bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors
Authors: Anfray Antoine , Drieu Antoine , Hingot Vincent , Hommet Yannick , Yetim Mervé , Rubio Marina , Deffieux Thomas , Tanter Mickael , Orset Cyrille , Vivien Denis
Published: October 2019

The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).
Clinical research on individualized hemodialysis preventing unconventional hypotension in diabetic nephropathy patient
Authors: Li Wen-Hong , Yin Yu-Min , Chen Hao , Rui Zhang-Ru , Yuan Yang , Yun He , Wang Jin-Wen
Published: October 2019

Objective:

This study aims to evaluate the effectiveness of individualized hemodialysis for unconventional hypotension in diabetic nephropathy patients.

Methods:

A total of 60 patients were selected and randomly divided into study group and control group. The control group used the standard dialysis model, while the study group used the individualized hemodialysis scheme, in which the dialysis was performed using an individualized dialysis machine temperature control, pattern of natrium, and pattern of step ultrafiltration in combination with dialysate-containing glucose.

Results:

The total occurrence rate of hypotension, dry weight standard-reaching rate, and blood quality during and after dialysis in the study group were superior to those in the control group ( P < 0.05). Furthermore, the symptom scores in the study group (dizziness score, chest distress score, sweating score, muscle spasm score, gastrointestinal symptom score, and temporary mind change score) were lower than those in the control group ( P < 0.05). The serum sodium, potassium, and chloride concentration in these two groups after dialysis was not statistically different ( P > 0.05).

Conclusion:

The combined application of low temperature, pattern of natrium, pattern of step ultrafiltration, and dialysate-containing glucose individualization is safe and effective for preventing and controlling the occurrence of intradialytic hypotension (IDH), improve symptoms, and improve the dry weight standard-reaching rate.
A note on the Greek and Ethiopic text of 1 Enoch 5:8
Authors: Litvinau Fiodar
Published: October 2019

Greek and Ethiopic versions of 1 Enoch 5:8 preserve a different text at the end of the passage. This note aims to demonstrate the superiority of the Ethiopic text of 1 En. 5:8 over the version preserved in Codex Panapolitanus by arguing that the Greek reading must be treated as a scribal addition influenced by Gnostic terminology.
Measuring the Antimicrobial Activity of Lauric Acid against Various Bacteria in Human Gut Microbiota Using a New Method
Authors: Matsue Miki , Mori Yumiko , Nagase Satoshi , Sugiyama Yuta , Hirano Rika , Ogai Kazuhiro , Ogura Kohei , Kurihara Shin , Okamoto Shigefumi
Published: October 2019

Lauric acid (LA) has a broad spectrum of anti-microbiological activities against enveloped viruses and various bacteria, and might be useful to protect against microbial infection and control the balance and distribution of bacteria in human gut microbiota. It is not necessarily more difficult to measure antimicrobial activity the traditional way, but it is, however, more laborious. In the present study, we developed a new method to measure the antimicrobial activity of LA in multiple samples with a microplate reader. A “test complex” (TC) was produced consisting of 100 μL of agar medium with LA in the bottom layer and 300 μL of broth in the top layer in 96-well deep-well microplates. Afterward, analysis of the broth in the top layer showed that the antimicrobial activity was the same as that of the “control complex,” (CC) which consisted of 100 μL of agar medium in the bottom layer and 300 μL of broth with LA in the top layer. Furthermore, evaluation of the antimicrobial effect of the TC when using a microplate reader was the same as that with the use of the colony counting method. The colony counting method has confirmed that the antimicrobial activity of LA when bacteria are inoculated into the broth was equivalent between CC and TC, and we validated this by correlating the number of bacteria with absorbance. In addition, the broth itself in TC was transparent enough that the turbidity of broth can be used as an index of the number of bacteria, which enabled the use of a microplate reader for multiple samples. For human gut microbes, LA was shown to have low antimicrobial activity against commensal lactic acid bacteria, but high antimicrobial activity against pathogenic Bacteroides and Clostridium, suggesting that LA might modulate intestinal health, as confirmed by the proposed method.
PRMT5 Promotes Human Lung Cancer Cell Apoptosis via Akt/Gsk3β Signaling Induced by Resveratrol
Authors: Li Yong , Yang Yanxia , Liu Xiaoping , Long Yiwen , Zheng Yonghua
Published: October 2019

Protein arginine methyltransferase 5 (PRMT5) is implicated in various types of human cancer and tumor development, especially in lung cancer. Nevertheless, it is still unclear whether suppression of PRMT5 could promote lung cancer cell apoptosis and chemosensitivity induced by resveratrol, and the underlying molecular mechanism remains completely unknown. Here, we showed that PRMT5 was overexpressed in human lung cancer tissues and different types of lung cancer cell lines. Moreover, we constructed PRMT5 stable knockdown cell lines (A549 and ASCT-a-1) and investigated the roles of PRMT5 and the related signaling pathway in lung cancer cell apoptosis induced by resveratrol. Our results indicated that inhibition or down-regulation of PRMT5 by GSK591, a PRMT5-specific inhibitor, or shRNAs markedly enhanced cell apoptosis and chemosensitivity stimulated by resveratrol. Further investigation showed that inhibition or down-regulation of PRMT5 further reduced Akt/GSK3β phosphorylation and the downstream targets cyclin D1 and E1 expression upon resveratrol treatment. Our findings suggest that PRMT5 is a pivotal mediator for human lung cancer cell death induced by resveratrol, which also reveals that PRMT5 may serve as a new therapeutic target for the treatment of human lung cancer.
E pluribus unum? Language diversity and the harmonization of company law in the European Union
Authors: Mucciarelli Federico M
Published: October 2019

This work addresses the impact of language diversity and nation-specific doctrinal structures on harmonized company law in the EU. With this aim, two emblematic case studies will be analysed. The first case study is related to the definition of ‘merger’ adopted in the Company Law Directive 2017/1132 (originally in the Third Company Law Directive and the Cross-Border Merger Directive); by relying on the example of the SEVIC case decided by the Court of Justice of the European Union (CJEU), it will be shown that scholars’ and courts’ conception of the definition of ‘merger’ varies according to own domestic doctrinal structures. The second case study is related to the notion of ‘registered office’, which is key for establishing the scope of several harmonizing provisions and the freedom of establishment; this paper analyses terminological fluctuations across language versions of EU legislation and the impact of domestic taxonomies and legal debates upon the interpretation of these notions. These case studies show that company law concepts, despite their highly technical nature, are influenced by discourse constructions conducted within national interpretative communities, and by the language used to draft statutory instruments and discuss legal issues. The task of the CJEU is to counterbalance these local tendencies, and yet it is unlikely that doctrinal structures, rooted in national languages and legal cultures, will disappear.
Applying the Capability, Opportunity, and Motivation Behaviour Model (COM-B) to Guide the Development of Interventions to Improve Early Detection of Atrial Fibrillation
Authors: Jatau Abubakar Ibrahim , Peterson Gregory M , Bereznicki Luke , Dwan Corinna , Black J Andrew , Bezabhe Woldesellassie M , Wimmer Barbara C
Published: October 2019

Objective:

The primary objective of this study is to use the Capability, Opportunity, and Motivation Behaviour (COM-B) model to identify potential strategies aimed at improving the early detection of atrial fibrillation (AF) in the general population.

Methods:

We undertook a review of the literature to identify factors associated with participation in community-based screening for AF, followed by mapping of the factors generated into the components of the COM-B model, and validation of the model by an expert panel. The Behaviour Change Wheel (BCW) was used to nominate potential intervention strategies and steps to guide the design and implementation of community-based screening for AF.

Results:

A total of 28 factors from 21 studies were mapped into the COM-B model. Based on the BCW approach, 24 intervention strategies and 7 steps that could guide the design and implementation of community-based screening for AF were recommended.

Conclusion:

The application of the COM-B model demonstrated how factors influencing the participation of individuals with undiagnosed AF in community-based screening could be identified. The model could also serve as a guide for the design and implementation of interventions for improving AF detection in the general population.
Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype
Authors: Zhou Yuan , Claflin Suzi B , Stankovich Jim , van der Mei Ingrid , Simpson Steve , Roxburgh Richard H , Kalincik Tomas , Blizzard Leigh , Lugaresi Alessandra , Alroughani Raed , Sajedi Seyed Aidin , Butzkueven Helmut , Pucci Eugenio , Spitaleri Daniele LA , Granella Franco , Cristiano Edgardo , Yamout Bassem , Hughes Stella , Gouider Riadh , Sánchez Menoyo José Luis , Olascoaga Javier , McGuigan Chris , Shaw Cameron , Kermode Allan G , Kasa Krisztian , Al-Harbi Talal , Altintas Ayse , Laureys Guy , Fragoso Yara , Hardy Todd A , Csepany Tunde , Sirbu Carmen-Adella , Decoo Danny , Sas Attila , Alvarez-Cermeño Jose C , Kotkata Karim , Millán-Pascual Jorge , Taylor Bruce V
Published: October 2019

Background:

The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups.

Objective:

We evaluated sex-specific and onset phenotype–specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets.

Methods:

Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype–specific MSSS matrices. We compared matrices using permutation analysis.

Results:

Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix ( p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex.

Conclusion:

The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.
Serum neurofilament levels correlate with retinal nerve fiber layer thinning in multiple sclerosis
Authors: Bsteh Gabriel , Berek Klaus , Hegen Harald , Teuchner Barbara , Buchmann Arabella , Voortman Margarete M , Auer Michael , Wurth Sebastian , Zinganell Anne , Di Pauli Franziska , Deisenhammer Florian , Khalil Michael , Berger Thomas
Published: October 2019

Background:

Serum neurofilament light chain (sNfL) levels and peripapillary retinal nerve fiber layer (pRNFL) are both emerging biomarkers of neuro-axonal damage in multiple sclerosis (MS). However, data on the relation between sNfL and pRNFL are scarce.

Objective:

We aimed to determine the relation of sNfL levels with pRNFL thinning in a large cohort of relapsing–remitting (RR) MS patients.

Methods:

We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL levels were measured using single-molecule array (SimoaTM) assay. Annualized loss of pRNFL (aLpRNFL) was determined by individual linear regression models. Correlations between single and repeated sNfL levels and aLpRNFL were analyzed using multivariate linear regression and mixed-effect models.

Results:

After correction for sex, age, and baseline sNfL, an sNfL increase of 10 pg/mL was associated with an aLpRNFL of −0.7 µm (95% confidence interval (CI): (−1.3, −0.2), p < 0.001). Patients with ⩾2 sNfL measurements >75th percentile displayed higher aLpRNFL (2.2 µm, standard deviation (SD) 0.6) compared to patients with no sNfL measure >75th percentile (0.4 µm, SD 0.2, p < 0.001). Between 15% and 20% of the aLpRNFL variance could be predicted from sNfL levels.

Conclusion:

sNfL levels contribute to the prediction of retinal thinning in patients with RRMS, strengthening its value as a biomarker of neuro-axonal damage.
The rise of democratic legitimation: why international organizations speak the language of democracy
Authors: Dingwerth Klaus , Schmidtke Henning , Weise Tobias
Published: October 2019

To justify their authority, international organizations (IOs) have long relied on a functional narrative that highlights effective problem-solving based on rational-legal expertise and neutrality. Today, IOs increasingly legitimize their authority in the language of democracy. Yet not all of them do so to the same extent, in the same manner, or consistently over time. In this article, we offer a comprehensive theoretical and empirical account of democratic legitimation in global governance. Our analysis builds on a new dataset, measuring the extent to which global IOs use democratic narratives in legitimizing their authority throughout the period from 1980 to 2011. The central findings are threefold. First, our data reveal a far-reaching rise of democratic legitimation in global governance. For many organizations, this increase remains relatively modest; for others, the democratic legitimation narrative becomes central. Second, this variation is mainly explained by a combination of two factors: (a) public visibility and protest constitute the driving forces of democratic legitimation and (b) IOs’ reaction to these legitimacy pressures unfolds in a path-dependent manner. Once organizations begin to take up democratic narratives, it seems to become costly to leave this path and shift to yet another set of norms. By contrast, the conventional wisdom that democratic legitimation follows in the footsteps of internationalized authority is not supported by our analysis.
Sport-event portfolios: An analysis of their ability to attract revenue from tourism
Authors: Salgado-Barandela Jesyca , Barajas Ángel , Sánchez-Fernández Patricio
Published: October 2019

Some cities strategically plan multiple small and medium-size sport events on different dates in their annual calendar of activities and avoid focusing on a single event of great magnitude. This is how the concept of a sport-event portfolio arises. This article aims to present a method to quantify the injection of sports-tourism money into a city from a portfolio of events. This methodology is applied to the portfolio of a small town with a policy oriented toward the promotion of tourism through the organization of sport events. The income generated by sports tourists in the 2017–2018 biennium is estimated using 1123 surveys conducted from four events included in the town’s portfolio. The research findings of this article are pioneers in the quantitative field of the study of event portfolios. This provides new opportunities for planning a strategy to attract tourism revenues.
Dialogical construction of parental feeding strategies during family mealtimes
Authors: Bova Antonio
Published: October 2019

This study focuses on social interactions during family mealtimes to examine the types of arguments used by parents to convince their children to eat. The results of this study show that feeding practices during mealtimes are dialogically constructed by parents and children together. Parents mostly used arguments based on the quality and quantity of food, adapting their language to the child’s level of understanding. Future research might consider the observations and the subtle qualitative analyses of social interactions among family members as examples of possible ways to recognize the dialogical construction of feeding practices during mealtimes.
Pilot Testing the Theoretical Framework of Acceptability in a Process Evaluation of a Community Pharmacy–Based Men’s Mental Health Promotion Program
Authors: Murphy Andrea Lynn , Gardner David Martin
Published: October 2019

The objective of this study was to assess men’s acceptability of a men’s mental health promotion program in community pharmacies through pilot testing the theoretical framework of acceptability (TFA) as part of the process evaluation. Five men were interviewed about their experiences with the Headstrong program to learn about the acceptability of the program. The TFA was used as the deductive coding scheme and consists of seven constructs including affective attitude, burden, intervention coherence, ethicality, opportunity costs, perceived effectiveness, and self-efficacy. Three constructs, affective attitude, perceived effectiveness, and intervention coherence, from the TFA were coded in all five transcripts. The most frequently coded constructs were affective attitude and perceived effectiveness, coded 19 and 17 times, respectively. Interviewees all reported good relationships with their pharmacists, which influenced their willingness, attitude, and low burden for participation in Headstrong. Each of the men expressed comments reflecting anticipated effectiveness of the program outside of their own experience and how it could impact other men. Use of the TFA as part of a process evaluation of men’s experiences in a men’s mental health program was useful in identifying men’s perceptions of the program’s acceptability. Further research regarding how the quality of existing relationships with clinicians and patients impacts the TFA constructs of affective attitudes, perceived effectiveness, and burden would be useful.
Objective Comparison Between Spreader Grafts and Flaps for Mid-Nasal Vault Reconstruction: A Randomized Controlled Trial
Authors: Zeid Nabil Galal , Mohamed Ahmed Shawky , ElSayed ElFouly Mahmoud , Azooz Khaled Omar , Aleryan Mohamed Muddather , Abd Elmottaleb Sabaa Mohamed
Published: October 2019

Objective:

The goal of rhinoplasty is not exclusively aesthetic and the nasal function should always be considered. Several rhinoplasty techniques can participate in nasal valve dysfunction (eg, dorsal hump reductions). Therefore, mid-nasal vault reconstruction by spreader grafts or flaps is mandatory in these cases. To date, there is a literature gap in comparing both techniques objectively. This study shows an objective comparison between spreader grafts and flaps for mid-nasal vault reconstruction.

Material and Methods:

This study was a double-blind randomized controlled trial including 40 patients who were randomly divided into 2 groups. Group 1 (20 patients) underwent spreader grafts insertion, whereas group 2 (20 patients) underwent spreader flap placement technique. Pre-operative active anterior rhinomanometry measurements were compared to 6-month post-operative measurements. Data were summarized as mean (standard deviation) for the quantitative variables. Comparisons between the 2 groups were done using unpaired t test.

Results:

In both groups, a significant decrease in nasal resistance was noted in both the right and left sides 6 months post-operatively ( P < .001). However, the comparison between the 2 both groups showed no statistical significance.

Conclusion:

Both spreader grafts and flaps, which are used for the mid-nasal vault reconstruction, have comparable and effective results in reducing the nasal resistance as evidenced by active anterior rhinomanometry measurements.
High-Risk Plastic Surgery: An Analysis of 108,303 Cases From the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP)
Authors: Wan Melissa , Zhang Jacques X. , Ding Yichuan , Jin Yiwen , Bedford Julie , Nagarajan Mahesh , Bucevska Marija , Courtemanche Douglas J. , Arneja Jugpal S.
Published: October 2019

Background:

There is a lack of large-scale data that examine complications in plastic surgery. A description of baseline rates and patient outcomes allows better understanding of ways to improve patient care and cost-savings for health systems. Herein, we determine the most frequent complications in plastic surgery, identify procedures with high complication rates, and examine predictive risk factors.

Methods:

A retrospective analysis of the 2012 to 2016 American College of Surgeons National Surgical Quality Improvement Program plastic surgery data set was conducted. Complication rates were calculated for the entire cohort and each procedure therein. Microsurgical procedures were analyzed as a subgroup, where multivariate logistic regression models determined the risk factors for surgical site infection (SSI) and related reoperation.

Results:

We identified 108 303 patients undergoing a plastic surgery procedure of which 6 264 (5.78%) experienced ≥1 complication. The outcome with the highest incidence was related reoperation (3.31%), followed by SSI (3.11%). Microsurgical cases comprised 6 148 (5.68%) of all cases, and 1211 (19.33%) experienced ≥1 complication. Similar to the entire cohort, the related reoperation (12.83%) and SSI (5.66%) were common complications. Increased operative time was a common independent risk factor predictive of a related reoperation or development of an SSI ( P < 001). Of all microsurgeries, 23.3% had an operative time larger than 10 hours which lead to faster increase in reoperation likelihood.

Conclusions:

The complication rate in plastic surgery remains relatively low but is significantly increased for microsurgery. Increased operative time is a common risk factor. Two-team approaches and staged operations could be explored, as a large portion of microsurgeries are vulnerable to increased complications.
Several Ways Generation Z May Shape the Medical School Landscape
Authors: Plochocki Jeffrey H
Published: October 2019

Just as medical colleges have adapted to the Millennial generation of students, a new generation is poised to enter as matriculants. Learner attributes of this generation, Generation Z, are in stark contrast to previous ones, but more than that, they provide new challenges that undergraduate universities are already facing. This article aims to highlight some of these challenges, including those relating to student counseling services, volunteering activities, learning environments, and learner perspectives. These challenges are framed and discussed within the context of medical education.
Changes in Aqueous and Vitreous Inflammatory Cytokine Levels in Retinal Vein Occlusion: A Systematic Review and Meta-analysis
Authors: Minaker Samuel A. , Mason Ryan H. , Bamakrid Motaz , Lee Yung , Muni Rajeev H.
Published: October 2019

Purpose:

Evidence suggests that inflammatory cytokines not only play a role in the pathogenesis of retinal vein occlusion (RVO) but also may be useful as biomarkers to predict disease severity and response to treatment. We aimed to quantitatively summarize data on inflammatory cytokines associated with RVO.

Methods:

A systematic search of peer-reviewed English-language articles was performed without year limitation up to August 19, 2019. Studies were included if they provided data on aqueous or vitreous cytokine concentrations in patients with RVO. Data were extracted from 116 studies that encompassed 3242 study eyes with RVO and 1402 control eyes. Effect sizes were generated as standardized mean differences (SMDs) of cytokine concentrations between patients with RVO vs controls.

Results:

Among the 4644 eyes in 116 studies, aqueous and vitreous concentrations (SMD, 95% CI, and P value) of interleukin (IL)-6 (aqueous: 1.23, 0.65 to 1.81, P < .001 vitreous: 0.70, 0.49 to 0.90, P < .001), IL-8 (aqueous: 1.11, 0.73 to 1.49, P < .001; vitreous: 1.19, 0.73 to 1.65, P < .001), monocyte chemoattractant protein 1(aqueous: 1.22, 0.72 to 1.72, P < .001; vitreous 1.42, 0.92 to 1.91, P < .001), vascular endothelial growth factor (VEGF) (aqueous: 1.52, 1.09 to 1.94, P < .001; vitreous: 0.99, 0.78 to 1.21, P < .001) were significantly higher in patients with RVO than in healthy controls. Only aqueous concentrations of IL-10 (0.81, 0.45 to 1.18, P < .001), angiopoietin 4 (1.96, 0.92 to 3.00, P < .001), and platelet-derived growth factor (PDGF)-AA (0.82, 0.35 to 1.30, P < .001) were significantly higher in patients with RVO than in healthy controls. Only the vitreous concentration of soluble intercellular adhesion molecule-1 (sICAM-1) (1.23, 0.83 to 1.63, P < .001) was significantly higher in patients with RVO. No differences, failed sensitivity analyses, or insufficient data were found between patients with RVO and healthy controls for the concentrations of the remaining cytokines.

Conclusions:

Several cytokines in addition to VEGF have the potential to be useful biomarkers and therapeutic targets in RVO.
Specific stimulation of T lymphocytes with erythropoietin for adoptive immunotherapy
Authors: Vinanica Natasha , Yong Arthur , Wong Desmond , Png Yi Tian , Seow See Voon , Imamura Masaru , Campana Dario
Published: October 2019

In adoptive T-cell immunotherapy of cancer, expansion and persistence of effector cells is a key determinant of response. We tested whether T lymphocytes could be rendered sensitive to erythropoietin (Epo) through ectopic expression of its wild-type receptor or a truncated form (EpoRm), which augments Epo signaling in erythrocyte progenitors. Both receptors could be expressed in human T lymphocytes; Epo ligation induced STAT5 phosphorylation, which was abrogated by nontoxic concentrations of the JAK1/2 inhibitor ruxolitinib. EpoRm had higher expression and triggered more potent stimulation than its wild-type counterpart, including superior T-cell survival and proliferation. Using a bicistronic vector, we expressed EpoRm together with an anti–CD19-41BB-CD3ζ chimeric antigen receptor (CAR), while maintaining the functions of each receptor. In the presence of Epo, EpoRm-CAR T cells had greater ex vivo expansion than CAR T cells and killed CD19+ leukemic cells more effectively in long-term cultures. In immunodeficient mice, physiologic levels of murine Epo were sufficient to preferentially expand EpoRm-CAR T cells, yielding a significantly higher antileukemic activity. Thus, outfitting adoptive T cells with EpoRm should yield greater effector-to-target ratios with a smaller number of infused cells; Epo or ruxolitinib administration could be used to adjust their levels postinfusion, maximizing antitumor activity and minimizing toxicity.
Excess mucus viscosity and airway dehydration impact COPD airway clearance
Authors: Lin Vivian Y. , Kaza Niroop , Birket Susan E. , Kim Harrison , Edwards Lloyd J. , LaFontaine Jennifer , Liu Linbo , Mazur Marina , Byzek Stephen A. , Hanes Justin , Tearney Guillermo J. , Raju S. Vamsee , Rowe Steven M.
Published: October 2019

The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).

Adult ferrets were exposed to cigarette smoke for 6 months, within vivomucociliary clearance measured by technetium-labelled DTPA retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells andex vivoferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.

Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed mucociliary clearance (−89.0%, p<0.01) and impaired tracheal MCT (−29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min−1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and ciliary beat frequency were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposurein vivoorin vitro, and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.

Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.
Circulating plasma exosomes in obstructive sleep apnoea and reverse dipping blood pressure
Authors: Khalyfa Abdelnaby , Gozal David , Chan Wen-Ching , Andrade Jorge , Prasad Bharati
Published: October 2019

Background

Obstructive sleep apnoea (OSA) increases the risk of an abnormal nondipping 24 h blood pressure profile, an independent risk factor for cardiovascular disease (CVD). We examined differential exosomal microRNA (miRNA) expression in untreated OSA patients with normal dipping blood pressure (NDBP) and reverse dipping blood pressure (RDBP), an extreme form of nondipping, to understand the mechanisms underlying nondipping blood pressure in OSA.

Methods

46 patients (15 RDBPversus31 NDBP) matched for OSA severity (respiratory event index 32.6±22.5versus32.2±18.1 events·h−1; p=0.9), age (54.8±12.9versus49±9.9 years; p=0.09) and body mass index (36.2±6.6versus34.4±6.8 kg·m−2; p=0.4) were included. Plasma exosomes were characterised by flow cytometry and functionalin vitroreporter assays were conducted on cultured endothelial cells. Exosome miRNA cargo was profiled with microarrays followed by bioinformatics analyses.

Results

Exosomes from RDBP patients increased the permeability of endothelial cell tight junctions and adhesion molecule expression. Principal component analyses of miRNA array data showed strict separation and identification of the two groups. A restricted and validated signature of exosomal miRNAs was identified in the RDBPversusNDBP group. Their predicted target genes involved phosphatidylinositol 3-kinase-Akt (p=0.004), Ras (p=3.42E-05), Wnt (p=0.003) and hypoxia inducible factor-1 signalling (p=0.04), inflammatory mediator regulation of transient receptor potential channels (p=0.01), and several cancer-related pathways.

Conclusions

Patients with RDBP have altered miRNA cargoes in circulating exosomes that invokein vitroendothelial dysfunction. A selected number of circulating exosomal miRNAs play an important role in abnormal circadian regulation of blood pressure and may provide prognostic biomarkers of CVD risk in OSA.
Correction to: Nitrogen application and different water regimes at booting stage improved yield and 2-acetyl-1-pyrroline (2AP) formation in fragrant rice
Authors: Mo Zhaowen , Li Yanhong , Nie Jun , He Longxin , Pan Shenggang , Duan Meiyang , Tian Hua , Xiao Lizhong , Zhong Keyou , Tang Xiangru
Published: October 2019

It was highlighted that the original article (Mo et al. 2019) contained an error in Fig. 1f which revealed the biosynthesis pathway of 2AP. This Correction article shows the correct Fig. 1 and incorrect Fig. 1. The original article has been updated.
Association mapping of a locus that confers southern stem canker resistance in soybean and SNP marker development
Authors: Maldonado dos Santos João Vitor , Ferreira Everton Geraldo Capote , Passianotto André Luiz de Lima , Brumer Bruna Bley , Santos Adriana Brombini Dos , Soares Rafael Moreira , Torkamaneh Davoud , Arias Carlos Alberto Arrabal , Belzile François , Abdelnoor Ricardo Vilela , Marcelino-Guimarães Francismar Corrêa
Published: October 2019

Background

Southern stem canker (SSC), caused by Diaporthe aspalathi (E. Jansen, Castl. & Crous), is an important soybean disease that has been responsible for severe losses in the past. The main strategy for controlling this fungus involves the introgression of resistance genes. Thus far, five main loci have been associated with resistance to SSC. However, there is a lack of information about useful allelic variation at these loci. In this work, a genome-wide association study (GWAS) was performed to identify allelic variation associated with resistance against Diaporthe aspalathi and to provide molecular markers that will be useful in breeding programs.

Results

We characterized the response to SSC infection in a panel of 295 accessions from different regions of the world, including important Brazilian elite cultivars. Using a GBS approach, the panel was genotyped, and we identified marker loci associated with Diaporthe aspalathi resistance through GWAS. We identified 19 SNPs associated with southern stem canker resistance, all on chromosome 14. The peak SNP showed an extremely high degree of association (p-value = 6.35E-27) and explained a large amount of the observed phenotypic variance (R2 = 70%). This strongly suggests that a single major gene is responsible for resistance to D. aspalathi in most of the lines constituting this panel. In resequenced soybean materials, we identified other SNPs in the region identified through GWAS in the same LD block that clearly differentiate resistant and susceptible accessions. The peak SNP was selected and used to develop a cost-effective molecular marker assay, which was validated in a subset of the initial panel. In an accuracy test, this SNP assay demonstrated 98% selection efficiency.

Conclusions

Our results suggest relevance of this locus to SSC resistance in soybean cultivars and accessions from different countries, and the SNP marker assay developed in this study can be directly applied in MAS studies in breeding programs to select materials that are resistant against this pathogen and support its introgression.
A novel approach with holmium laser ablation for endoscopic management of intrahepatic biliary stricture
Authors: Lou Jianying , Hu Qida , Ma Tao , Chen Wei , Wang Ji , Pankaj Prasoon
Published: November 2019

Background

Hepatolithiasis, featuring high incidence, severe symptoms, and common recurrence, poses a heavy disease burden. Endoscopic management provides an opportunity to cure hepatolithiasis, but fails to properly resolve biliary stricture without additional interventional techniques. An innovative approach towards endoscopic management of biliary stricture is required.

Methods

Holmium laser ablation was applied to biliary strictures via endoscopic access. Patients’ demographic, operative, and follow-up data after receiving holmium laser ablation were retrospectively collected for analysis.

Results

A total of 15 patients (4 males and 11 females) underwent stricture ablation by holmium laser via cholangioscopy. All the patients successfully received holmium laser ablation, indicating a technical success rate of 100%. No postoperative mortality or no major perioperative complication was observed. During the follow-up period, the recurrence-free rate was 73% at 2 years and 67% at 5 years.

Conclusions

We successfully developed a novel technique of biliary stricture removal by cholangioscopic holmium laser ablation with satisfying clinical outcomes.
CTNS mRNA molecular analysis revealed a novel mutation in a child with infantile nephropathic cystinosis: a case report
Authors: Papizh Svetlana , Serzhanova Victoria , Filatova Alexandra , Skoblov Mikhail , Tabakov Vyacheslav , van den Heuvel Lambert , Levtchenko Elena , Prikhodina Larisa
Published: October 2019

Background

Cystinosis is an autosomal recessive lysosomal storage disorder characterized by accumulation of cystine in lysosomes throughout the body. Cystinosis is caused by mutations in theCTNSgene that encodes the lysosomal cystine carrier protein cystinosin.CTNSmutations result in either complete absence or reduced cystine transporting function of the protein. The diagnosis of nephropathic cystinosis is generally based on measuring leukocyte cystine level, demonstration of corneal cystine crystals by the slit lamp examination and confirmed by genetic analysis of theCTNSgene.

Case presentation

A boy born to consanguineous Caucasian parents had the characteristic clinical features of the infantile nephropathic cystinosis including renal Fanconi syndrome (polydipsia/polyuria, metabolic acidosis, hypokalemia, hypophosphatemia, low molecular weight proteinuria, glycosuria, cystine crystals in the cornea) and elevated WBC cystine levels. Initially we performed RFLP analysis of the common in the Northern European population 57-kb deletion of proband’s DNA, then a direct Sanger sequencing which revealed no mutations in the coding part of theCTNSgene. To confirm the diagnosis we performed RT-PCR analysis of total RNA obtained from patient-derived fibroblasts in combination with cDNA sequencing. This revealed the skipping of exon 4 and exon 5 in theCTNSin our patient. Therefore, we detected a novel 9-kb homozygous deletion in theCTNSgene at genomic DNA level, spanning region from intron 3 to intron 5. In order to identify the inheritance pattern of the deletion we analyzed DNA of proband’s mother and father. Both parents were found to be heterozygous carriers of theCTNSmutation.

Conclusions

Analysis ofCTNSgene transcript allowed to identify a large homozygous deletion in the patient with infantile nephropathic cystinosis. Mutational detection at RNA level may be an efficient tool to establish the genetic defect in some cystinosis patients.
Association of physical activity with adiposity in preschoolers using different clinical adiposity measures: a cross-sectional study
Authors: Arhab Amar , Messerli-Bürgy Nadine , Kakebeeke Tanja H. , Stülb Kerstin , Zysset Annina , Leeger-Aschmann Claudia S. , Schmutz Einat A. , Meyer Andrea H. , Munsch Simone , Kriemler Susi , Jenni Oskar G. , Puder Jardena J.
Published: October 2019

Background

More research is needed about the association between physical activity (PA), sedentary behaviour (SB), and adiposity in preschoolers, particularly using more direct clinical measures of adiposity. Therefore, the main objective of this study was to investigate the association between objectively measured PA and different clinical adiposity measures in a large sample of preschoolers.

Methods

Four hundred sixty-three predominantly normal-weight (77%) 2–6-year-old preschool children participated in the Swiss Preschoolers’ Health Study (SPLASHY). Physical activity was measured using accelerometers and was analyzed using 15-s (uni-axial) epoch length using validated cut-offs. Adiposity measures included body mass index (BMI), the sum of four skinfolds, and waist circumference (WC). Multilevel linear regression modeling, adjusted for age, sex and wear time, was used to assess the association between PA and SB with BMI, WC, and skinfold thickness.

Results

Total PA and different PA intensities were positively and SB was inversely associated with BMI in the total sample and in the normal-weight children (p < 0.05). Total PA was inversely associated with skinfold thickness in overweight and obese children (p < 0.05), while there was only a weak association for vigorous PA (p > 0.05). Moderate and moderate-to-vigorous PA were positively, and SB was negatively associated with WC in the total sample and in the normal-weight children (p < 0.05). Additional adjustment for potential sociocultural and biological confounding variables attenuated some of the results.

Conclusions

In this very young and predominantly normal-weight population, PA is positively related to BMI and WC, but this relationship is not observed in overweight and obese children. In this latter population, PA is inversely, and SB is positively related to skinfold thickness. Skinfold thickness could represent a useful and simple clinical measure of body fat in preschoolers. The role of vigorous PA in the prevention of early childhood obesity should be further investigated in future studies.

Trial registration

ISRCTN ISRCTN41045021. Retrospectively registered 06 May 2014.
Exploring HIV concern in a population of Dominican American women midlife and older
Authors: Odlum Michelle , Black Danielle , Yoon Sunmoo , Maher Cassidy , Lawrence Steven , Osborne Jennel
Published: October 2019

Background

The feminization and ethnic diversification of HIV infection, has resulted in a call for gender- and culture-specific prevention strategies for at-risk groups including Latinos in the United States. The steadily changing demographic profile of the AIDS epidemic challenges prevention strategies to remain relevant and up-to-date, particularly in populations of women midlife and older where an understanding of risk remains under explored. As the CDC requests country-specific HIV risk profiles for Latino communities in the US, understanding the socio-economic, behavioral and personal risk reasons of HIV risk for older Dominican women is critical for prevention.

Methods

We conducted focus group discussions informed by the Theory of Gender and Power (TGP). The three constructs of the TGP: 1) Affective influences/social norms; 2) Gender-specific norms and.

3) Power and Authority guided the thematic analysis and identified themes that described the socio-cultural and contextual reasons that that contribute to perceptions of HIV risk.

Results

Sixty Dominican American women ages 57–73 participated in our focus group discussions. Sexual Division of Labour: 1) Economic Dependence; 2) Financial Need and 3) Education and Empowerment. Sexual Division of Power: 4) HIV Risk and 5) Relationship Dynamics. Cathexis: Affective Influences/Social Norms: 6) HIV/AIDS Knowledge and 7) Prevention and Testing. Importantly, participants were concerned about partner fidelity when visiting the Dominican Republic, as the country accounts for the second highest HIV rates in the Caribbean.

Conclusions

Our results confirm previous findings about perceptions of HIV risk and provide additional insight into aging-related aspects of HIV risk for Latino women midlife and older.
Dying in acute hospitals: voices of bereaved relatives
Authors: Ó Coimín Diarmuid , Prizeman Geraldine , Korn Bettina , Donnelly Sarah , Hynes Geralyn
Published: October 2019

Background

Internationally there is an increasing concern about the quality of end-of-life care (EoLC) provided in acute hospitals. More people are cared for at end of life and die in acute hospitals than in any other healthcare setting. This paper reports the views of bereaved relatives on the experience of care they and the person that died received during their last admission in two university adult acute tertiary hospitals.

Methods

Relatives of patients who died were invited to participate in a post-bereavement postal survey. An adapted version of VOICES (Views of Informal Carers - Evaluation of Services) questionnaire was used.VOICES MaJamhas 36 closed questions and four open-ended questions. Data were gathered in three waves and analysed using SPSS and NVivo. 356 respondents completed the survey (46% response rate).

Results

The majority of respondents (87%:n = 303) rated the quality of care as outstanding, excellent or good during the last admission to hospital. The quality of care by nurses, doctors and other staff was highly rated. Overall, care needs were well met; however, findings identified areas of care which could be improved, including communication and the provision of emotional and spiritual support. In addition, relatives strongly endorsed the provision of EoLC in single occupancy rooms, the availability of family rooms on acute hospital wards and the provision of bereavement support.

Conclusions

This research provides a powerful snapshot in time into what works well and what could be improved in EoLC in acute hospitals. Findings are reported under several themes, including the overall quality of care, meeting care needs, communication, the hospital environment and support for relatives. Results indicate that improvements can be made that build on existing good practice that will enhance the experience of care for dying persons and their relatives. The study adds insights in relation to relative’s priorities for EoLC in acute hospitals and can advance care providers’, policy makers’ and educationalists’ priorities for service improvement.