of the recurrent HNRNPH2 mutation). We propose that defective function of HNRNPH2 and HNRNPH1 nuclear localization signal has similar clinical consequences. An important difference between the two diseases is that the HNRNPH1‐associated syndrome may occur in boys (as in the case of our proband) which is well explained by the autosomal (chr5q35.3) rather than X‐linked localization of the HNRNPH2 gene.
Surface property alterations and osteoblast attachment to contaminated titanium surfaces after different surface treatments: An in vitro study
Authors: Lee Bor‐Shiunn , Shih Kuang‐Shao , Lai Chern‐Hsiung , Takeuchi Yasuo , Chen Yi‐Wen
Published: June 2018

Background

Studies have reported a high prevalence of peri‐implantitis. The etiology of peri‐implantitis remains unclear and no available treatments result in total resolution of established peri‐implantitis.

Purpose

To investigate the factors that interfere with osteoblast adhesion to contaminated titanium surfaces after different surface treatments.

Materials and Methods

Grade 4 titanium discs were randomly divided into 5 groups and each group was divided into 2 subgroups, with one contaminated with Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), and the other contaminated with Porphyromonas gingivalis (P. gingivalis). Group 1 did not receive bacterial inoculation or surface debridement and served as a control. Group 2 received A. actinomycetemcomitans or P. gingivalis inoculation, separately. Group 3 received bacterial inoculation and titanium curette debridement, followed by normal saline irrigation. Group 4 received bacterial inoculation, curette debridement, normal saline irrigation, and ultrasonication. Group 5 received bacterial inoculation, curette debridement, normal saline irrigation, and placement in 0.12% chlorhexidine. After various surface treatments, the surface roughness and hydrophilicity of the titanium surface were measured, the number of adhered osteoblast cells was calculated, and the amount of residual lipopolysaccharide (LPS) was quantified.

Results

A. actinomycetemcomitans and P. gingivalis biofilms noticeably reduced surface hydrophilicity. Groups 3‐5 showed decreased hydrophilicity and fewer adhered osteoblast cells compared with the control group. Although ultrasonication was more effective in removing LPS than curette debridement and chlorhexidine, cell adhesion was not as high as with clean titanium discs.

Conclusions

The non‐surgical treatment used in this study was not effective in removing LPS from titanium surfaces and increasing osteoblast adhesion. A more effective method to remove LPS completely is required to enhance the treatment outcome of peri‐implantitis.
Inter‐arm systolic blood pressure dependence on hand dominance
Authors: Mayrovitz Harvey N.
Published: June 2018

Inter‐arm systolic blood pressure differences (SBP‐DIFF) ≥ 10 mmHg have been reported useful to predict future cardiovascular‐related morbidities. Although well studied in patients, there is little information on healthy young adults and the role of hand‐dominance as a factor affecting SBP‐DIFF. As dominant arms (DOM) tend to have greater girth and muscle development than nondominant arms (NDOM) it was reasoned that cuff pressures needed to obtain SBP may be greater on DOM causing DOM SBP to be greater. To test this hypothesis and also provide typical values, SBP was measured in left and right‐handers (29·4 ± 10·4 years) in whom handedness was clearly defined. Handedness was determined by a multi‐question form in 90 young adults (45 male) and SBP‐DIFF determined via simultaneous measurements done in triplicate on seated subjects. The percentage of left‐handers in male and female sub‐groups were equal at 37·8%. Results show that the absolute SBP‐DIFF in left‐handers (mean ± SD) was 4·4 ± 3·8 mmHg and for right‐handers was 5·0 ± 4·2 mmHg (P = 0·362). There was also no statistically significant difference among 1st, 2nd and 3rd measured SBP‐DIFF for either right or left‐handers or differences between right and left‐handers. Results show no evidence of a higher SBP in DOM and thus clarifies the hand‐dominance issue as a factor not generally needing to be considered in clinical assessments. A potentially useful secondary outcome was the finding that 14·8% of this group had at least one measured SBP‐DIFF ≥ 10 mmHg a fact that may have future relevance.
Programmed death‐ligand 1 immunoexpression in matched biopsy and liquid‐based cytology samples of advanced stage non‐small cell lung carcinomas
Authors: Jain Deepali , Sukumar Supraja , Mohan Anant , Iyer Venkateswaran K.
Published: June 2018

Objective

Programmed death‐ligand 1 (PD‐L1) immunohistochemistry (IHC) is essential in patients of advanced non‐small‐cell lung cancer to determine eligibility for immunotherapy. PD‐L1 IHC assays have been clinically validated only on formalin‐fixed paraffin‐embedded tissue; however, lung cancer is frequently diagnosed on cytology. PD‐L1 immunocytochemistry (ICC) has shown high concordance of immunoexpression between cytology samples and paired small biopsies. Feasibility of liquid‐based cytology (LBC) smears for PD‐L1 ICC has not been analysed previously.

Methods

PD‐L1 ICC and IHC (clone SP263) were performed on paired LBC smears and small biopsies, respectively, in patients with advanced non‐small‐cell lung cancer. Cases with fewer than 100 viable tumour cells on LBC smear/biopsy were excluded from analysis. PD‐L1 was interpreted positive when 25% or more tumour cells showed membranous and/or cytoplasmic protein expression of any intensity greater than background staining.

Results

A total of 26 patients, harbouring adenocarcinomas (50%) and squamous cell carcinomas (50%), had available bronchial brushings/washings processed as LBC smears and concurrently obtained endobronchial biopsies. PD‐L1 IHC was interpreted positive in 46% (12/26) biopsies. PD‐L1 ICC was interpreted positive in 35% (9/26) LBC smears, all of which were IHC‐positive. No IHC‐negative case was positive on cytology. The overall concordance between LBC smears and small biopsies was 88.4%.

Conclusion

PD‐L1 ICC can be performed on LBC processed smears, with certain challenges in interpretation inherent to LBC smears and their processing methods. Nevertheless, they represent a potential resource for ICC, especially when alternate histology material is not available. Future studies are required to validate the predictive value of PD‐L1 ICC on LBC smears.
The enigma of a pulmonary papillary lesion
Authors: Kumar Rajesh , Gupta Nalini , Singh Navneet , Vasishta Rakesh Kumar , Rajwanshi Arvind
Published: June 2018

Pulmonary papillary adenoma is a rare neoplasm with approximately 27 cases reported in English literature. The diagnosis by image guided fine needle aspiration cytology can be challenging. We present a further case and discuss the subtle cytomorphological features which characterise this rare entity.
Neural representations of the body in 60‐day‐old human infants
Authors: Meltzoff Andrew N. , Saby Joni N. , Marshall Peter J.
Published: June 2018

The organization of body representations in the adult brain has been well documented. Little is understood about this aspect of brain organization in human infancy. The current study employed electroencephalography (EEG) with 60‐day‐old infants to test the distribution of brain responses to tactile stimulation of three different body parts: hand, foot, and lip. Analyses focused on a prominent positive response occurring at 150–200 ms in the somatosensory evoked potential at central and parietal electrode sites. The results show differential electrophysiological signatures for touch of these three body parts. Stimulation of the left hand was associated with greater positive amplitude over the lateral central region contralateral to the side stimulated. Left foot stimulation was associated with greater positivity over the midline parietal site. Stimulation of the midline of the upper lip was associated with a strong bilateral response over the central region. These findings provide new insights into the neural representation of the body in infancy and shed light on research and theories about the involvement of somatosensory cortex in infant imitation and social perception.
Constructing citizen engagement in health research priority‐setting to attend to dynamics of power and difference
Authors: Pratt Bridget
Published: June 2018

Engaging citizens is vital to achieving people‐centred health research. This paper aims to put attention to dynamics of power and dynamics of difference back at the centre of citizen engagement in health research priority‐setting. Without attention to power and difference, engagement can lead to presence without voice and voice without influence, particularly for disadvantaged and marginalised groups. By analysing six key bodies of literature, the paper first identifies the different components of engagement—who initiates, for what purpose, who participates, and how they participate—and the dynamics of power and dynamics of difference relevant to them. For each component of engagement, the ethical considerations relating to those dimensions of power and dimensions of difference are characterised for the research priority‐setting context and preliminary guidance on how they might be addressed is provided. An initial framework comprised of a series of questions reflecting these ethical considerations has been developed for use by researchers and citizens when designing engagement processes for research projects. Where researchers and citizens attend to the framework's questions and then revise their priority‐setting processes’ design to better represent diversity and mitigate power disparities, more inclusive citizen engagement is promoted. Disadvantaged and marginalised groups are more likely to be present and heard, which, in turn, will help generate research projects with topics and questions that encompass and more accurately reflect their health needs.
Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates
Authors: Elvert Ralf , Herling Andreas W. , Bossart Martin , Weiss Tilo , Zhang Baohong , Wenski Pierre , Wandschneider Jörn , Kleutsch Sabrina , Butty Uwe , Kannt Aimo , Wagner Michael , Haack Torsten , Evers Andreas , Dudda Angela , Lorenz Martin , Keil Stefanie , Larsen Philip J.
Published: June 2018

Aim

We performed acute and chronic studies in healthy and diet‐induced obese animals using mouse‐specific or monkey‐specific dual GLP‐1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP‐1R agonist liraglutide was used as comparator.

Methods

The mouse‐specific dual agonist and liraglutide were tested in lean wild type, GLP‐1R knockout and diet‐induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake.

Results

The mouse‐specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist‐treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP‐1R−/− mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey‐specific dual agonist reduced total energy intake to 60%‐70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed.

Conclusions

In DIO mice and non‐human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP‐1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.
Clinical outcomes in real‐world patients with type 2 diabetes switching from first‐ to second‐generation basal insulin analogues: Comparative effectiveness of insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ cohort study
Authors: Sullivan Sean D. , Bailey Timothy S. , Roussel Ronan , Zhou Fang Liz , Bosnyak Zsolt , Preblick Ronald , Westerbacka Jukka , Gupta Rishab A. , Blonde Lawrence
Published: June 2018

Aims

To compare clinical outcomes in patients with type 2 diabetes (T2D) switching from insulin glargine 100 units/mL (Gla‐100) or insulin detemir (IDet) to insulin glargine 300 units/mL (Gla‐300) or insulin degludec (IDeg).

Materials and Methods

We conducted a retrospective, observational study of electronic medical records for Gla‐300/IDeg adult switchers (March 1, 2015 to January 31, 2017) with active records for 12‐month baseline (glycated haemoglobin [HbA1c] used a 6‐month baseline period) and 6‐month follow‐up periods. Gla‐300 and IDeg switchers were propensity score‐matched using baseline demographic and clinical characteristics. Outcomes were HbA1c change and goal attainment (among patients with HbA1c captured at follow‐up), and hypoglycaemia with fixed follow‐up (intention‐to‐treat [ITT]; 6 months) and variable follow‐up (on‐treatment [OT]; to discontinuation or 6 months).

Results

Each matched cohort comprised 1592 patients. The mean decrease in HbA1c and HbA1c goal (<7.0% [53 mmol/mol] and <8.0% [64 mmol/mol]) attainment rates were similar for Gla‐300 (n = 742) and IDeg (n = 727) switchers. Using fixed follow‐up (ITT method), hypoglycaemia incidence decreased significantly from baseline with Gla‐300 (all hypoglycaemia: 15.6% to 12.7%; P = .006; hypoglycaemia associated with inpatient/emergency department [ED] encounter: 5.3% to 3.5%; P = .007), but not with IDeg. After adjusting for baseline hypoglycaemia, no significant differences in hypoglycaemia incidence and event rate were found at follow‐up (ITT) for Gla‐300 vs IDeg. Using variable follow‐up (OT), hypoglycaemia incidence was similar in both groups, but Gla‐300 switchers had a lower inpatient/ED hypoglycaemia event rate at follow‐up (adjusted rate ratio 0.56; P = .016).

Conclusions

In a real‐world setting, switching from Gla‐100 or IDet to Gla‐300 or IDeg was associated with similar improvements in glycaemic control and hypoglycaemia in adult patients with T2D.
Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non‐SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real‐world meta‐analysis of 4 observational databases (OBSERVE‐4D)
Authors: Ryan Patrick B. , Buse John B. , Schuemie Martijn J. , DeFalco Frank , Yuan Zhong , Stang Paul E. , Berlin Jesse A. , Rosenthal Norman
Published: June 2018

Aims

Sodium glucose co‐transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk of below‐knee lower extremity (BKLE) amputation. This study examined the real‐world comparative effectiveness within the SGLT2i class and compared with non‐SGLT2i antihyperglycaemic agents.

Materials and methods

Data from 4 large US administrative claims databases were used to characterize risk and provide population‐level estimates of canagliflozin's effects on hospitalization for heart failure (HHF) and BKLE amputation vs other SGLT2i and non‐SGLT2i in T2DM patients. Comparative analyses using a propensity score–adjusted new‐user cohort design examined relative hazards of outcomes across all new users and a subpopulation with established cardiovascular disease.

Results

Across the 4 databases (142 800 new users of canagliflozin, 110 897 new users of other SGLT2i, 460 885 new users of non‐SGLT2i), the meta‐analytic hazard ratio estimate for HHF with canagliflozin vs non‐SGLT2i was 0.39 (95% CI, 0.26‐0.60) in the on‐treatment analysis. The estimate for BKLE amputation with canagliflozin vs non‐SGLT2i was 0.75 (95% CI, 0.40‐1.41) in the on‐treatment analysis and 1.01 (95% CI, 0.93‐1.10) in the intent‐to‐treat analysis. Effects in the subpopulation with established cardiovascular disease were similar for both outcomes. No consistent differences were observed between canagliflozin and other SGLT2i.

Conclusions

In this large comprehensive analysis, canagliflozin and other SGLT2i demonstrated HHF benefits consistent with clinical trial data, but showed no increased risk of BKLE amputation vs non‐SGLT2i. HHF and BKLE amputation results were similar in the subpopulation with established cardiovascular disease. This study helps further characterize the potential benefits and harms of SGLT2i in routine clinical practice to complement evidence from clinical trials and prior observational studies.