bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of a single dose of furosemide
Authors: Ayalasomayajula Surya , Schuehly Uwe , Pal Parasar , Chen Fabian , Zhou Wei , Sunkara Gangadhar , Langenickel Thomas H.
Published: January 2018

Aims

Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two‐period, single‐sequence study in healthy subjects.

Methods

All subjects (n = 28) received 40 mg oral single‐dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated.

Results

Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration–time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24‐h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0–4‐h, 4–8‐h and 0–24‐h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM‐HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group.

Conclusions

Sacubitril/valsartan reduced plasma Cmax and AUC and 24‐h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.
Reversal of mecamylamine‐induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses
Authors: Alvarez‐Jimenez Ricardo , Hart Ellen P. , Prins Samantha , de Kam Marieke , van Gerven Joop M.A. , Cohen Adam F. , Groeneveld Geert Jan
Published: January 2018

Aims

Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor.

Methods

This randomized, double‐blind, double‐dummy, placebo‐controlled, four‐way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine.

Results

Thirty‐three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double‐dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short‐ and long‐term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and β power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine.

Conclusions

Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short‐ and long‐term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.
Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a critical appraisal
Authors: Thomson J. , Wernham A.G.H. , Williams H.C.
Published: January 2018

Aim

Blauvelt et al. aimed to compare the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids (TCS) vs. placebo with TCS in adults with moderate-to-severe atopic dermatitis (AD).

Setting and design

This multicentre randomized, double-blinded, placebo-controlled trial was conducted in hospitals, clinics and academic institutions across 161 sites in 14 countries.

Study exposure

Adults with moderate-to-severe AD were randomly assigned (3: 1: 3) to receive subcutaneous dupilumab 300 mg once weekly plus TCS, dupilumab 300 mg every 2 weeks plus TCS or placebo plus TCS until week 52.

Outcomes

Co-primary efficacy end points were percentage of patients achieving Investigator's Global Assessment (IGA) 0/1 and 2 points or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16.

Results

In total, 740 patients were included in the trial: 319 were randomly assigned to dupilumab once weekly, 106 to dupilumab every 2 weeks and 315 to the placebo arm. At week 16, more patients in the dupilumab groups achieved the co-primary end points: IGA 0/1 [39% (n = 125) once-weekly dosing, 39% (n = 41) every 2 weeks dosing vs. 12% (n = 39) receiving placebo; P < 0·0001] and EASI-75 [64% (n = 204) and 69% (n = 73) vs. 23% (n = 73); P < 0·0001]. While no new safety signals were identified, adverse effects were noted in 261 (83%) of those receiving dupilumab once weekly plus TCS, 97 (88%) receiving dupilumab every 2 weeks plus TCS and 266 (84%) for those receiving placebo plus TCS. Rates of conjunctivitis, injection site reactions and local herpes simplex infections were higher in the dupilumab groups than in the placebo group.

Conclusions

Blauvelt et al. concluded that dupilumab treatment added to TCS improved AD up to week 52 vs. TCS alone, and also demonstrated acceptable safety.
Outcomes and toxicities in patients with intermediate‐risk prostate cancer treated with brachytherapy alone or brachytherapy and supplemental external beam radiation therapy
Authors: Schlussel Markovic Emily , Buckstein Michael , Stone Nelson N. , Stock Richard G.
Published: January 2018

Objective

To evaluate the cancer control outcomes and long‐term treatment‐related morbidity of brachytherapy as well as combination brachytherapy and external beam radiation therapy (EBRT) in patients with intermediate‐risk prostate cancer.

Materials and Methods

A retrospective review was conducted in a prospectively collected database of patients with intermediate‐risk prostate cancer who were treated either with brachytherapy or brachytherapy and EBRT, with or without androgen deprivation therapy (ADT), in the period 1990–2014. Urinary and erectile dysfunction symptoms were measured using the International Prostate Symptom Score (IPSS), the Mount Sinai erectile function scale and the Sexual Health Inventory for Men (SHIM). Cancer control endpoints included biochemical failure and development of distant metastases. All statistical analyses were carried out using the Statistical Package for Social Science (SPSS). Survival curves were calculated using Kaplan–Meier actuarial methods and compared using log‐rank tests. Cox regression multivariate analyses were used to test the effect of multiple variables on treatment outcomes.

Results

A total of 902 patients were identified, with a median follow‐up of 91 months. Of these, 390 received brachytherapy and 512 received combination therapy with EBRT. In patients with one intermediate‐risk factor, the addition of EBRT did not significantly affect freedom from biochemical failure or distant metastases. Among patients with two or three intermediate‐risk factors, added EBRT did not improve freedom from biochemical failure. Significant differences in late toxicity between patients treated with brachytherapy vs combination brachytherapy and EBRT were identified including urge incontinence (P < 0.001), haematuria (P < 0.001), dysuria (P < 0.001), and change in quality‐of‐life IPSS (P = 0.002). These symptoms were reported by patients at any point during treatment follow‐up. Analysis of patients who were potent before treatment using actuarial methods showed that patients receiving combination therapy more frequently experienced loss of potency, as measured by the Mount Sinai erectile function scale (P = 0.040).

Conclusion

Brachytherapy monotherapy results in equal biochemical and distant control in both patients with one and more than one intermediate‐risk features. While no significant benefit was shown, we believe that the addition of EBRT may prevent recurrence in patients with multiple intermediate‐risk features and should be considered.
Collectivism and employees' innovative behavior: The mediating role of team identification and the moderating role of leader‐member exchange
Authors: Song Derun , Liu Hefu , Gu Jibao , He Changqing
Published: January 2018

Based on the social identity theory and leader‐member exchange (LMX) literature, the present study examined the underlying relationship between employees' collectivism and their innovative behavior. Specifically, we explored the mediating role of team identification and the moderating role of LMX in the above relationship. Results from a survey of 457 employees in 30 organizations indicate that employees' team identification partially mediates the relationship between their collectivism and innovative behavior, and that this mediating relationship has conditional effects on the moderator variable LMX. The findings contribute to the literature by clarifying how (through team identification) and when (based on LMX) employees' collectivism is related positively to their innovative behavior.
Cellular stress induces cancer stem‐like cells through expression of DNAJB8 by activation of heat shock factor 1
Authors: Kusumoto Hiroki , Hirohashi Yoshihiko , Nishizawa Satoshi , Yamashita Masamichi , Yasuda Kazuyo , Murai Aiko , Takaya Akari , Mori Takashi , Kubo Terufumi , Nakatsugawa Munehide , Kanaseki Takayuki , Tsukahara Tomohide , Kondo Toru , Sato Noriyuki , Hara Isao , Torigoe Toshihiko
Published: January 2018

In a previous study, we found that DNAJB8, a heat shock protein (HSP) 40 family member is expressed in kidney cancer stem‐like cells (CSC)/cancer‐initiating cells (CIC) and that it has a role in the maintenance of kidney CSC/CIC. Heat shock factor (HSF) 1 is a key transcription factor for responses to stress including heat shock, and it induces HSP family expression through activation by phosphorylation. In the present study, we therefore examined whether heat shock (HS) induces CSC/CIC. We treated the human kidney cancer cell line ACHN with HS, and found that HS increased side population (SP) cells. Western blot analysis and qRT‐PCR showed that HS increased the expression of DNAJB8 and SOX2. Gene knockdown experiments using siRNAs showed that the increase in SOX2 expression and SP cell ratio depends on DNAJB8 and that the increase in DNAJB8 and SOX2 depend on HSF1. Furthermore, treatment with a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, decreased the expression of DNAJB8 and SOX2 and the ratio of SP cells. Taken together, the results indicate that heat shock induces DNAJB8 by activation of HSF1 and induces cancer stem‐like cells.
Fathers Are Parents, Too! Widening the Lens on Parenting for Children's Development
Authors: Cabrera Natasha J. , Volling Brenda L. , Barr Rachel
Published: January 2018

Why do fathers matter? Recent conceptual and theoretical advances regarding father–child relationships have demonstrated that fathers affect children's outcomes both directly and indirectly. To attain a complete developmental account of the ecologically rich contexts of child development, in this article, we recommend best practices regarding the conceptualization and assessment of father–child relationships that reflect contemporary family life. We also discuss conceptual and measurement issues pertaining to father–child relationships in different family configurations, including those with resident and nonresident fathers. We conclude with recommendations that can help developmental researchers advance our understanding of fathering, parenting, and children's development.
The use of omalizumab in allergen immunotherapy
Authors: Dantzer J. A. , Wood R. A.
Published: January 2018

Although omalizumab (anti‐IgE) is currently only approved for the treatment of asthma and chronic idiopathic urticaria, it has also been studied as an off‐label treatment for numerous allergic conditions, including use as an adjunct to allergen immunotherapy in the treatment of allergic rhinitis, asthma, venom hypersensitivity and food allergy. We conducted a review of publications involving the use of omalizumab with allergen immunotherapy, by searching PubMed with key search terms of “omalizumab” and “immunotherapy.” Omalizumab has been used in combination with inhalant allergen immunotherapy for the treatment of seasonal allergic rhinitis and comorbid asthma. While there have been no randomized controlled trials evaluating the addition of omalizumab to venom IT, several case reports and small patient series have been published on the use of omalizumab with venom IT. Omalizumab has been used in conjunction with oral immunotherapy for the treatment of milk, peanut and egg, as well as other foods in multi‐allergen protocols. In conclusion, omalizumab used in conjunction with immunotherapy has shown promising results, especially in the reduction of adverse reactions. At this stage, larger, randomized, placebo‐controlled trials are needed to better identify those patients who would benefit the most from the addition of omalizumab to immunotherapy, as well as optimal dosing strategies and duration of treatment.
Knowledge, attitudes, representations and declared practices of nurses and physicians about obesity in a university hospital: training is essential
Authors: Bucher Della Torre S. , Courvoisier D. S. , Saldarriaga A. , Martin X. E. , Farpour‐Lambert N. J.
Published: January 2018

In the context of a worldwide obesity epidemic, healthcare providers play a key role in obesity management. Knowledge of current guidelines and attitudes to prevent stigmatization are especially important. This study aimed to assess knowledge, attitudes, beliefs, perception of opportunity for intervention, declared practices and need for training and material of nurses and physicians about obesity in a Swiss University Hospital. A total of 834 physicians and nurses filled an online survey. The questionnaire was based on literature, exploratory interviews and expert committee review. It was pre‐tested with 15 physicians and nurses. Participants declared a low level of negative attitudes towards individuals living with obesity. However, the results highlighted a lack of knowledge to diagnose obesity in adults and children, as well as confidence and training to care of patients with obesity. One‐third of providers did not know how to calculate body mass index. Half of providers felt it was part of their role to take care of patients with obesity, even if 55% of them had the feeling that they did not have adequate training. Nurses and physicians working in a university hospital showed a low level of negative attitudes but a lack of knowledge and skills on obesity management. Training should be improved in this population to insure adequate and coherent messages and equal access to evidence‐based treatment for patients living with obesity.
Modification of oxygen concentrators based on questionnaire survey
Authors: Shinoda Masahiro , Shinkai Masaharu , Nagashima Akimichi , Nagai Kenjiro , Takagi Kei , Kaneko Takeshi
Published: January 2018

Background

In this study, we conducted a questionnaire survey to clarify and improve problems related to oxygen concentrators.

Methods

Using a questionnaire survey of 30 patients receiving long‐term oxygen therapy for chronic respiratory failure, we investigated the necessity of using a remote controller, portability, fire prevention system, built‐in battery type and so on. Patients were divided into two groups according to age, sex, underlying conditions and amount of oxygen prescribed, then analyzed accordingly.

Results

Mean age was 72.3 ± 8.09 years. The mean flow rate for prescribed oxygen was 1.10 L/min at rest and 2.96 L/min under exertion. Median duration of use was 17.5 months. Built‐in battery type, environmentally friendly system and voice guidance system received the most attention according to four‐grade evaluations of each function. Significant differences were seen in design features in patients less than 72 years old (P = .03), in voice guidance system in patients who only used the equipment during exertion (P = .01), and in brand imaging in those using the equipment under exertion at a flow ≥3 L/min (P = .04). In questionnaire results for the three most desired features, built‐in battery type was of primary concern, followed by portability and use of a remote control.

Conclusions

Overall, built‐in battery type, portability, use of a remote control and an environmentally friendly system were desired features for oxygen concentrators. Desired features could vary according to age and the amount of oxygen prescribed.
Cardiorespiratory fitness and age‐related arterial stiffness in women with systemic lupus erythematosus
Authors: Montalbán‐Méndez Cristina , Soriano‐Maldonado Alberto , Vargas‐Hitos José A. , Sáez‐Urán Luis M. , Rosales‐Castillo Antonio , Morillas‐de‐Laguno Pablo , Gavilán‐Carrera Blanca , Jiménez‐Alonso Juan
Published: January 2018

Background

The aim of this study was twofold: (i) to examine the association of cardiorespiratory fitness with arterial stiffness in women with systemic lupus erythematosus; (ii) to assess the potential interaction of cardiorespiratory fitness with age on arterial stiffness in this population.

Materials and methods

A total of 49 women with systemic lupus erythematosus (mean age 41.3 [standard deviation 13.8] years) and clinical stability during the previous 6 months were included in the study. Arterial stiffness was assessed through pulse wave velocity (Mobil‐O‐Graph® 24 hours pulse wave velocity monitor). Cardiorespiratory fitness was estimated with the Siconolfi step test and the 6‐minute walk test.

Results

Cardiorespiratory fitness was inversely associated with pulse wave velocity in crude analyses (P < .05), although this relationship was attenuated when age and other cardiovascular risk factors were controlled. There was a cardiorespiratory fitness × age interaction effect on pulse wave velocity, regardless of the test used to estimate cardiorespiratory fitness (P < .001 for the Siconolfi step test; P = .005 for the 6‐minute walk test), indicating that higher cardiorespiratory fitness was associated with a lower increase in pulse wave velocity per each year increase in age.

Conclusions

The results of this study suggest that cardiorespiratory fitness might attenuate the age‐related arterial stiffening in women with systemic lupus erythematosus and might thus contribute to the primary prevention of cardiovascular disease in this population. As the cross‐sectional design precludes establishing causal relationships, future clinical trials should confirm or contrast these findings.
Gender, ethnicity, and unequal opportunity in colonial Uganda: European influences, African realities, and the pitfalls of parish register data
Authors: De Haas Michiel , Frankema Ewout
Published: January 2018

The renaissance of African economic history in the past decade has opened up new research avenues for studying the long‐term social and economic development of Africa. A sensitive treatment of African realities in the evaluation of European colonial legacies and a critical stance towards the use of new sources and approaches is crucial. In this article, we engage with a recent article by Meier zu Selhausen and Weisdorf to show how selection biases in, and Eurocentric interpretations of, parish registers have provoked an overly optimistic account of European influences on the educational and occupational opportunities of African men and women. We confront their dataset, drawn from the marriage registers of the Anglican Cathedral in Kampala, with Uganda's 1991 census, and show that trends in the literacy and numeracy of men and women born in Kampala lagged half a century behind those who wedded in Namirembe Cathedral. We run a regression analysis showing that access to schooling during the colonial era was unequal along lines of gender and ethnicity. We foreground the role of Africans in the spread of education, and we argue that European influences were not just diffusive but also divisive, and that gender inequality was reconfigured rather than eliminated under colonial rule.
A questionnaire‐based study evaluating differences between dental students in Paris (F) and Malmö (SE) regarding diagnosis and treatment decisions of patients with different severity levels of periodontal diseases
Authors: Milosavljevic A. , Stavropoulos A. , Descroix V. , Götrick B.
Published: January 2018

Aim

To evaluate differences between last‐year dental students in Paris (F) and Malmö (SE) Dental Schools, in regard to their judgement and decision‐making within periodontology.

Materials and Methods

Ninety‐six last‐year dental students from Paris and 45 from Malmö participated in a questionnaire study based on four patient cases: (i) Patient case with generalised alveolar bone loss but no signs of inflammation (Well‐maintained), (ii) Patient case with generalised alveolar bone loss and signs of inflammation (Periodontitis), (iii) Patient case with no alveolar bone loss and no signs of inflammation (Healthy) and (iv) Patient case with no alveolar bone loss but with signs of inflammation (Gingivitis). Through multiple‐choice questions, the students judged each case as healthy or diseased proposed a diagnosis and treatment measures and estimated the treatment time for each patient. Furthermore, they assessed the prognosis of each patient in case of no treatment.

Results

Based on a response rate of 83%, the majority in both groups judged all the patients as diseased. More Paris students diagnosed the healthy and the gingivitis case as having periodontitis (P < .05). Furthermore, a larger number of students from Paris recommended several treatment measures and estimated longer treatment times for all the cases (P < .05) and estimated a higher risk for disease progression for the healthy and the gingivitis case (P < .05).

Conclusions

Significant variation between students from Paris and Malmö Dental Schools in regard to judgement and decision‐making was observed; this may in turn imply that there is still need of improving consistency amongst undergraduate educations in periodontology in Europe.
Respiratory dysfunction progresses with age in Kcna1‐null mice, a model of sudden unexpected death in epilepsy
Authors: Simeone Kristina A. , Hallgren Jodi , Bockman Charles S. , Aggarwal Ankita , Kansal Vikash , Netzel Lauren , Iyer Shruthi H. , Matthews Stephanie A. , Deodhar Malavika , Oldenburg Peter J. , Abel Peter W. , Simeone Timothy A.
Published: January 2018

Objective

Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD).

Methods

Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/−, and Kcna1−/− littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32‐36, P40‐46, and P48‐56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT‐qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh.

Results

Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea‐hypopnea (A‐H), an atypical breathing sequence of A‐H‐tachypnea‐A‐H, increased tidal volume, and hyperventilation induced by MCh. The MCh‐provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached SD. MCh‐induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near‐SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs, and MCh‐mediated airway smooth muscle contractions exhibited similar half‐maximal effective concentration( EC50) in isolated Kcna1+/+ and Kcna1−/− trachea.

Significance

The Kcna1−/− model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.
Ancient DNA reveals the timing and persistence of organellar genetic bottlenecks over 3,000 years of sunflower domestication and improvement
Authors: Wales Nathan , Akman Melis , Watson Ray H. B. , Sánchez Barreiro Fátima , Smith Bruce D. , Gremillion Kristen J. , Gilbert M. Thomas P. , Blackman Benjamin K.
Published: January 2018

Here, we report a comprehensive paleogenomic study of archaeological and ethnographic sunflower remains that provides significant new insights into the process of domestication of this important crop. DNA from both ancient and historic contexts yielded high proportions of endogenous DNA, and although archaeological DNA was found to be highly degraded, it still provided sufficient coverage to analyze genetic changes over time. Shotgun sequencing data from specimens from the Eden's Bluff archaeological site in Arkansas yielded organellar DNA sequence from specimens up to 3,100 years old. Their sequences match those of modern cultivated sunflowers and are consistent with an early domestication bottleneck in this species. Our findings also suggest that recent breeding of sunflowers has led to a loss of genetic diversity that was present only a century ago in Native American landraces. These breeding episodes also left a profound signature on the mitochondrial and plastid haplotypes in cultivars, as two types were intentionally introduced from other Helianthus species for crop improvement. These findings gained from ancient and historic sunflower specimens underscore how future in‐depth gene‐based analyses can advance our understanding of the pace and targets of selection during the domestication of sunflower and other crop species.
Possible role of CYP2B6 genetic polymorphisms in ifosfamide‐induced encephalopathy: report of three cases
Authors: Duflot Thomas , Marie‐Cardine Aude , Verstuyft Céline , Filhon Bruno , Pereira Tony , Massy‐Guillemant Nathalie , Joannidès Robinson , Bellien Jérémy , Lamoureux Fabien
Published: January 2018

Ifosfamide (IFA) is a potent alkylating antitumoral agent, but its use is limited by neurological side effects. IFA is a racemic mixture of two enantiomeric forms, R‐IFA and S‐IFA with a stereoselective metabolism by CYP3A4 and CYP2B6, leading either to bioactive or to toxic pathways. In three consecutive cases of pediatric patients who exhibited IFA‐induced encephalopathy (IIE), genotyping of clinically relevant single‐nucleotide polymorphisms associated with decreased CYP3A4 and CYP2B6 activities was performed. Genetic investigations revealed the presence of CYP2B6 rs4803419 (C>T) in one patient while the two others carried the CYP2B6*6 allelic variant. All patients carried CYP3A4 wild‐type genotype (CYP3A4*1/*1). Because CYP2B6‐deficient alleles may be responsible for an increased conversion of S‐IFA into neurotoxic metabolites, screening for CYP2B6 polymorphisms may help to avoid IIE and improve clinical outcomes.
PACING OUT A POLYGLOT POETICS: AN INTERVIEW WITH ULRIKE DRAESNER AT THE VICTORIA AND ALBERT MUSEUM
Authors: Braun Rebecca
Published: January 2018

To what extent is reading a book like walking into a museum? In this conversation, held in early 2017 at the Victoria and Albert Museum, London, Rebecca Braun and Ulrike Draesner explore how identities are forged in both language and material things, and how narratives, both poetic and prosaic, are spatially arranged. The conversation takes inspiration from material objects on display in the Europe Galleries of the museum to cast a fresh angle on Draesner's literary practice in her recent work: the novel, Sieben Sprünge vom Rand der Welt, the poetry collection, subsong, and a new text that draws on the life in exile of the expressionist poet and painter Kurt Schwitters.
Splicing analysis of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ‐glutamyltransferase
Authors: Wang Neng‐Li , Qiu Yi‐Ling , Guan Wen‐Cai , Li Gang , Lu Yi , Zhang Mei‐Hong , Luan Wei‐Sha , Wang Jian‐She
Published: January 2018

Aim

The aim of this study was to analyze the pathogenicity of rare/novel synonymous or intronic variants identified in ABCB11 heterozygotes presenting as progressive intrahepatic cholestasis with low γ‐glutamyltransferase.

Methods

The enrolled variants were identified in ABCB11 between October 2009 and June 2016. The effects on pre‐RNA splicing were analyzed by in silico tools and minigene splicing assay.

Results

There were three intronic (c.908 + 5G > A, c.2815‐8A > G, and c.612‐15_‐6del10bp) and two synonymous (c.1809G > A, p.K603 K and c.2418C > T, p.G806G) variants with unknown significance identified in ABCB11 of five ABCB11 heterozygotes. Parental studies were carried out for four patients, and revealed that the variants with unknown significance were compound heterozygous with other pathogenic variants. The five variants with unknown significance had minor allele frequency <0.1% or were absent from controls, and had positive prediction results by in silico tools. The effects on pre‐RNA splicing were further confirmed by minigene splicing assay. c.908 + 5A caused abnormal splicing in at least 78.5 ± 3.8% of products using a cryptic splice site (ss) 22 nucleotides (nt) upstream of the wild‐type (WT) 5′ss. Seven nucleotides of intron 22 upstream of the WT 3'ss was retained for all products from c.2815‐8G. c.612‐15_‐6del caused exon 8 skipping in 24.8 ± 7.7% of products, and 55 nt of exon 8 downstream of the WT 3′ss removal in remaining products. c.1809A led to exon 15 skipping. c.2418 T removed exon 20 and 62 nt of exon 21 downstream of the WT 3′ss by using a cryptic ss.

Conclusions

We successfully identified five pathogenic synonymous or intronic variants with some common features. These features might help to choose the right variant for further functional assay.
Levels of oxidative stress biomarkers and bone resorption regulators in apical periodontitis lesions infected by Epstein–Barr virus
Authors: Jakovljevic A. , Andric M. , Nikolic N. , Coric V. , Krezovic S. , Carkic J. , Knezevic A. , Beljic‐Ivanovic K. , Pljesa‐Ercegovac M. , Miletic M. , Soldatovic I. , Radosavljevic T. , Jovanovic T. , Simic T. , Ivanovic V. , Milasin J.
Published: January 2018

Aim

To investigate whether apical periodontitis lesions infected by Epstein–Barr virus (EBV) exhibit higher levels of oxidative stress biomarkers [8‐hydroxydeoxyguanosine (8‐OHdG) and oxidized glutathione (GSSG)] and bone resorption regulators [receptor activator of nuclear factor (NF‐κB) ligand (RANKL) and osteoprotegerin (OPG)] compared to EBV‐negative periapical lesions and healthy pulp tissues.

Methodology

The experimental group consisted of 30 EBV‐positive and 30 EBV‐negative periapical lesions collected in conjunction with apicoectomy. The pulp tissues of 20 impacted third molars were used as healthy controls. The qualitative and quantitative analysis of EBV was performed by nested and real‐time polymerase chain reaction (PCR), respectively. The levels of RANKL and OPG were analysed by reverse transcriptase real‐time PCR. The levels of 8‐OHdG and GSSG were determined by enzyme‐linked immunosorbent assay (ELISA). Mann–Whitney U‐test and Spearman's correlation were used for statistical analysis.

Results

The levels of RANKL, OPG, 8‐OHdG and GSSG were significantly higher in apical periodontitis lesions compared to healthy pulp controls (P = 0.001, P < 0.001, P < 0.001 and P < 0.05, respectively). RANKL and OPG mRNA expression was significantly higher in EBV‐positive compared to EBV‐negative periapical lesions (P < 0.05). There was no significant correlation between EBV copy numbers and levels of RANKL, OPG, 8OH‐dG and GSSG in apical periodontitis.

Conclusion

Levels of bone resorption regulators and oxidative stress biomarkers were increased in apical periodontitis compared to healthy pulp tissues. EBV‐positive periapical lesions exhibited higher levels of RANKL and OPG compared to EBV‐negative periapical lesions. EBV may contribute to progression of apical periodontitis via enhanced production of bone resorption regulators.
In situ TiC particle reinforced TiCuZrNi brazing alloy for joining C/C composites to Ti6Al4V
Authors: Song Xinrui , Li Hejun , Casalegno Valentina , Salvo Milena , Ferraris Monica , Zeng Xierong
Published: January 2018

Chromium carbide modified C/C and Ti6Al4V were successfully joined using a TiCuZrNi brazing alloy in powder form. The braze/composite interface and the mechanical strength of C/C‐Ti6Al4V joints were evaluated. The apparent shear strength of chromium carbide modified C/C joined to Ti6Al4V, measured by single lap test in compression, was 52 ± 6 MPa, which was highest among that without chromium carbide modification (15 ± 2 MPa) and the intrinsic C/C shear strength. The fractography of joints without chromium carbide modification indicated that failure mainly occurred at the TiC layer formed at the composite/braze interface while the joints with chromium carbide modification failed within the C/C.
Endocytosed soluble cowpox virus protein CPXV012 inhibits antigen cross‐presentation in human monocyte‐derived dendritic cells
Authors: Spel Lotte , Luteijn Rutger D. , Drijfhout Jan W. , Nierkens Stefan , Boes Marianne , Wiertz Emmanuel J.H.
Published: January 2018

Viruses may interfere with the MHC class I antigen presentation pathway in order to avoid CD8+ T cell‐mediated immunity. A key target within this pathway is the peptide transporter TAP. This transporter plays a central role in MHC class I‐mediated peptide presentation of endogenous antigens. In addition, TAP plays a role in antigen cross‐presentation of exogenously derived antigens by dendritic cells (DCs). In this study, a soluble form of the cowpox virus TAP inhibitor CPXV012 is synthesized for exogenous delivery into the antigen cross‐presentation route of human monocyte‐derived (mo)DCs. We show that soluble CPXV012 localizes to TAP+ compartments that carry internalized antigen and is a potent inhibitor of antigen cross‐presentation. CPXV012 stimulates the prolonged deposition of antigen fragments in storage compartments of moDCs, as a result of reduced endosomal acidification and reduced antigen proteolysis when soluble CPXV012 is present. Thus, a dual function can be proposed for CPXV012: inhibition of TAP‐mediated peptide transport and inhibition of endosomal antigen degradation. We propose this second function for soluble CPXV012 can serve to interfere with antigen cross‐presentation in a peptide transport‐independent manner.
Subsets of activated monocytes and markers of inflammation in incipient and progressed multiple sclerosis
Authors: Gjelstrup Mikkel Carstensen , Stilund Morten , Petersen Thor , Møller Holger Jon , Petersen Eva Lykke , Christensen Tove
Published: January 2018

Multiple sclerosis (MS) is an immune mediated, inflammatory and demyelinating disease of the central nervous system (CNS). Substantial evidence points toward monocytes and macrophages playing prominent roles early in disease, mediating both pro‐ and anti‐inflammatory responses. Monocytes are subdivided into three subsets depending on the expression of CD14 and CD16, representing different stages of inflammatory activation. To investigate their involvement in MS, peripheral blood mononuclear cells from 40 patients with incipient or progressed MS and 20 healthy controls were characterized ex vivo. In MS samples, we demonstrate a highly significant increase in nonclassical monocytes (CD14+CD16++), with a concomitant significant reduction in classical monocytes (CD14++CD16−) compared with healthy controls. Also, a significant reduction in the surface expression of CD40, CD163, and CD192 was found, attributable to the upregulation of the nonclassical monocytes. In addition, significantly increased levels of human endogenous retrovirus (HERV) envelope (Env) epitopes, encoded by both HERV‐H/F and HERV‐W, were specifically found on nonclassical monocytes from patients with MS; emphasizing their involvement in MS disease. In parallel, serum and cerebrospinal fluid (CSF) samples were analyzed for soluble biomarkers of inflammation and neurodegeneration. For sCD163 versus CD163, no significant correlations were found, whereas highly significant correlations between levels of soluble neopterine and the intermediate monocyte (CD14++CD16+) population was found, as were correlations between levels of soluble osteopontin and the HERV Env expression on nonclassical monocytes. The results from this study emphasize the relevance of further focus on monocyte subsets, particularly the nonclassical monocytes in monitoring of inflammatory diseases.

See also: News and Commentary by Ajami & Steinman
The profile of diabetes healthcare professionals in Indonesia: a scoping review
Authors: Ligita T. , Wicking K. , Harvey N. , Mills J.
Published: January 2018

Aim

To explore and synthesize evidence of the literature about healthcare professionals involved in the provision of diabetes management within an Indonesian context.

Background

Indonesia is challenged to control the major burden of diabetes prevalence rate that requires a multidimensional approach with the aim to optimize existing health services by involving healthcare professionals who can promote access and provide diabetes management.

Methods

This literature review, which is integrated with a scoping study framework, used the electronic databases including CINAHL, PubMed, Scopus and Web of Science to locate papers particular to the Indonesian context. From the total of 568 papers found, 20 papers were selected.

Results

The literature review identified physicians, nurses, pharmacists, dieticians and diabetes educators as the providers of diabetes care and management in Indonesia. Collaborative management involving either interdisciplinary or intradisciplinary teams was mentioned in several papers. Internal challenges included limited skills and knowledge. External challenges included high patient volumes; a shortage of healthcare professionals and reduced funding.

Conclusions

Overcoming the challenges cannot be undertaken with a workforce dominated by any one single healthcare professional. Coordinating with the government to improve the implementation of different roles in diabetes management will improve patient outcomes and thus reduce the burden of diabetes.

Implication for nursing and health policy

Health policy reform should support nurses and other healthcare professionals in their professional development at all levels of health care. Policy makers can use the review findings to modify the current healthcare system to address key issues in workforce development; funding for services and medications; and fostering multidisciplinary care for diabetes management.
Rapid induction of small heat shock proteins improves physiological adaptation to high temperature stress in peanut
Authors: Chakraborty K. , Bishi S. K. , Singh A. L. , Zala P. V. , Mahatma M. K. , Kalariya K. A. , Jat R. A.
Published: January 2018

With the changing climatic scenario and increasing global mean temperature, heat stress became a major limiting factor for today's agriculture. To identify the underlying mechanism associated with heat tolerance in peanut, two experiments (field and growth chamber) were conducted with four genotypes (ICGS 44, GG 7, AK 159 and DRG 1) having differential high temperature stress sensitivity. Field grown plants under three different temperature (D1, D2 and D3) regimes simulated three temperature treatment effects with a variability of 3–4/4–5°C in mean day/night temperature, respectively. In growth chamber, imposition of heat shock (10°C above ambient inside growth chamber) revealed not only rapid induction (within 0.5 hr) of HSPs, especially small HSPs (HSP 17, HSP 40) in tolerant genotypes, but also its sustenance for longer duration (2 hr), which might help them to have better physiological adaptation strategies under high temperature stress. This was evident from significant advancement in phenophases observed with increase in temperature by 15–18 days at physiological maturity, while pollen viability and membrane stability reduced below 50% and 41%, respectively in DRG 1 with increase in mean day/night temperature. Maintenance of higher photosynthesis and transpiration rate and stomatal conductance helped the tolerant genotype ICGS 44 to keep relatively cooler canopy and higher photosynthates, ensuring better physiological condition in this genotype under heat stress. Significant increase (~2.5‐fold) in inositol and hexoses (glucose and fructose) content and reduction (>50%) in sucrose content in leaf tissues indicated degradation of storage carbohydrates for improved osmotic adjustment especially in tolerant genotypes under elevated temperature.
Controllable wear behaviors of silicon nitride sliding against sintered polycrystalline diamond via altering humidity
Authors: Qin Wenbo , Yue Wen , Wang Chengbiao
Published: January 2018

The tribological behaviors of silicon nitride (Si3N4) sliding against sintered polycrystalline diamond (PCD) were investigated by varying the relative humidity (RH) in the testing atmosphere. The results indicated that higher RH corresponds to higher wear loss of Si3N4 and the wear loss of PCD almost fell close to zero. Especially in the case of 85% RH, both a maximum wear loss of Si3N4 and a maximum friction coefficient were achieved. In addition, this study revealed insights into the interface chemistry effects on the wear behavior of Si3N4 under humidity. When water molecules were introduced into the testing atmosphere, the hydrolysis reaction occurred on the Si3N4 surface with the formation of the Si‐O‐Si bond across the sliding interface. And then, the hydration reaction dominated the process, during which Si‐OH was formed through the bond fracture of the Si‐O‐Si. The X‐ray photoelectron spectroscopy results showed that the ratios of Si‐OH/Si‐O and Si‐N/Si‐OH+Si‐O bonds increased as the relative RH levels increased. As a consequence, the wear loss of Si3N4 significantly increased. Thus, due to the hydrolysis and hydration reactions, the tribological behaviors of Si3N4 against sintered polycrystalline diamond can be essentially controlled via varying RH levels.
Synthesis and color properties of the TiO2@CoAl2O4 blue pigments with low cobalt content applied in ceramic glaze
Authors: He Xuanmeng , Wang Fen , Liu Hui , Niu Lijun , Wang Xinzhen
Published: January 2018

The TiO2@CoAl2O4 complex blue pigments with low cobalt content were synthesized through calcinations of the precursor obtained from coprecipitating Co2+ and Al3+ to form Co‐Al LDHs (layered double hydroxides) on the surface of TiO2 particles. The structure and the properties of the synthesized pigments were characterized by XRD, SEM, TEM, UV‐Vis spectroscopy, XPS, and colorimeter. The precursors of the blue TiO2@CoAl2O4 complex pigments were consisted of LDHs shell layer encapsulated TiO2 microsphere. After calcinations at 1100°C, the LDHs shell layer were absolutely transformed to the spinel CoAl2O4, and the pigments presented a core‐shell structure and uniform sphere morphology (the diameter of microsphere was about 780 nm). The absorption bands at around 547, 584, and 624 nm in the Uv‐Vis absorption spectra of the TiO2@CoAl2O4 complex pigments were corresponded to the characteristic absorption bands of the spinel CoAl2O4, revealed the pigments with a bright blue hue. In addition, as the mass ratio of CoAl2O4/TiO2 increased to 0.4, the blue component of the pigments reached to 27.89 and slight color variation with the increase in the CoAl2O4 content in a range, possessed low cobalt content and exhibited a stabile performance in commercial low‐temperature ceramic glazes. The XGT results showed that the TiO2@CoAl2O4 complex pigments with low cobalt content presented bright color in ceramic glaze. Especially, the synthesized pigments reduced the usage and toxicity of cobalt, which were efficiency for economy and environmental protection.
Magnetocrystalline anisotropy in the Co/Fe codoped Aurivillius oxide with different perovskite layer number
Authors: Gu Wen , Li Xiaoning , Sun Shujie , Zhu Liuyang , Fu Zhengping , Lu Yalin
Published: January 2018

Perpendicular magnetic anisotropic materials are of great interest for their huge potential to realize high‐density nonvolatile memory and logic chips. Designing such materials with lower cost and better magnetoelectric coupling still remains major challenges. In this work, aurivillius oxide ceramics with highly [00l]‐oriented grains were prepared by a facile pressureless sintering method, and the perovskite layer number was modified by varying the cobalt content. Afterwards, the unique perpendicular magnetic anisotropy and the intriguing anisotropic ferroelectric properties have been observed. The magnetic properties of the Aurivillius oxides with different layer numbers have been carefully investigated by field cooling, zero field cooling, and the magnetization with a varying field. The magnetic anisotropy in the oriented ceramics is demonstrated to be caused by the magnetocrystalline anisotropy with the easy magnetization direction along the c‐axis, which possibly arises from the unquenched 3d orbitals combined with the special layered crystal structures. The magnetocrystalline anisotropy becomes weaker in the ceramics with lower numbered perovskite layers, whereas the orientation degree of the ceramics and the ferroelectric anisotropy show quite opposite trends. Furthermore, the weak magnetoelectric coupling is also observed in the ceramics. This special anisotropic multiferroic properties may open up a new window for the Aurivillius materials.