bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction to a special issue on child and adolescent feeding and eating disorders and avoidant/restrictive food intake disorder
Authors: Eddy Kamryn T. , Thomas Jennifer J.
Published: February 2019

Objective

We are very pleased to introduce a special issue of the International Journal of Eating Disorders on child and adolescent feeding and eating disorders and avoidant/restrictive food intake disorder (ARFID).

Method

Contributions focused on five main themes: (1) the definition and assessment of ARFID; (2) the clinical phenomenology of ARFID; (3) similarities and differences between ARFID and anorexia nervosa (AN); (4) novel treatments for ARFID; and (5) new ideas for improving treatment outcomes in AN.

Results

These papers highlight the importance of clear operationalization and measurement of the ARFID diagnostic criteria. ARFID phenotypes bear both similarities and important differences in clinical profile, course, and outcome from AN. Findings suggest the utility of adapting existing treatments for restrictive eating disorders to apply to ARFID and engender clinical creativity to move beyond existing treatments and develop novel interventions that address the heterogeneity of ARFID. Furthermore, burgeoning understanding of ARFID offers the potential that novel treatments for ARFID may also be applied to improve outcomes for AN.

Discussion

This collection of papers features child and adolescent feeding and eating disorder patient groups that have been understudied and we hope that this catalyzes clinical research in these important presentations.
Enhancing immunity prevents virus‐induced T‐cell‐mediated immunopathology in B cell‐deficient mice
Authors: Straub Tobias , Pircher Hanspeter
Published: February 2019

Hyper‐activated or deviated immune responses can result in immunopathological diseases. Paradoxically, immunodeficiency represents a frequent cause of such immune‐mediated pathologies. Immunopathological manifestations are commonly treated by immunosuppression, but in situations in which immunodeficiency is the basis of disease development, enhancing immunity may represent an alternative treatment option. Here, we tested this counterintuitive concept in a preclinical model using infection of mice with lymphocytic choriomeningitis virus (LCMV). Firstly, we demonstrate that infection of B‐cell‐deficient (B−/−) but not of wild‐type (WT) mice with the LCMV strain Docile induced a rapid and fatal CD8+ T‐cell‐mediated immunopathological disease. Similar to WT mice, LCMV‐infected B−/− mice generated a potent, functional LCMV‐specific CD8+ T‐cell response but exhibited prolonged viral antigen presentation and increased vascular leakage in liver and lungs. Secondly, we were able to prevent this virus‐induced immunopathology in B−/− mice by active or passive T‐cell immunizations or by treatment with LCMV‐specific virus neutralizing or non‐neutralizing monoclonal antibodies (mAb). Thus, boosting antiviral immunity did not aggravate immunopathology in this model, but prevented it by decreasing the formation of target structures for damage‐causing CD8+ T cells.
Silole Amino Acids with Aggregation‐Induced Emission Features Synthesized by Hydrosilylation
Authors: Arribat Mathieu , Rémond Emmanuelle , Richeter Sébastien , Gerbier Philippe , Clément Sébastien , Cavelier Florine
Published: February 2019

The synthesis of silole amino acids was achieved through hydrosilylation of alkene or alkyne‐containing amino acids with 1‐methyl‐2,3,4,5‐tetraphenyl‐1H‐silole, using Karstedt's catalyst with yield up to 95 % and without epimerization. After selective deprotection of carboxylic acid or amine functions respectively, C‐ or N‐peptide coupling with an alanine moiety proved their possible incorporation into peptides. A model tripeptide was synthesized by solid phase synthesis with the N‐Fmoc protected silole amino acid version. The silole moiety can be also grafted on a precursor peptide directly on the solid support. These amino acids and peptides exhibit AIE properties with λem ca. 500 nm and Δλ ca. 100 nm. This approach constitutes an alternative and promising strategy for incorporation of such AIE fluorogens to peptides.
Patients’ Global Impression of Change in the management of peripheral neuropathic pain: Clinical relevance and correlations in daily practice
Authors: Perrot Serge , Lantéri‐Minet Michel
Published: February 2019

Background

Patient‐Reported Outcome (PRO) instruments have been developed to evaluate pain management in daily practice; the Patients’ Global Impression of Change (PGIC) is particularly recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. The prospective non‐interventional multicenter PRO‐QURE study aimed at assessing correlations between PGIC and pain measurements and treatment effects in patients followed in French pain centres.

Methods

Respectively, 495 and 379 patients with peripheral neuropathic pain initiating treatment with capsaicin 8% cutaneous patch(es) (female, 62.6%; mean age, 54.0 ± 14.8 years; post‐surgical or traumatic pain, 52.7%; mean pain duration, 42.2 ± 54.1 months; DN4 score >4, 92.9%) completed the PGIC and several other PRO instruments before (baseline) and 3 months (M3) after treatment application.

Results

At M3, improvement (“much improved” or “very much improved”) was observed in 23.0% of patients, associated with decreases of −3.0 ± 2.2, −2.5 ± 2.4, and −23.1 ± 19.7 in BPI pain intensity, BPI pain interference and NPSI total scores, respectively. The highest Spearman's rank correlation coefficients with PGIC were found for pain intensity (BPI: r = −0.479, p < 0.001), satisfaction with current state (Patient Acceptable Symptomatic State: r = 0.455, p < 0.001), and treatment effectiveness (TSQM: r = 0.431, p < 0.001); correlation coefficients were lower for all NPSI scores, BPI pain interference score, HAD scores and EQ‐5D‐3L index.

Conclusions

In daily clinical practice, significant improvement in peripheral neuropathic pain, as assessed by PGIC scores, significantly correlated with changes in well‐established measures of pain intensity, pain interference with activities of daily living, mood and quality of life, confirming its clinical interest as PRO measure in real‐world conditions.

Significance

Clinically important improvement in peripheral neuropathic pain, as assessed by PGIC scores, significantly correlated with well‐established measures of pain intensity, pain interference in daily life and treatment efficacy. This result, associated with the ease of administration and scoring, encourages the widespread use of the PGIC in daily practice.
Revisiting established medicines: An overview of systematic reviews about ibuprofen and paracetamol for treating pain in children
Authors: Radman Marija , Babic Andrija , Runjic Edita , Jelicic Kadic Antonia , Jeric Milka , Moja Lorenzo , Puljak Livia
Published: February 2019

Background and objective

We explored how systematic reviews evaluated paracetamol and ibuprofen for treating pain in children, as these two non‐opioid analgesics are well‐established medicines included in most national essential medicines lists.

Databases and data treatment

We carried out an overview of systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions (PROSPERO registration: 42016045367). We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (CDSR) and Database of Reviews of Effects (DARE) up to 23 August 2017. We used AMSTAR checklist to analyse methodological quality of included SRs.

Results

We found 17 SRs with 72 unique RCTs; the majority of those trials included under 100 children. Positive conclusive evidence was found in only one SR, regarding safety of paracetamol. Conclusions of other SRs for efficacy and safety of ibuprofen and paracetamol were inconclusive, unclear, or there was no opinion. Only one SR analysed efficacy of ibuprofen and other non‐steroidal anti‐inflammatory drugs (NSAIDs) in chronic pain and the conclusion was that there was no evidence from RCTs that NSAIDs were effective for chronic non‐cancer pain in children and adolescents. Most of the SRs addressed very narrow questions, included few trials, with few children and were of low or medium methodological quality.

Conclusions

Most SRs on two relevant medicines have inconsistent conclusions and doubt upon their effectiveness. Instead of focusing on very narrow questions, SRs should examine more comprehensive research topics to obtain a general sense of consistency, particularly when analysing established medicines.

Significance

Evidence behind two analgesics—ibuprofen and paracetamol—that are well‐established medicines for children in most countries appears limited, judging by the systematic reviews. The discrepancy between clinical use and the extensive evidence we reviewed may be a result of the selective criteria in the reviews examined. We need new, and better evidence syntheses supporting the use of these two medicines in wide indications regarding pain in children.
Comparing the effectiveness of integrating ergonomics and motor control to conventional treatment for pain and functional recovery of work‐related neck–shoulder pain: A randomized trial
Authors: Tsang Sharon M. H. , So Billy C. L. , Lau Rufina W. L. , Dai Jie , Szeto Grace P. Y.
Published: February 2019

Background

Work‐related neck and shoulder pain (WRNSP) is highly prevalent among patients who seek physiotherapy treatment. Clinicians may tend to focus on teaching home exercises and provide general advice about workplace improvement. The present study investigates the short‐ and long‐term impact of an intervention approach that emphasizes on integrating the motor control re‐education with ergonomic advice.

Methods

Participants diagnosed with WRNSP (n = 101) were randomly assigned into two groups in this randomized controlled trial. The Ergo‐motor Group (EM, n = 51) received an integrated intervention with ergonomic advice/modifications and motor control training individualized for each participant based on their specific work demands. Control Group (CO, n = 50) received treatment for pain relief and general exercises of their necks at a designated physiotherapy clinic. Neck pain intensity and functional outcome measures were assessed before, immediately and 1‐year after the 12‐week intervention programmes. Global Rating of Change Score was used to evaluate the perceived recovery at 1‐year follow‐up.

Results

Both groups reported significant reductions in pain and functional disability scores at post‐intervention (EM, n = 44; CO, n = 42) and 1‐year follow‐up (EM, n = 40; CO, n = 38); however, no significant between‐group differences were found (p > 0.05). Significantly higher rating in global recovery score was reported in EM group at 1‐year follow‐up (p < 0.05).

Conclusions

Intervention integrating ergonomic advice/modification with motor control exercise was found to be equally effective as pain relief and general exercise for pain and functional recovery. However, at 1‐year follow‐up, such integrated approach resulted in significantly better global recovery perceived by people with WRNSP.

Significance

Integrating ergonomic intervention and motor control training achieved similar reduction in pain and functional outcomes compared to conventional physiotherapy at post‐intervention and at 1‐year follow‐up, for patients with moderate level of work‐related neck–shoulder pain and mild degree of functional disability. The Ergo‐motor Group reported significantly better perceived overall recovery at 1‐year follow‐up.
Complete withdrawal is the most feasible treatment for medication‐overuse headache: A randomized controlled open‐label trial
Authors: Engelstoft Ida Maria Storm , Carlsen Louise Ninett , Munksgaard Signe Bruun , Nielsen Mia , Jensen Rigmor Højland , Bendtsen Lars
Published: February 2019

Background

Complete stop of acute medication and/or migraine medication for treatment of medication‐overuse headache (MOH) has previously been reported more effective in reducing headache days and migraine days per month compared with restricted intake of acute medication. However, it is unknown whether complete stop or restricted intake is the most feasible treatment for patients.

Objectives

To investigate whether feasibility of withdrawal in MOH is different between complete stop of acute medication and restricted intake, and whether reductions in headache‐related medication dependence, anxiety and depression differ between the treatments.

Methods

Medication‐overuse headache patients were included in a prospective, open‐label, outpatient study and randomized to two months of withdrawal with either no analgesics or acute migraine medication (programme A) or acute medication restricted to 2 days/week (programme B). After 6 and 12 months, patients graded feasibility of withdrawal. Dependence was measured by Severity of Dependence Scale (SDS), while anxiety and depression were measured by Hospital Anxiety and Depression Scale (HADS).

Results

We included 72 MOH patients with primary migraine and/or tension‐type headache. Forty‐nine completed withdrawal and the SDS questionnaire at 12‐month follow‐up, and the feasibility of withdrawal was significantly higher in programme A compared to programme B (p < 0.001). At 12 months, the dependence was reduced by 44% in programme A compared to 26% in programme B (p = 0.053), while the anxiety score was reduced by 32% and 11%, respectively (p = 0.048).

Conclusions

Withdrawal with complete stop of acute medication was more feasible and most effective in reducing headache‐related anxiety compared with restricted intake.

Significance

A complete stop of all analgesics is the most effective treatment for MOH regarding reduction in headache days but has often been regarded as too challenging for patients. However, in this study, complete stop appears to be more feasible compared with restricted intake of analgesics seen from the patients’ perspective.
Photochemical and photocatalytic degradation of 1‐propanol using UV/H2O2: Identification of malonate as byproduct
Authors: Ferreira Santos Mauro Sergio , Gomes Cordeiro Thiago , Cieslarova Zuzana , Gutz Ivano Gebhardt Rolf , Garcia Carlos D.
Published: February 2019

1‐propanol is a primary alcohol extensively used in the pharmaceutical, chemical, and food industries. It has been also found as a contaminant in the atmosphere and is considered a model compound to mimic the behavior and fate of aliphatic alcohols exposed to environmental conditions. In order to understand that role of relevant variables, this paper presents results obtained with a simple experimental set‐up to investigate the reactivity of 1‐propanol under mild oxidizing conditions. Coupling this system with CE‐C4D allowed the quantification of the carboxylic acids formed. For the described experiments, aqueous solutions of 1‐propanol were placed inside a photoreactor and oxidized upon the addition of TiO2 and/or H2O2. According to the described results, the addition of H2O2 (0.1% w/w) was the most significant variable, roughly tripled the amount of carboxylic acids generated and led to the conversion of up to 70% of the initially available 1‐propanol (1 mmol/L). More importantly, the reaction yielded the formation (within 10 min) of propionate (50 µmol/L), acetate (400 µmol/L), formate (50 µmol/L), and malonate (200 µmol/L). The latter is critically important because it represents the first example of the photochemical oxidation of both terminal carbons of the C3‐chain of 1‐propanol under mild conditions, and opens new avenues for the production of this important chemical building block.
A novel bidirectional pendulum tuned mass damper using variable homogeneous friction to achieve amplitude‐independent control
Authors: Matta Emiliano
Published: February 2019

Passive tuned mass dampers (TMDs) are widely used in controlling structural vibrations. Although their principle is well established, the search for improved arrangements is still under way. This effort has recently produced an innovative paradigm of bidirectional pendulum TMD (BTMD) that, moving along a specially designed three‐dimensional (3D) surface, can simultaneously control two in‐plane orthogonal structural modes. In existing versions of BTMDs, energy dissipation is provided either by ordinary horizontal viscous dampers or by an original arrangement of vertical friction dampers. In this paper, a new paradigm is proposed, in which energy dissipation comes from the tangential friction arising along the pendulum surface out of an optimal spatially variable friction coefficient pattern. Within this paradigm, if the friction coefficient is taken proportional to the modulus of the pendulum surface gradient, the dissipation model results nonlinear homogeneous in the small‐displacement domain, and the performance of the absorber, herein called the homogeneous tangential friction BTMD (HT‐BTMD), results independent from the excitation level. The present work introduces this concept, derives the analytical model of the HT‐BTMD, establishes a method for its optimal design, and numerically verifies its seismic effectiveness in comparison with viscously damped devices. The validity and feasibility of the concept are demonstrated through experimental tests on a small‐scale lab prototype, which also show the efficacy of a stepwise approximation of the homogeneous friction pattern. The new device proves a competing alternative to existing BTMDs, and homogeneous tangential friction proves a promising new paradigm to provide pendular systems with amplitude‐independent structural damping.
Extended methods for gene–environment‐wide interaction scans in studies of admixed individuals with varying degrees of relationships
Authors: Chen Yalei , Adrianto Indra , Iannuzzi Michael C. , Garman Lori , Montgomery Courtney G. , Rybicki Benjamin A. , Levin Albert M. , Li Jia
Published: February 2019

The etiology of many complex diseases involves both environmental exposures and inherited genetic predisposition as well as interactions between them. Gene–environment‐wide interaction studies (GEWIS) provide a means to identify the interactions between genetic variation and environmental exposures that underlie disease risk. However, current GEWIS methods lack the capability to adjust for the potentially complex correlations in studies with varying degrees of relationships (both known and unknown) among individuals in admixed populations. We developed novel generalized estimating equation (GEE) based methods—GEE‐adaptive and GEE‐joint—to account for phenotypic correlations due to kinship while accounting for covariates, including, measures of genome‐wide ancestry. In simulation studies of admixed individuals, both methods controlled family‐wise error rates, an advantage over the case‐only approach. They demonstrated higher power than traditional case–control methods across a wide range of underlying alternative hypotheses, especially where both marginal and interaction effects were present. We applied the proposed method to conduct a GEWIS of a known sarcoidosis risk factor (insecticide exposure) and risk of sarcoidosis in African Americans and identified two novel loci with suggestive evidence of G × E interaction.
Magnetic nanoFe2O3 – incorporated PEBA membranes for CO2/CH4 and CO2/N2 separation: experimental study and grand canonical Monte Carlo and molecular dynamics simulations
Authors: Riasat Harami Hossein , Asghari Morteza , Mohammadi Amir H.
Published: February 2019

Mixed matrix membranes (MMMs) comprised of organic selective polymers and inorganic nano‐particles under the name of fillers have attracted much attention in the field of gas separation. In this study, poly (amide‐6‐b‐ethylene oxide) [PEBA]/Fe2O3 mixed matrix membranes were prepared using the dry phase separation technique with ethanol / water (70/30 wt%) as solvent. Various amount of Fe2O3 nanoparticles were chosen to disperse within the polymer matrix (0, 0.5, 1, 1.5 and 2 wt% of polymer). To prepare this type of novel membrane, a magnetic field of 0.3 T was used to align the position of NPs. The structural properties and surface morphology of prepared membranes were characterized by field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM). Field emission scanning electron microscopy analysis was also used to study the physical bonding. Phase identification and crystallinity, effective area, and distribution of pore size were investigated by X‐ray diffraction (XRD) and Brunauer–Emmett–Teller (BET) analysis. Carbon dioxide permeability through these membranes increased with pressure in the range of 2 to 14 bar. Magnetic membrane loaded with 1.5 wt% of Fe2O3 gave the best performance: CO2 permeability, CO2/CH4, and CO2/N2 selectivity were enhanced by 30, 42 and 81%, compared to a pure membrane, respectively. The results indicated that the magnetic MMMs gave better separation performance than pure membranes. Molecular simulation has also been used to investigate the structural and transport properties of fabricated membranes. Structural characterizations like radial distribution function (RDF), fractional free volume (FFV), and X‐ray diffraction were applied to the simulated membrane cells. Grand canonical Monte Carlo (GCMC) and molecular dynamic (MD) simulations, were used to calculate the selectivity and diffusivity of membranes. Results from experimental tests and simulation runs revealed that the selectivity and permeability of fabricated and simulated membranes are consistent. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd.
The distinctive character of lumpy limestones (Early Jurassic, Lusitanian Basin, W Portugal)
Authors: Coimbra Rute , Duarte Luís Vitor
Published: February 2019

Ephemeral carbonate facies presenting restricted geographical and temporal occurrence hold the key to complete the knowledge of past environmental conditions. Far from representing environments widespread throughout the geological history, ephemeral lithofacies embody equally relevant but more unusual scenarios. This is the case of the lumpy limestones, a puzzling facies encased on a worldwide‐relevant stratigraphic section of the Portuguese Jurassic archive but still lacking a deeper understanding of the processes leading to their development. An extensive revision and update of the singularities of the lumpy limestones is presented, based on a systematic description of the lithic elements occurring in three sections. These represent different positions along the Pliensbachian (Early Jurassic) paleoplatform of the Lusitanian Basin (Western Portugal). The lumps were analysed regarding their abundance, distribution, appearance, and degree of sorting, based on field observation, macro‐ and microfacies inspection. Apart from shared stratigraphic trends, which highlight prevailing paleoenvironmental conditions during the Early Jurassic times, the main differences in spatial distribution across the Lusitanian Basin are also discussed, taking into account the specific paleogeographic setting of each studied locality. The presence of lumps but also absence is considered relevant, as for each case a specific paleoenvironmental context and/or syn‐ to post‐depositional processes can be assigned. A new lump classification scheme is brought forward, accounting for the high variety identified in lump architecture and aspect. A depositional model offering alternative paleoenvironmental scenarios is presented for the development of the variety of lump types identified, combining physical (mechanical) and biological processes involved in the occurrence and distribution of this facies. Depending on the presence/absence of lumps, lump type, abundance, and distribution, these scenarios include considerable fluctuations in oxygen availability and bottom current intensity, which affect deposition/accumulation, bioturbation, and related syn‐sedimentary conditions. Physical and mechanically dominated processes driven by sedimentary instability and/or heterogeneity are also introduced. A dynamic depositional framework is presented, clarifying the depositional to late‐diagenetic evolution accounting for the singularity of the lumpy limestone facies in the context of the Lower Jurassic in the western Iberia margin.
Preventative care utilization and associated health‐related measurements among older adults following the 2009 health reform in China
Authors: Lee Yen‐Han , Chang Yen‐Chang , Liu Ching‐Ti
Published: February 2019

Purpose

It is unclear if older adults' preventive health care utilization is associated with better health in China, as the elderly population and prevalence of chronic disease have escalated.

Methods

Applying the Donabedian's model for evaluating quality of health care, we analyzed data from the 2012 and 2014 waves of the Chinese Longitudinal Healthy Longevity Survey with 5304 older adults 65 years old and above. The study used propensity score matching to decrease selection bias on preventive care utilization. Preventive care utilization was defined as the use of annual physical examination at least once a year among older adults. Three ordered logistic regression models were performed to evaluate preventive care utilization and three health‐related measurements of current health status, overall health status improvement in the past 12 months, and life satisfaction, controlling for socioeconomic, demographic, and biological factors.

Results

Older adults who used preventive care reported better health status, overall health status improvement in the past 12 months, and life satisfaction (adjusted odds ratios [AORs] = 1.24, 1.20, 1.30, respectively; allPs < 0.01), compared with participants who did not use preventive care.

Conclusion

The research findings suggest that the Chinese central government should continue to enhance the role of preventive care services with further reforms in order to improve older adults' health and life conditions.
Computer aided diagnosis of brain abnormalities using texture analysis of MRI images
Authors: Gilanie Ghulam , Bajwa Usama Ijaz , Waraich Mustansar Mahmood , Habib Zulfiqar
Published: February 2019

The drive of this study is to develop a robust system. A method to classify brain magnetic resonance imaging (MRI) image into brain‐related disease groups and tumor types has been proposed. The proposed method employed Gabor texture, statistical features, and support vector machine. Brain MRI images have been classified into normal, cerebrovascular, degenerative, inflammatory, and neoplastic. The proposed system has been trained on a complete dataset of Brain Atlas‐Harvard Medical School. Further, to achieve robustness, a dataset developed locally has been used. Extraordinary results on different orientations, sequences of both of these datasets as per accuracy (up to 99.6%), sensitivity (up to 100%), specificity (up to 100%), precision (up to 100%), and AUC value (up to 1.0) have been achieved. The tumorous slices are further classified into primary or secondary tumor as well as their further types as glioma, sarcoma, meningioma, bronchogenic carcinoma, and adenocarcinoma, which could not be possible to determine without biopsy, otherwise.
Nucleolar spindle‐associated protein 1 promotes tumorigenesis and predicts poor prognosis in human esophageal squamous cell carcinoma
Authors: Guan Chengqi , Liu Zhaoxiu , Lu Cuihua , Xiao Mingbing , Shi Hui , Ni Runzhou , Bian Zhaolian
Published: February 2019

The microtubule binding protein, nucleolar spindle‐associated protein 1 (NUSAP1), has a crucial function in mitosis and its expression is closely associated with carcinogenesis. Herein, we aimed to determine the function of NUSAP1 in the development of human esophageal squamous cell carcinoma (ESCC), and the association of NUSAP1 expression with ESCC. Immunohistochemical staining of ESCC tissue sections indicated that NUSAP1 was expressed to a higher degree in tumor tissues than in adjacent nontumor tissues. NUSAP1 levels were relevant closely to histological differentiation (P = 0.049). Overall survival was longer in patients with lower NUSAP1 levels (
P < 0.001). NUSAP1 expression (
P = 0.002), histological differentiation (
P < 0.001), tumor depth (
P = 0.045), lymph node metastases (
P < 0.001), and tumor‐node‐metastasis staging (
P = 0.008) were greatly associated with overall survival using univariate analysis. Multivariate analysis suggested that histological differentiation (
P = 0.014) and NUSAP1 expression (
P = 0.026) could be independent prognostic markers for ESCC. Additionally, the biological behavior of ESCC cells was investigated in vitro and in vivo. Suppression of NUSAP1 inhibited cellular proliferation and invasion, and induced cell cycle arrest and apoptosis in vitro. More importantly, knockdown of
NUSAP1 led to inhibition of tumor formation in nude mice. These findings indicated that NUSAP1 is a potential prognostic biomarker in ESCC, and is an ESCC oncogene. Thus, NUSAP1 could represent a therapeutic target for ESCC.
Protein kinase B/AKT mediates insulin‐like growth factor 1‐induced phosphorylation and nuclear export of histone deacetylase 5 via NADPH oxidase 4 activation in vascular smooth muscle cells
Authors: Pietruczuk Paulina , Jain Ashish , Simo‐Cheyou Estelle R. , Anand‐Srivastava Madhu B. , Srivastava Ashok K.
Published: February 2019

Insulin‐like growth factor 1 (IGF‐1) mediates the generation of reactive oxygen species (ROS) and the activation of growth promoting signaling pathways. Histone deacetylases (HDACs) regulate gene transcription by deacetylating lysine residues in histone and nonhistone proteins and a heightened HDAC activation, notably of HDAC5, is associated with vascular disorders, such as atherosclerosis. Although the contribution of IGF‐1 in these pathologies is well documented, its role in HDAC phosphorylation and activation remains unexplored. Here, we examined the effect of IGF‐1 on HDAC5 phosphorylation in vascular smooth muscle cells (VSMCs) and identified the signaling pathways involved in controlling HDAC5 phosphorylation and nuclear export. Treatment of A10 VSMCs with IGF‐1 enhanced HDAC5 phosphorylation. Blockade of the IGF‐1 receptor tyrosine kinase (TK) activity with the specific pharmacological inhibitor, AG1024, significantly inhibited IGF‐1‐induced HDAC5 phosphorylation, whereas the epidermal growth factor receptor (EGFR) TK antagonist, AG1478, had no effect. Inhibition of the mitogen‐activated protein kinase pathway with U0126, SP600125, or SB203580, did not affect HDAC5 phosphorylation, whereas two inhibitors of the phosphoinositide 3‐kinase (PI3K)/AKT pathways, wortmannin and SC66, almost completely attenuated IGF‐1‐induced responses as confirmed by immunoblotting of phospho‐HDAC5 and by small interfering RNA (siRNA)‐induced AKT silencing. Moreover, the NAD(P)H oxidase (Nox) inhibitor, diphenyleneiodonium (DPI), and Nox4 siRNA, attenuated IGF‐1‐induced phosphorylation of HDAC5 and AKT. The HDAC5 phosphorylation resulted in its nuclear export, which was reversed by SC66 and DPI. Our results indicate that IGF‐1‐induced phosphorylation and nuclear export of HDAC5 involve Nox4‐dependent ROS generation and PI3K/AKT signaling pathways.
VEGF‐A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress‐mediated autophagy
Authors: Zou Jiang , Fei Qin , Xiao Hui , Wang Hao , Liu Ke , Liu Meidong , Zhang Huali , Xiao Xianzhong , Wang Kangkai , Wang Nian
Published: February 2019

Proangiogenesis is generally regarded as an effective approach for treating ischemic heart disease. Vascular endothelial growth factor (VEGF)‐A is a strong and essential proangiogenic factor. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy are implicated in the process of angiogenesis. This study is designed to clarify the regulatory mechanisms underlying VEGF‐A, ROS, ER stress, autophagy, and angiogenesis in acute myocardial infarction (AMI). A mouse model of AMI was successfully established by occluding the left anterior descending coronary artery. Compared with the sham‐operated mice, the microvessel density, VEGF‐A content, ROS production, expression of vascular endothelial cadherin, positive expression of 78 kDa glucose‐regulated protein/binding immunoglobulin protein (GRP78/Bip), and LC3 puncta in CD31‐positive endothelial cells of the ischemic myocardium were overtly elevated. Moreover, VEGF‐A exposure predominantly increased the expression of beclin‐1, autophagy‐related gene (ATG) 4, ATG5, inositol‐requiring enzyme‐1 (IRE‐1), GRP78/Bip, and LC3‐II/LC3‐I as well as ROS production in the human umbilical vein endothelial cells (HUVECs) in a dose and time‐dependent manner. Both beclin‐1 small interfering RNA and 3‐methyladenine treatment predominantly mitigated VEGF‐A‐induced tube formation and migration of HUVECs, but they failed to elicit any notable effect on VEGF‐A‐increased expression of GRP78/Bip. Tauroursodeoxycholic acid not only obviously abolished VEGF‐A‐induced increase of IRE‐1, GRP78/Bip, beclin‐1 expression, and LC3‐II/LC3‐I, but also negated VEGF‐A‐induced tube formation and migration of HUVECs. Furthermore,
N‐acetyl‐
l‐cysteine markedly abrogated VEGF‐A‐increased ROS production, IRE‐1, GRP78/Bip, beclin‐1 expression, and LC3‐II/LC3‐I in the HUVECs. Taken together, our data demonstrated that increased spontaneous production of VEGF‐A may induce angiogenesis after AMI through initiating ROS–ER stress‐autophagy axis in the vascular endothelial cells.
Pharmacogenetic Profile and the Occurrence of Visual Hallucinations in Patients With Sporadic Parkinson's Disease
Authors: Damasceno dos Santos Erinaldo Ubirajara , Duarte Elaine Bandeira Cavalcanti , Miranda Laura Maria Ramos , Asano Amdore Guescel C. , Asano Nadja Maria Jorge , Maia Maria De Mascena Diniz , de Souza Paulo Roberto Eleutério
Published: February 2019

Visual hallucinations are significant nonmotor symptoms in the course of treatment of Parkinson's disease. Previous studies have shown that the interindividual variability and pharmacogenetic profile of Parkinson's disease patients seem to influence the occurrence of visual hallucinations. In our study, we investigated a possible relationship of sequence variants in DRD1, DRD2, DRD3, DAT1, and COMT genes with the presence of visual hallucinations in Parkinson's disease patients. A total of 224 Brazilian patients from the Pro‐Parkinson service at the Clinical Hospital of the University of Pernambuco, diagnosed with sporadic Parkinson's disease, were enrolled. Parkinson's disease patients were divided into 2 groups based on the presence or absence of visual hallucinations. The sequence variants for DRD1, DRD2, DRD3, DAT1, and COMT were determined through the polymerase chain reaction‐restriction fragment length polymorphism technique. Multiple Poisson regression analyses showed that individuals carrying the DRD3 Ser/Ser and Ser/Gly genotypes presented increased prevalence ratios of visual hallucinations (9.7‐fold and 4.4‐fold, respectively; P < .001). Regarding DAT1 rs28363170, there was a 9.82‐fold increase in the prevalence ratio in patients with the 10/11 genotype, 8.78‐fold for the 10/8 genotype, and 2.44‐fold for the 9/8 genotypes (P < .001, for all). In addition, visual hallucinations were also associated with use of transdermal patches with rotigotine (PR, 3.7; 95%CI, 1.2‐10.9; P = .017) and rasagiline (PR, 2.8; 95%CI, 1.3‐6.0; P = .006). Our results suggest that the genetic variants DRD3 and DAT1, along with other therapeutic confounders, may influence the prevalence ratio of visual hallucinations.
The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor‐α inhibitor
Authors: Suzuki Taketo , Mizoshita Tsutomu , Tanida Satoshi , Sugimura Naomi , Katano Takahito , Nishie Hirotada , Kataoka Hiromi
Published: February 2019

Background and Aim

Tacrolimus (TAC) is an important therapeutic option for remission induction in patients with refractory ulcerative colitis (UC). However, there is little evidence available on long‐term outcomes and maintenance treatments after TAC therapy, especially in cases with previous tumor necrosis factor‐α (TNF‐α) inhibitor therapy.

Methods

Long‐term outcomes and remission induction after TAC treatment were retrospectively examined in refractory UC patients with and without previous TNF‐α inhibitor therapy.

Results

The mean disease activity index and the endoscopic activity index scores decreased significantly during the 12‐week treatment after TAC therapy in both groups, showing a significantly greater decrease in the group without TNF‐α inhibitor therapy than in the group with previous TNF‐α inhibitor therapy. One year or more after TAC therapy, TNF‐α inhibitor and/or azathioprine was used as maintenance therapy in most cases in the group without previous TNF‐α inhibitor treatment, while azathioprine was primarily used in the group with previous TNF‐α inhibitor treatment. Colectomy was performed in 45.5% (5/11) and 15.6% (7/45) of the groups with and without previous TNF‐α inhibitor therapy, respectively, and the group without previous TNF‐α inhibitor treatment had a better colectomy‐free rate than the group with previous TNF‐α inhibitor treatment after TAC therapy on Kaplan–Meier analysis.

Conclusions

TAC is effective for remission induction in refractory UC patients with and without previous TNF‐α inhibitor treatment. Maintenance medication after TAC therapy is an issue for the future, especially in UC cases with previous TNF‐α inhibitor treatment failure.
Synthesis and Pharmacological Investigations of Novel Pyrazolyl and Hydrazonoyl Cyanide Benzimidazole Entities
Authors: Khalifa Mohamed E. , Gobouri Adil A. , Kabli Fahad M. , Altalhi Tariq A. , Almalki Abdulraheem S. A. , Elemshaty Amira M.
Published: February 2019

Various novel benzimidazole entities linked to pyrazolyl and hydrazonoyl cyanide substrates carrying aryl and heteroaryl groups (8a–e to 10a–e) were synthesized using new route syntheses and were focused on their pharmacological evaluation as one of the most important factors for the determination of the activity of these synthesized compounds. The obtained benzimidazoles' series were fully characterized and exhibited remarkable pharmacological activity upon in vitro screening for their antibacterial activity against strains of selected pathogenic Gram‐positive bacteria (Staphylococcus aureus) and Gram‐negative bacteria (Escherichia coli) comparing with Ampicillin and Kanamycin as standard antibacterial agents and against human liver cancer cell lines (HepG2) as antitumor agents as well.
The cholic acid extension study in Zellweger spectrum disorders: Results and implications for therapy
Authors: Klouwer Femke C. C. , Koot Bart G. P. , Berendse Kevin , Kemper Elles M. , Ferdinandusse Sacha , Koelfat Kiran V. K. , Lenicek Martin , Vaz Frédéric M. , Engelen Marc , Jansen Peter L. M. , Wanders Ronald J. A. , Waterham Hans R. , Schaap Frank G. , Poll‐The Bwee Tien
Published: February 2019

Introduction

Currently, no therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes. In a previous study, we showed that oral cholic acid (CA) treatment can suppress bile acid synthesis in ZSD patients and, thereby, decrease plasma levels of toxic C27‐bile acid intermediates, one of the biochemical abnormalities in these patients. However, no effect on clinically relevant outcome measures could be observed after 9 months of CA treatment. It was noted that, in patients with advanced liver disease, caution is needed because of possible hepatotoxicity.

Methods

An extension study of the previously conducted pretest‐posttest design study was conducted including 17 patients with a ZSD. All patients received oral CA for an additional period of 12 months, encompassing a total of 21 months of treatment. Multiple clinically relevant parameters and markers for bile acid synthesis were assessed after 15 and 21 months of treatment.

Results

Bile acid synthesis was still suppressed after 21 months of CA treatment, accompanied with reduced levels of C27‐bile acid intermediates in plasma. These levels significantly increased again after discontinuation of CA. No significant changes were found in liver tests, liver elasticity, coagulation parameters, fat‐soluble vitamin levels or body weight.

Conclusions

Although CA treatment did lead to reduced levels of toxic C27‐bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21 months of treatment. We discuss the implications for CA therapy in ZSD based on these results.
The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy
Authors: Coughlin Curtis R. , Swanson Michael A. , Spector Elaine , Meeks Naomi J. L. , Kronquist Kathryn E. , Aslamy Mezhgan , Wempe Michael F. , van Karnebeek Clara D. M. , Gospe Sidney M. , Aziz Verena G. , Tsai Becky P. , Gao Hanlin , Nagy Peter L. , Hyland Keith , van Dooren Silvy J. M. , Salomons Gajja S. , Van Hove Johan L. K.
Published: February 2019

Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over‐expressed in an E.coli‐based expression system to measure α‐aminoadipic semialdehyde dehydrogenase activity and production of α‐aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under‐diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.
An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency
Authors: O'Callaghan Benjamin , Bosch Annet M. , Houlden Henry
Published: February 2019

Riboflavin transporter deficiency (RTD) is a rare neurological condition that encompasses the Brown‐Vialetto‐Van Laere and Fazio‐Londe syndromes since the discovery of pathogenic mutations in the SLC52A2 and SLC52A3 genes that encode human riboflavin transporters RFVT2 and RFVT3. Patients present with a deteriorating progression of peripheral and cranial neuropathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory compromise which when left untreated can be fatal. Considerable progress in the clinical and genetic diagnosis of RTDs has been made in recent years and has permitted the successful lifesaving treatment of many patients with high dose riboflavin supplementation. In this review, we first outline the importance of riboflavin and its efficient transmembrane transport in human physiology. Reports on 109 patients with a genetically confirmed diagnosis of RTD are then summarized in order to highlight commonly presenting clinical features and possible differences between patients with pathogenic SLC52A2 (RTD2) or SLC52A3 (RTD3) mutations. Finally, we focus attention on recent work with different models of RTD that have revealed possible pathomechanisms contributing to neurodegeneration in patients.
A review on analytical methods for natural berberine alkaloids
Authors: Wang Jiahui , Jiang Yanyan , Wang Bing , Zhang Ning
Published: February 2019

Berberine alkaloids, a group of protoberberine alkaloids under the classification of isoquinoline alkaloids, include berberine, coptisine, palmatine, columbamine, dehydrocorydaline, jatrorrhizine, and epiberberine from natural sources. Studies have shown that berberine alkaloids have various pharmacological functions, such as antibacterial, antiviral, blood pressure‐lowering, hypoglycaemic, antiarrhythmia, and anticancer effects. Therefore, it is worthwhile to develop analytical methods to investigate the pharmacokinetics and activity mechanisms of berberine alkaloids and to study berberine alkaloids more comprehensively. Current analytical methods for berberine alkaloids include liquid chromatography, thin‐layer chromatography, ultraviolet spectroscopy, capillary electrophoresis, and gas chromatography. The most widely used detection method is mass spectrometry. In order to provide a systematic and comprehensive summary and to serve as a reference for the future pharmacokinetics studies and analysis of berberine alkaloids, analytical methods for natural berberine alkaloids that have been used in the past ten years are reviewed here.
Separation of betacyanins from flowers of Amaranthus cruentus L. in a polar solvent system by high‐speed counter‐current chromatography
Authors: Spórna‐Kucab Aneta , Kumorkiewicz Agnieszka , Szmyr Natalia , Szneler Edward , Wybraniec Sławomir
Published: February 2019

Betacyanin extract of Amaranthus cruentus L. flowers was fractionated by semi‐preparative high‐speed counter‐current chromatography in a highly polar solvent system: propan‐1‐ol/acetonitrile/(NH4)2SO4satd. soln/H2O (1.0:0.5:1.2:1.0, v/v/v/v) in tail‐to‐head mode with 76% retention of the stationary phase. The crude extract as well as the fractions containing betacyanins were analyzed by liquid chromatography with tandem mass spectrometry as well as by high‐resolution ion‐trap time‐of‐flight mass spectrometry detection technique for the molecular formulae and multi‐step fragmentation pattern elucidation. Four betacyanins; namely, amaranthin, betanin, 6′‐O‐formyl‐amaranthin, and 6′‐O‐malonyl‐amaranthin as well as their diastereomeric forms differing in the configuration of the C‐15 carbon atom were identified in the fractions. Amaranthin was the dominant pigment in the extract and was additionally analyzed by nuclear magnetic resonance correlation techniques after the counter‐current chromatographic and high‐performance liquid chromatographic isolation. Betacyanins were highly enriched during a single high‐speed counter‐current chromatographic step; therefore, the tentative identification of new compounds for the whole Amaranthaceae family, 6′‐O‐formyl‐amaranthin and 6′‐O‐malonyl‐amaranthin was possible. Different elution profiles of the pigments observed in the counter‐current chromatographic system in comparison to high‐performance liquid chromatography system confirm a complementarity of both the techniques especially in the separation of diastereomeric pairs of betacyanins.