bluuebunny/crossref_metadata_2025 huggingface dataset:
Enantioselective complexation of 1‐phenylethanol with chiral compounds bearing urea moiety
Authors: Cuřínová Petra , Dračínský Martin , Jakubec Martin , Tlustý Martin , Janků Kristýna , Izák Pavel , Holakovský Roman
Published: March 2018

A detailed study of diastereomeric complexes of chiral ureido‐1,1′‐binaphthalene derivatives with chiral 1‐phenylethanol showed that a derivative bearing only one urea unit makes five times more stable complex with (S)‐enantiomer than with (R)‐enantiomer of the alcohol. This phenomenon could be used in chiral discrimination processes. The influence of individual parts of the structure on the complexation properties is shown. The probable structure of diastereomeric complexes based on experimental results and computational methods is proposed.
Minimizing Real Driving Emissions of Heavy Duty Vehicles – Exhaust Systems and Legislation
Authors: von Pyschow Christian , Geißelmann Andreas , Beidl Christian
Published: March 2018

Trotz sich stetig verbessernder Luftqualität werden die gesetzlich vorgeschriebenen Immissionsziele in urbanen Gebieten noch nicht eingehalten. Deshalb sind im Automobilbereich – auch im Bereich der Nutzfahrzeuge – weitere Verschärfungen der Grenzwerte und vor allem der Testprozeduren zur Überprüfung in Betrieb befindlicher Fahrzeuge angedacht bzw. bereits verabschiedet. Für Nutzfahrzeuge werden Verfahren zur Bestimmung von Realemissionen und anstehende Verschärfungen der gesetzlichen Prozeduren vorgestellt sowie mögliche Maßnahmen zur Einhaltung dieser strengeren Auflagen.
Electrocardiographic predictors of validated right ventricular outflow tract septal pacing for correct localization of transthoracic echocardiography
Authors: Wei Huiqiang , Tang Jiaojiao , Chen Dongli , Zhang Qianhuan , Liang Yuanhong , Liu Lie , Wu Shulin , Lin Chunying , Yang Zhiming , Chai Chanjuan
Published: March 2018

Background

Electrocardiographic (ECG) characteristics of true right ventricular outflow tract (RVOT) septal pacing have not been clearly demonstrated.

Hypothesis

We hypothesized that ECG parameters would help operators differentiate true RVOT septum from non‐septal septum.

Methods

We analyzed 151 patients who underwent pacemaker implantation with a ventricular lead in the RVOT. Transthoracic echocardiographic (TTE) determination of pacing sites was applied in all patients after implantation. A 12‐lead ECG was recorded during forced ventricular pacing.

Results

According to TTE orientation, pacing at the RVOT septum was achieved in 94 patients (62.3%). Compared with nonseptal pacing, septal pacing had significantly shorter QRS duration (139.2 ± 18.5 ms vs 155.5 ± 14.7 ms; P < 0.001). More frequent negative or isoelectric QRS vector in lead I (76% vs 32%; P < 0.001), lead II/III R‐wave amplitude ratio < 1 (52% vs 25%; P = 0.001), and aVR/aVL QS‐wave amplitude ratio < 1 (59% vs 32%; P = 0.001) were observed in septal pacing. Transitional zone (TZ) score (3.8 ± 0.96 vs 4.2 ± 0.90; P = 0.004) and TZ index (0.3 ± 0.5 vs 0.6 ± 0.7; P = 0.008) were significantly lower in septal pacing than in nonseptal pacing, respectively. In multivariate analysis, paced QRS duration and negative or isoelectric QRS vector in lead I independently predicted RVOT septal pacing (P < 0.001). At ROC curve analysis, paced QRS duration ≤145 ms identified RVOT septal pacing with 85.1% sensitivity and 78.9% specificity.

Conclusions

This study reveals the heterogeneity of lead placement within the RVOT. Narrower paced QRS duration and negative or isoelectric QRS vector in lead I independently predict RVOT septal pacing.
Identifying Small‐Molecule Binding Sites for Epigenetic Proteins at Domain–Domain Interfaces
Authors: Bowkett David , Talon Romain , Tallant Cynthia , Schofield Chris , von Delft Frank , Knapp Stefan , Bruton Gordon , Brennan Paul E.
Published: March 2018

Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well‐enclosed binding site amenable to small‐molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain–domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognising and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain–domain interfaces. For the tandem plant homeodomain–bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.
A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer
Authors: Pishvaian Michael J. , Slack Rebecca S. , Jiang Wei , He A. Ruth , Hwang Jimmy J. , Hankin Amy , Dorsch‐Vogel Karen , Kukadiya Divyesh , Weiner Louis M. , Marshall John L. , Brody Jonathan R.
Published: March 2018

BACKGROUND

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA‐damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects.

METHODS

A single‐arm, open‐label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies. Fifty patients received temozolomide (150 mg/m2/d) on days 1 to 5 and veliparib (40 mg twice daily) on days 1 to 7 of each 28‐day cycle. Another 5 patients with mismatch repair–deficient (dMMR) tumors were also enrolled. Twenty additional patients were then treated with temozolomide at 200 mg/m2/d. Archived tumor specimens were used for immunohistochemistry to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)‐methylguanine‐DNA methyltransferase (MGMT) protein expression levels.

RESULTS

The combination was well tolerated, although some patients required dose reductions for myelosuppression. The primary endpoint was successfully met with a DCR of 24% and 2 confirmed partial responses. The median progression‐free survival was 1.8 months, and the median overall survival was 6.6 months. PTEN protein expression and MGMT protein expression were not predictors of DCR. There was also a suggestion of worse outcomes for patients with dMMR tumors.

CONCLUSIONS

In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m2/d, and it was clinically active. PARP inhibitor–based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337‐46. © 2018 American Cancer Society.
Long‐term safety and survival with gefitinib in select patients with advanced non–small cell lung cancer: Results from the US IRESSA Clinical Access Program (ICAP)
Authors: Hirsch Fred R. , Sequist Lecia V. , Gore Ira , Mooradian Meghan , Simon George , Croft Elisabeth F. , DeVincenzo Diana , Munley Jiefen , Stein Dara , Freivogel Klaus , Sifakis Frangiscos , Bunn Paul A.
Published: March 2018

BACKGROUND

This is the first report of long‐term (>10 years) safety, tolerability, and survival data on patients with non–small cell lung cancer (NSCLC) who received treatment with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.

METHODS

Patients with advanced NSCLC (N = 191) who entered the IRESSA Clinical Access Program (ICAP) (June 2011 to January 2013) and had previously obtained a clinical benefit from gefitinib therapy (including patients who had received gefitinib since 2001) were analyzed for adverse events (AEs). A subset of patients (n = 79) underwent retrospective chart review to capture demographic, safety, and survival data.

RESULTS

Seventy‐five of 191 patients (39%) remained on long‐term gefitinib therapy as of September 2016. Overall, serious AEs (SAEs) were reported in 64 patients (34%), the majority of which were attributed to underlying disease or comorbidities; only 3 patients (1.6%) had SAEs that were considered as possibly gefitinib‐related. In the retrospective chart review cohort, 70% of patients were women; 58% were former smokers, and 30% were never‐smokers; 56% were diagnosed with adenocarcinoma, and 13% were diagnosed with squamous carcinoma. Although EGFR mutational status was tested in only 17 patients (22%), it was assumed that most tumors were EGFR‐mutation‐positive. The median duration of gefitinib therapy was 11.1 years (7.8 years before and 3.5 years during ICAP), with 10‐year and 15‐year survival rates of 86% and 59%, respectively, from the initiation of therapy.

CONCLUSIONS

A subset of long‐term NSCLC survivors who were receiving gefitinib had an excellent long‐term safety profile. Although it is assumed that most of these patients' tumors harbor EGFR mutations, molecular studies of available tumor specimens are planned to uncover the features that predict long‐term survival. Cancer 2018;124:2407‐14. © 2018 American Cancer Society.
Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results
Authors: Hu Jiyi , Bao Cihang , Gao Jing , Guan Xiyin , Hu Weixu , Yang Jing , Hu Chaosu , Kong Lin , Lu Jiade J.
Published: March 2018

BACKGROUND

Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (NPC) after a definitive dose of radiotherapy (RT) is challenging and usually associated with severe toxicities. Intensity‐modulated carbon ion RT (IMCT) offers physical/biologic advantages over photon‐based intensity‐modulated RT. Herein, the authors report their initial experience of IMCT in previously irradiated patients with locoregionally recurrent NPC.

METHODS

Patients with locoregionally recurrent, poorly differentiated or undifferentiated NPC who underwent salvage therapy with IMCT at the Shanghai Proton and Heavy Ion Center between May 2015 and August 2017 were included in the current study. The IMCT doses were 50 to 66 Gray equivalent (GyE) (2.0‐3.0 GyE/daily fraction), delivered via raster scanning technology. The 1‐year overall survival, disease‐specific survival, progression‐free survival (PFS), local recurrence‐free survival, regional recurrence‐free survival, and distant metastasis‐free survival were calculated. Univariate and multivariate analyses of PFS were performed to identify possible predictive factors.

RESULTS

Among the 75 patients included, 4 patients, 14 patients, 29 patients, and 28 patients, respectively, had recurrent American Joint Committee on Cancer stage I, stage II, stage III, and stage IVA/B disease. With a median follow‐up of 15.4 months (range, 2.6‐29.7 months), the 1‐year overall survival, disease‐specific survival, PFS, local recurrence‐free survival, regional recurrence‐free survival, and distant metastasis‐free survival rates were 98.1%, 98.1%, 82.2%, 86.6%, 97.9%, and 96.2%, respectively. A higher fraction size of 3 GyE (vs <3 GyE) or a higher biological equivalent dose significantly improved the PFS rate on univariate analysis, but not on multivariate analysis. No patient developed acute toxicity of grade ≥2 during IMCT. Late treatment‐induced severe (grade 3 or 4) toxicities were infrequent, but included mucosal necrosis (9.3%), xerostomia (1.3%), and temporal lobe necrosis (1.3%).

CONCLUSIONS

This initial experience in the first 75 patients with locoregionally recurrent NPC was encouraging. Carbon ion RT could provide promising survival rates with infrequent severe toxicities for patients with locoregionally recurrent NPC. Cancer 2018;124:2427‐37. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Partitioning of the primate intraparietal cortex based on connectivity pattern and immunohistochemistry for Cat‐301 and SMI‐32
Authors: Mariani Otavio S. C. , Lima Bruss , Soares Juliana G. M. , Mayer Andrei , Franca João G. , Gattass Ricardo
Published: March 2018

We propose a partitioning of the primate intraparietal sulcus (IPS) using immunoarchitectural and connectivity criteria. We studied the immunoarchitecture of the IPS areas in the capuchin monkey using Cat‐301 and SMI‐32 immunohistochemistry. In addition, we investigated the IPS projections to areas V4, TEO, PO, and MT using retrograde tracer injections in nine hemispheres of seven animals. The pattern and distribution of Cat‐301 and SMI‐32 immunostaining revealed multiple areas in the IPS, in the adjoining PO cleft and in the annectant gyrus, with differential staining patterns found for areas V3d, DM, V3A, DI, PO, POd, CIP‐1, CIP‐2, VIPa, VIPp, LIPva, LIPvp, LIPda, LIPdp, PIPv, PIPd, MIPv, MIPd, AIPda, AIPdp, and AIPv. Areas V4, TEO, PO, MT, which belong to different cortical streams of visual information processing, receive projections from at least twenty different areas within the IPS and adjoining regions. In six animals, we analyzed the distribution of retrogradely labeled cells in tangential sections of flat‐mount IPS preparations. The lateral bank of the IPS projects to regions belonging both to the ventral (V4 and TEO) and dorsal (PO and MT) streams. The region on the floor of the IPS (i.e., VIP) projects predominantly to dorsal stream areas. Finally, the medial bank of the IPS (i.e., MIP) projects solely to the dorsalmedial stream (PO). Therefore, our data suggest that ventral and dorsal streams remain segregated within the IPS, and that its projections to the dorsal stream can be further segregated based on those targeting the dorsolateral versus the dorsomedial subdivisions.
Parallel rule‐based selective sampling and on‐demand learning to rank
Authors: e Freitas Mateus F. , Sousa Daniel X. , Martins Wellington S. , Rosa Thierson C. , Silva Rodrigo M. , Gonçalves Marcos A.
Published: March 2018

Learning to rank (L2R) works by constructing a ranking model from training data so that, given a new query, the model is able to generate an effective rank of the objects for the query. Almost all work in L2R focus on ranking accuracy leaving performance and scalability overlooked. However, performance is a critical factor, especially when dealing with on‐demand queries. In this scenario, Learning to Rank using association rules has been shown to be extremely effective but only at a high computational cost. In this work, we show how to exploit parallelism on rule‐based systems to: i) drastically reduce L2R training datasets using selective sampling and ii) to generate query customized ranking models on the fly. We present parallel algorithms and GPU implementations for these two tasks showing that dataset reduction takes only a few seconds with speedups up to 148x over a serial baseline, and that queries can be processed in only a few milliseconds with speedups of 1000x over a serial baseline and 29x over a parallel baseline for the best case. We also extend the implementations to work with multiple GPUs, further increasing the speedup over the baselines and showing the scalability of our proposed algorithms.
Quantification of alignment of vascular smooth muscle cells
Authors: Dorta Marcel P. , de Brito Isis V. , Pereira Alexandre C. , Alencar Adriano M.
Published: March 2018

Vascular smooth muscle cells (VSMCs) are essential components that keep the tonus of the arterial network, which is the channel used to conduct the blood from the heart to the peripheral areas of the body. It is known that mechanical and architectural changes in VSMCs may lead to functional modifications in the cardiovascular system; therefore, the quantitative characterization of these changes can help to elucidate questions that remain unclear in pathological situations, such as hypertension, vasospasm, vascular hypertrophy, and atherosclerosis. In this work, we have developed a new framework of image processing using the Sobel operator, associated with statistical analysis, to determine the degree of local alignment of actin filaments, which we found to be directly related with the distensibility of the arterial wall. We have also compared these results with the rigidity of the cytoskeleton of VSMCs. The results suggest that the alignment degree increases from peripheral arteries, such as carotid and femoral, to central arteries, as well coronary and thoracic aorta, which can indicate that the level of local alignment of the actin fibers in VSMCs is related with the mechanical behavior of the arterial wall. © 2018 International Society for Advancement of Cytometry
Hepatic and cardiac beneficial effects of a long‐acting Fc‐apelin fusion protein in diet‐induced obese mice
Authors: Wang Weimin , Zhang Dongming , Yang Rongze , Xia Wei , Qian Kun , Shi Zhengrong , Brown Robert , Zhou Huifen , Xi Yue , Shi Lin , Chen Ling , Xu Feng , Sun Xiaojian , Zhu Dalong , Gong Da‐Wei
Published: March 2018

Background

Apelin is a peptide ligand of the G‐protein‐coupled receptor APJ and exhibits anti‐diabetes and anti‐heart failure activities. However, short serum half‐life of the apelin peptide limits its potential clinical applications. This study aimed to develop a long‐acting apelin analog.

Methods

To extend apelin's in vivo half‐life, we made a recombinant protein by fusing the IgG Fc fragment to apelin‐13 (Fc‐apelin‐13), conducted pharmacokinetics studies in mice, and determined in vitro biological activities in suppressing cyclic adenosine monophosphate and activating extracellular signal‐regulated kinase signalling by reporter assays. We investigated the effects of Fc‐apelin‐13 on food intake, body weight, fasting blood glucose and insulin levels, glucose tolerance test, hepatic steatosis, and cardiac function and fibrosis by subcutaneous administration of Fc‐apelin‐13 in diet‐induced obese mice for 4 weeks.

Results

The estimated half‐life of Fc‐apelin‐13 in blood was approximately 33 hours. Reporter assays showed that Fc‐apelin‐13 was active in suppressing cyclic adenosine monophosphate response element and activating serum response element activities. Four weeks of Fc‐apelin‐13 treatment in obese mice did not affect food intake and body weight, but resulted in a significant improvement of glucose tolerance, and a decrease in hepatic steatosis and fibrosis, as well as in serum alanine transaminase levels. Moreover, cardiac stroke volume and output were increased and cardiac fibrosis was decreased in the treated mice.

Conclusions

Fc‐apelin‐13 fusion protein has an extended in vivo half‐life and exerts multiple benefits on obese mice with respect to the improvement of glucose disposal, amelioration of liver steatosis and heart fibrosis, and increase of cardiac output. Hence, Fc‐apelin‐13 is potentially a therapeutic for obesity‐associated disease conditions.
Metabolism study for CUMYL‐4CN‐BINACA in human hepatocytes and authentic urine specimens: Free cyanide is formed during the main metabolic pathway
Authors: Åstrand Anna , Vikingsson Svante , Lindstedt Daniel , Thelander Gunilla , Gréen Henrik , Kronstrand Robert , Wohlfarth Ariane
Published: March 2018

To further elucidate the metabolism of CUMYL‐4CN‐BINACA, a new synthetic cannabinoid with a cyano group, and to evaluate biomarkers, we incubated the substance in human hepatocytes and analysed 9 authentic urine specimens. We also quantified CUMYL‐4CN‐BINACA and cyanide in blood and provide comprehensive data on the 7 autopsy cases, 5 of them determined CUMYL‐4CN‐BINACA intoxications. For metabolite elucidation, CUMYL‐4CN‐BINACA was incubated with pooled human hepatocytes for up to 5 hours, urine samples were analysed with and without enzymatic hydrolysis. Data was acquired in data‐dependent mode by ultra‐high performance liquid chromatography–high resolution mass spectrometry (UHPLC–HRMS) with an Agilent 6550 QTOF. For quantitative analysis of CUMYL‐4CN‐BINACA, blood samples were precipitated and analysed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Cyanide was determined by gas chromatography–headspace–nitrogen phosphorus detection (GC–headspace–NPD). CUMYL‐4CN‐BINACA was metabolised via CYP450‐mediated hydroxylation at 4‐butyl position generating a cyanohydrin (M12), which releases free cyanide to form an aldehyde intermediate and eventually generates 4‐hydroxybutyl CUMYL‐BINACA (M11) and CUMYL‐BINACA butanoic acid (M10). Other minor metabolites were produced by hydroxylation, dihydroxylation, N‐dealkylation, and dihydrodiol formation; glucuronidation was observed. One urine sample showed high intensities of M10 and a wide variety of metabolites; the other samples contained fewer metabolites in low abundance and 1 sample showed no metabolites. CUMYL‐4CN‐BINACA blood concentrations ranged from 0.1 to 8.3 ng/g showing an overlap between fatal and non‐fatal concentrations. One blood sample contained 0.36 μg/g cyanide. Release of free cyanide during metabolism is worrying as it might induce liver toxicity. As suggested earlier, CUMYL‐BINACA butanoic acid is the most abundant biomarker in urine, but monitoring of additional metabolites or, even better, analysis for the parent in blood is recommended.
Effects of sodium‐glucose cotransporter 2 inhibitor, tofogliflozin, on the indices of renal tubular function in patients with type 2 diabetes
Authors: Nunoi Kiyohide , Sato Yuichi , Kaku Kohei , Yoshida Akihiro , Suganami Hideki
Published: March 2018

Aims

Little is known of the effect of sodium‐glucose cotransporter 2 (SGLT2) inhibitors on the renal tubules. We investigated the effect of the SGLT2 inhibitor, tofogliflozin (TOFO) on renal tubular indices, according to the degree of albuminuria, in type 2 diabetes mellitus (T2DM) patients with preserved renal function.

Materials and methods

A total of 988 patients, receiving TOFO, were enroled and divided into 3 groups, based on the urine albumin‐to‐creatinine ratio (UACR). The tubular indices (urinary N‐acetyl‐beta‐d‐glucosaminidase [NAG]‐to‐creatinine and urinary beta‐2 microglobulin [beta2MG]‐to‐creatinine ratios) and UACR were log‐transformed in the correlation analysis.

Results

Treatment with TOFO led to similar reductions in glycated haemoglobin (HbA1c) levels, from baseline to week 24, across all groups. The NAG level increased in the normoalbuminuria group and decreased in the macroalbuminuria group significantly (P < .001, both), but did not change in the microalbuminuria group. Significant reductions in the UACR were observed in both microalbuminuria and macroalbuminuria groups (P < .001, both). Significant negative correlations between changes in the NAG and beta2MG levels and their corresponding baseline values were observed in all participants. The reduction in the UACR was negatively correlated with baseline levels. The changes in the tubular indices were positively correlated with reductions in the UACR across groups.

Conclusions

Logarithmic reductions in the renal tubular indices, via SGLT2 inhibition, were observed in patients with T2DM. TOFO may not only improve the degree of albuminuria but may also have protective effects on the tubules.
Energetic Functionalized Azido/Nitro Imidazole Fused 1,2,3,4‐Tetrazine
Authors: Tang Yongxing , He Chunlin , Yin Ping , Imler Gregory H. , Parrish Damon A. , Shreeve Jean'ne M.
Published: March 2018

Despite the high potential of the azo‐coupled fused tricyclic 1,2,3,4‐tetrazine ring system in energetic materials, there are only very limited examples of such a scaffold. The oxidation of di‐N‐amino compound 1 with tert‐butyl hypochlorite (tBuOCl) gives rise to the unexpected chloro‐substituted compound 2, which behaves as a precursor to the structurally attractive diazido/nitro‐substituted fused tricyclic 1,2,3,4‐tetrazine 3. The structure is well characterized and is supported by single‐crystal X‐ray diffraction. Compound 3 was found to be a highly energetic and sensitive explosive.
Comorbidity between pain and mental illness – Evidence of a bidirectional relationship
Authors: Bondesson E. , Larrosa Pardo F. , Stigmar K. , Ringqvist Å. , Petersson I.F. , Jöud A. , Schelin M.E.C.
Published: March 2018

Background

Pain from various locations in the body and mental illness are common and the comorbidity between the two is well‐known although the temporal relationship remains to be determined. Our aim was to follow patients over time to study if pain (here dorsalgia/abdominal pain) or fibromyalgia lead to an increased risk of developing mental illness (here depression/anxiety) and/or the reverse, that is whether patients with mental illness have an increased risk to develop pain or fibromyalgia, compared to the rest of the population.

Methods

This prospective cohort study used the Skåne Healthcare Register, covering all care in the region of Skåne, southern Sweden (population ~1.3 million). The cohort included healthcare consultations in primary care, outpatient specialized care and inpatient care between 2007 and 2016 for all patients without prior registered diagnosis of mental illness or pain, aged 18 or older (n = 504,365).

Results

The incidence rate ratio (IRR) for developing mental illness after pain was 2.18 (95% CI = 2.14–2.22) compared to without pain. IRR for developing pain after mental illness was 2.02 (95% CI = 1.98–2.06) compared to without mental illness. Corresponding IRR for developing mental illness after fibromyalgia was 4.05 (95% CI = 3.58–4.59) and for developing fibromyalgia after mental illness 5.54 (95% CI = 4.99–6.16).

Conclusions

This study shows a bidirectional influence of similar magnitude of pain and mental illness, respectively. In monitoring patients with pain or mental illness, a focus on both conditions is thus important to develop appropriate, targeted interventions and may increase the likelihood of improved outcomes.

Significance

We followed a population‐based cohort over a period of 10 years, including incident cases of both exposure and outcome and found a bidirectional relationship between pain and mental illness. Clinicians need to pay attention on both conditions, in patients seeking care due to mental illness or pain.
Transcranial direct current stimulation for upper limb neuropathic pain: A double‐blind randomized controlled trial
Authors: Lewis G.N. , Rice D.A. , Kluger M. , McNair P.J.
Published: March 2018

Background

While promising, there are mixed findings for the efficacy of transcranial direct current stimulation (tDCS) for the management of chronic pain. The goal of this study was to evaluate the effect of anodal tDCS on pain and function in people with upper limb neuropathic pain.

Methods

The study was a double‐blinded, randomized controlled trial. Thirty participants were randomly allocated into active and sham tDCS groups. Baseline assessments of pain and function, as well as quantitative sensory testing (QST) to probe the function of the nociceptive system, were undertaken prior to participants receiving 5 days of active or sham anodal tDCS (1 mA) over the primary motor cortex. The outcome measures were re‐assessed 1, 3 and 8 weeks following the intervention.

Results

Group analyses revealed no significant improvement in pain, function, or QST measures over time in either group. However, there were significantly more individual responders (≥30% change in pain) in the active compared to the sham tDCS group at the final follow‐up. In the active group, there was a significant correlation indicating those with higher baseline pain had greater pain relief.

Conclusions

On group analyses, no evidence was provided that 1 mA tDCS is beneficial for people with upper limb neuropathic pain, although it may provide lasting pain relief for some individuals.

Significance

At the group level, we found no evidence that 5 days of active 1 mA tDCS is effective for people with upper limb neuropathic pain. However, there were more individual responders in the active tDCS group compared to sham, and those who responded early after treatment experienced sustained pain relief.
Efficacy and safety of a T‐type calcium channel blocker in patients with neuropathic pain: A proof‐of‐concept, randomized, double‐blind and controlled trial
Authors: Kerckhove N. , Pereira B. , Soriot‐Thomas S. , Alchaar H. , Deleens R. , Hieng V.S. , Serra E. , Lanteri‐Minet M. , Arcagni P. , Picard P. , Lefebvre‐Kuntz D. , Maindet C. , Mick G. , Balp L. , Lucas C. , Creach C. , Letellier M. , Martinez V. , Navez M. , Delbrouck D. , Kuhn E. , Piquet E. , Bozzolo E. , Brosse C. , Lietar B. , Marcaillou F. , Hamdani A. , Leroux‐Bromberg N. , Perier Y. , Vergne‐Salle P. , Gov C. , Delage N. , Gillet D. , Romettino S. , Richard D. , Mallet C. , Bernard L. , Lambert C. , Dubray C. , Duale C. , Eschalier A.
Published: March 2018

Background

T‐type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T‐type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain.

Methods

This proof‐of‐concept, multicentre, double‐blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add‐on therapy) to an inactive control (IC) in 114 patients with non‐diabetic peripheral neuropathic pain. After a 7‐day run‐in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention‐to‐treat population. This study is registered with EudraCT (2013‐004801‐26) and ClinicalTrials.gov (NCT02100046).

Results

The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per‐protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI −25.8; −5.4) from baseline compared to IC (−7.8%, 95% CI −14.3; −1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients.

Conclusion

Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events.

Significance

This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per‐protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T‐type calcium channel inhibition for the treatment of neuropathic pain.
Occurrence of filamentous fungi in maize destined for human consumption in South Africa
Authors: Ekwomadu Theodora I. , Gopane Ramokone E. , Mwanza Mulunda
Published: March 2018

One‐hundred maize samples were analyzed for fungal contamination using conventional and molecular methods. The percentage incidence of different genera isolated revealed the predominance of Fusarium (82%), Penicillium (63%), and Aspergillus species (33%) compared to other genera. Fusarium occurred in 90% and 74% of small scale and commercial samples, respectively, while Penicillium occurred in small scale and commercial samples at an incidence rate of 64% and 62%, respectively. However, among the species, Fusarium verticilloides have the highest incidence of 70% and 76% in commercial and small‐scale maize, respectively, while Penicillium digitatum has 56% total incidence. Aspergillus fumigatus (27%) were also the most dominant of these genera. Fungal genera isolated included Alternaria and Cladosporium although occurring at a lower incidence level of 30%, 32% and 16%, 20%, respectively, in small‐scale and commercial samples. The results emphasize that farmers and consumers should be alerted to the danger of fungal contamination in maize.
Revisiting the rigor–relevance relationship: An institutional logics perspective
Authors: Paterson Ted A. , Harms P. D. , Tuggle Christopher S.
Published: March 2018

The question of whether academic research should emphasize scientific rigor, practical relevance, or both simultaneously has been hotly debated in HRM research and other related disciplines for much of the past century. That said, empirical investigations of whether these values are mutually exclusive or compatible are surprisingly rare. Moreover, the perspective of the end consumers of research—practitioners—as to what research is relevant has been almost completely ignored. In the present study, we adopt an institutional logics perspective to assess the perceived relevance of common management research findings with two samples of 298 and 143 practicing managers, respectively. Further, we examine whether objective indicators of rigor and manager‐rated relevance impact academic legitimacy. The results indicate a positive relationship between rigor and relevance. Interestingly, practitioner ratings of relevance were stronger predictors of academic legitimacy than methodological rigor. Finally, research findings that deal with leadership topics are rated as most relevant to practitioners, whereas job characteristics, demographics, and human resource practices are seen as the least relevant to managers. The contributions of this study and implications for future research conclude the article.
Unethical behavior under relative performance evaluation: Evidence and remedy
Authors: Tzini Konstantina , Jain Kriti
Published: March 2018

Relative performance evaluation, wherein the performance of employees is evaluated relative to the performance of their peers, is popular within organizations. In this article, we report four experimental studies to explore the impact that such an evaluation system has on unethical behavior. We find that participants under relative performance evaluation expect others to be more likely to use unethical means (Study 1) and indulge more in unethical behavior themselves (Study 2). Drawing on these results, in Study 3 we propose a technique that we call consequential reflection to reduce intentions of unethical behavior, and we also test for the mediating role of perceived risks and benefits. In Study 4, we explore how individual differences in rational–intuitive decision‐making styles moderate the effectiveness of consequential reflection. Overall, the article provides evidence of moral side effects of relative performance evaluation. Furthermore, keeping in mind the constraints and needs of practitioners, we suggest a simple intervention to curb tendencies toward unethical behavior.
Alternative splice variants of DCLK1 mark cancer stem cells, promote self‐renewal and drug‐resistance, and can be targeted to inhibit tumorigenesis in kidney cancer
Authors: Ge Yang , Weygant Nathaniel , Qu Dongfeng , May Randal , Berry William L. , Yao Jiannan , Chandrakesan Parthasarathy , Zheng Wei , Zhao Lichao , Zhao Karena L. , Drake Michael , Vega Kenneth J. , Bronze Michael S. , Tomasek James J. , An Guangyu , Houchen Courtney W.
Published: March 2018

Renal cell carcinoma (RCC) is a common and devastating disease characterized by a hypoxic microenvironment, epithelial‐mesenchymal transition and potent resistance to therapy evidencing the presence of cancer stem cells (CSCs). Various CSC markers have been studied in RCC, but overall there is limited data on their role and most markers studied have been relatively nonspecific. Doublecortin‐like kinase 1 (DCLK1) is a validated CSC marker in the gastrointestinal tract and evidence for an equivalent role in other cancers is accumulating. We used bioinformatics, immunohistochemistry, flow cytometry, spheroid self‐renewal and chemoresistance assays in combination with overexpression and siRNA‐knockdown to study the stem cell‐supportive role of DCLK1 alternative splice variants (DCLK1 ASVs) in RCC. To target tumor cells expressing DCLK1 ASVs directly, we developed a novel monoclonal antibody (CBT‐15) and delivered it systemically to RCC tumor xenografts. DCLK1 ASVs were overexpressed, enriched together with CSC markers and predictive of overall and recurrence‐free survival in RCC patients. In vitro, DCLK1 ASVs were able to directly stimulate essential molecular and functional characteristics of renal CSCs including expression of aldehyde dehydrogenase, self‐renewal and resistance to FDA‐approved receptor tyrosine kinase and mTOR inhibitors, while targeted downregulation of DCLK1 reversed these characteristics. Finally, targeting DCLK1 ASV‐positive cells with the novel CBT‐15 monoclonal antibody blocked RCC tumorigenesis in vivo. These findings establish DCLK1 as a CSC marker with implications for therapy, disease progression and survival in RCC and demonstrate the therapeutic value of DCLK1‐targeted monoclonal antibodies against renal CSCs.
The digital Thailand strategy and the ASEAN community
Authors: Wongwuttiwat Jittima , Lawanna Adtha
Published: March 2018

The progress of Thailand's development needs to be monitored especially in the environment of the ASEAN Economic Community which started formally at the end of the year 2015. Furthermore, Thailand has also established the Thailand 4.0 strategy in alignment with the Thailand 12th Social and Economic Development Plan (2017–2021) and the ASEAN ICT Master Plan in order to drive the Thailand economy into a high‐income country and to be an ASEAN regional center. Because of the efficiency and effectiveness of ICT that can stimulate and support in most work areas, ICT aims to be the foundation of the country's development in other aspects. Thus, Thailand's Ministry of ICT has launched various ICT policies and programs for ICT administrators of different economic sectors because ICT has been considered as an engine of country development, and this causes Thailand to rely more on the adoption of ICT in various sectors. This study focuses on the progression of ICT development and investments, country infrastructures, the quality of the higher education system, business sophistication, and innovation, which are considered as the principal components of Thailand 4.0 strategy. The findings may assist the responsible authorities in both public and private organizations in monitoring, understanding, and expediting strategies and operations in order to achieve the objectives of Thailand 4.0 and to obtain competitive advantages across the ASEAN Economic Community. Furthermore, the findings also help to detect improvement of the Thailand's performance with respect to the 5 components development relative to the other ASEAN economies.
Benzo[a]pyrene‐decreased gap junctional intercellular communication via calcium/calmodulin signaling increases apoptosis in TM4 cells
Authors: Ji Xiaoli , Chou Xin , Ge Zehe , Ding Fan , Gao Hui , Wu Qing
Published: March 2018

The mechanism of male reproductive toxicity induced by benzo[a]pyrene (BaP) is poorly understood. Gap junctional intercellular communication (GJIC) is known to play a critical role in maintaining spermatogenesis. The aim of the present study was to determine the toxic effects of BaP in Sertoli cells, and to explore the possibility and potential mechanisms of BaP‐induced changes in the level of GJIC, and the relationship between GJIC and BaP‐induced apoptosis. We treated mouse Sertoli cell lines (TM4) with different concentrations (0.1–100 μm) of BaP for 1–48 hours, and found that GJIC exhibited a dose‐ and time‐dependent downregulation. Treatment with 10 μm BaP increased apoptosis, intracellular Ca2+ level ([Ca2+]i) and calmodulin (CaM) protein expression, and decreased the protein level of connexin 43 (Cx43) (also known as gap junction α‐1 protein [GJA1]) in TM4 cells. However, BaP had no effect on the phosphorylation of Cx43 at Ser279/282, Ser255, Ser368 or Ser262. Downregulation of [Ca2+]i by BAPTA‐AM significantly attenuated the BaP‐induced GJIC suppression, Cx43 protein decrease and CaM protein increase. Interestingly, inhibition of CaM expression by W7 partially recovered BaP‐induced GJIC inhibition, but had no effect on BaP‐induced Cx43 protein decrease. Pretreatment with the GJIC activator retinoic acid significantly mitigated BaP‐induced apoptosis. In conclusion, these results suggest that BaP can decrease GJIC via Ca2+/CaM signaling, and that BaP‐induced GJIC suppression increases apoptosis in TM4 cells.
Effects of antigen removal on a porcine osteochondral xenograft for articular cartilage repair
Authors: Elder Steve , Chenault Hudson , Gloth Paul , Webb Katie , Recinos Ruth , Wright Emily , Moran Dalton , Butler James , Borazjani Abdolsamad , Cooley Avery
Published: March 2018

Given the limited availability of fresh osteochondral allografts and uncertainty regarding performance of decellularized allografts, this study was undertaken as part of an effort to develop an osteochondral xenograft for articular cartilage repair. The purpose was to evaluate a simple antigen removal procedure based mainly on treatment with SDS and nucleases. Histology demonstrated a preservation of collagenous structure and removal of most nuclei. Immunohistochemistry revealed the apparent retention of α‐Gal within osteocyte lacunae unless the tissue underwent an additional α‐galactosidase processing step. Cytoplasmic protein was completely removed as shown by Western blot. Quantitatively, the antigen removal protocol was found to extract approximately 90% of DNA from cartilage and bone, and it extracted over 80% of glycosaminoglycan from cartilage. Collagen content was not affected. Mechanical testing of cartilage and bone were performed separately, in addition to testing the cartilage–bone interface, and the main effect of antigen removal was an increase in cartilage hydraulic permeability. In vivo immunogenicity was assessed by subcutaneous implantation into DBA/1 J mice, and the response was typical of a foreign body rather than immune reaction. Thus, an osteochondral xenograft produced as described has the potential for further development into a treatment for osteochondral lesions in the human knee. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2251‐2260, 2018.
A MMP7‐sensitive photoclickable biomimetic hydrogel for MSC encapsulation towards engineering human cartilage
Authors: Aisenbrey Elizabeth A. , Bryant Stephanie J.
Published: March 2018

Cartilage tissue engineering strategies that use in situ forming degradable hydrogels for mesenchymal stem cell (MSC) delivery are promising for treating chondral defects. Hydrogels that recapitulate aspects of the native tissue have the potential to encourage chondrogenesis, permit cellular mediated degradation, and facilitate tissue growth. This study investigated photoclickable poly(ethylene glycol) hydrogels, which were tailored to mimic the cartilage microenvironment by incorporating extracellular matrix analogs, chondroitin sulfate and RGD, and crosslinks sensitive to matrix metalloproteinase 7 (MMP7). Human MSCs were encapsulated in the hydrogel, cultured up to nine weeks, and assessed by mRNA expression, protein production and biochemical analysis. Chondrogenic genes, SOX9, ACAN, and COL2A1, significantly increased with culture time, and the ratios of COL2A1:COL10A1 and SOX9:RUNX2 reached values of ∼20–100 by week 6. The encapsulated MSCs degraded the hydrogel, which was nearly undetectable by week 9. There was substantial deposition of aggrecan and collagen II, which correlated with degradation of the hydrogel. Minimal collagen X was detectable, but collagen I was prevalent. After week 1, extracellular matrix elaboration was accompanied by a ∼twofold increase in compressive modulus with culture time. The MMP7‐sensitive cartilage mimetic hydrogel supported MSC chondrogenesis and promoted macroscopic neocartilaginous matrix elaboration representative of fibrocartilage. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2344‐2355, 2018.
Influence of CuO/MgO ratio on the gene expression, cytocompatibilty, and antibacterial/anticancerous/analgesic drug loading kinetics for (15‐x) CuO‐xMgO‐10P2O5‐60SiO2‐10CaO‐5ZnO (2.5 ≤ x ≤ 12.5) mesoporous bioactive glasses
Authors: Bains Rupinderjeet , Sharma Piyush , Mir Rameez Ahmad , Jeet Suninder , Kaur Gurbinder , Pandey Om Prakash
Published: March 2018

In the present study, novel mesoporous bioactive glasses (MBGs) (15‐x)CuO‐xMgO‐10P2O5‐60SiO2‐10CaO‐5ZnO (2.5 ≤ x ≤ 12.5, varying in steps of 2) are synthesized using the sol‐gel technique. The structural phases of the glasses/glass ceramics were studied by XRD. The pH variation and simulated body fluids (SBF) studies demonstrated the in‐vitro bioactivity of all the MBGs. MBGs possess surface area variation between 98.22 and 442.41 cm2/g. The pore size of MBGs lies in the range of 5.8–8.8 nm. The cytotoxicity assays were conducted for MG63 human osteosarcoma cell line depicting non‐toxic behavior of all MBGs at 7.8125 μg/ml. In addition to this, the effect of the magnesium on the gene expression was also investigated using reverse transcription–polymerase chain reaction (RT‐qPCR). The MBGs were loaded with the antibacterial (vancomycin/amoxicillin), anticancerous (doxorubicin), and analgesic (Iburofen) drugs. Ibuprofen and amoxicillin drugs were almost fully loaded in all the MBGs, whereas doxorubicin and vancomycin drugs illustrated variation in loading with decreasing copper content. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2116‐2130, 2018.
High-Impact Mechanical Loading Increases Bone Material Strength in Postmenopausal Women—A 3-Month Intervention Study
Authors: Sundh Daniel , Nilsson Martin , Zoulakis Michail , Pasco Courtney , Yilmaz Melis , Kazakia Galateia J , Hellgren Martin , Lorentzon Mattias
Published: March 2018

Bone adapts to loading in several ways, including redistributing bone mass and altered geometry and microarchitecture. Because of previous methodological limitations, it is not known how the bone material strength is affected by mechanical loading in humans. The aim of this study was to investigate the effect of a 3-month unilateral high-impact exercise program on bone material properties and microarchitecture in healthy postmenopausal women. A total of 20 healthy and inactive postmenopausal women (aged 55.6 ± 2.3 years [mean ± SD]) were included and asked to perform an exercise program of daily one-legged jumps (with incremental number, from 3×10 to 4×20 jumps/d) during 3 months. All participants were asked to register their performed jumps in a structured daily diary. The participants chose one leg as the intervention leg and the other leg was used as control. The operators were blinded to the participant's choice of leg for intervention. The predefined primary outcome was change in bone material strength index (BMSi), measured at the mid tibia with a handheld reference probe indentation instrument (OsteoProbe). Bone microstructure, geometry, and density were measured with high-resolution peripheral quantitative computed tomography (XtremeCT) at the ultradistal and at 14% of the tibia bone length (distal). Differences were analyzed by related samples Wilcoxon signed rank test. The overall compliance to the jumping program was 93.6%. Relative to the control leg, BMSi of the intervention leg increased 7% or 0.89 SD (p = 0.046), but no differences were found for any of the XtremeCT-derived bone parameters. In conclusion, a unilateral high-impact loading program increased BMSi in postmenopausal women rapidly without affecting bone microstructure, geometry, or density, indicating that intense mechanical loading has the ability to rapidly improve bone material properties before changes in bone mass or structure. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.