bluuebunny/crossref_metadata_2025_split huggingface dataset:
Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage
Authors: Tsuchitani Toshiaki , Akiyoshi Takeshi , Imaoka Ayuko , Ohtani Hisakazu 
Published: July 2021

Abstract
Background
Irinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear. The aim of this study was to quantitatively evaluate how P-gp activity changes in rats with CPT-11-induced gastrointestinal damage, as assessed by the absorption of digoxin (DGX), a typical P-gp substrate.

Methods
Male Sprague-Dawley rats were intravenously administered CPT-11 at a dose of 60 mg/kg/day for 4 days to induce gastrointestinal damage. Then, the rats were administered DGX orally (40 μg/kg), after some of them were orally administered clarithromycin (CAM; 10 mg/kg), a P-gp inhibitor. DGX (30 μg/kg) was administered intravenously to determine the bioavailability (BA). The rats’ DGX plasma concentration profiles were determined using LC-MS/MS.

Results
CPT-11 treatment decreased the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUCpo) of DGX, which does not contradict to the DABE study. Although in the CPT-11-treated group the BA of DGX was significantly decreased to 40% of the control value, CAM did not affect the BA of DGX in the CPT-11-treated group.

Conclusions
Increased P-gp expression in rats with CPT-11-induced gastrointestinal damage is not necessarily associated with increased P-gp activity or contribution to the drug absorption in vivo. The decreased DGX absorption observed in this study might be attributable to other factors, such as a reduction in the absorptive surface area of the gastrointestinal tract.
Potentially harmful excipients in neonatal medications: a multicenter nationwide observational study in Japan
Authors: Saito Jumpei , Nadatani Naomi , Setoguchi Makoto , Nakao Masahiko , Kimura Hitomi , Sameshima Mayuri , Kobayashi Keiko , Matsumoto Hiroaki , Yoshikawa Naoki , Yokoyama Toshihiro , Takahashi Hitomi , Suenaga Mei , Watanabe Ran , Imai Kinuko , Obara Mami , Hashimoto Mari , Yamamoto Kazuhiro , Fujiwara Naoko , Sakata Wakako , Nagai Hiroaki , Enokihara Takeshi , Katayama Sayaka , Takahashi Yuta , Araki Mariko , Iino Kanako , Akiyama Naoko , Katsu Hiroki , Fushimi Kumiko , Takeda Tomoya , Torimoto Mayumi , Kishi Rina , Mitsuya Naoki , Kihara Rie , Hasegawa Yuki , Hamada Yukihiro , Kimura Toshimi , Wada Masaki , Tanzawa Ayano , Yamatani Akimasa 
Published: July 2021

AbstractBackgroundA multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted.MethodsA multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE.ResultsPrescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified.ConclusionsNeonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.
Physical activity, confidence and quality of life among cancer patient-carer dyads
Authors: Ng Siu-man , Fung Melody H. Y. , Chan Jessie S. M. , Chan Celia H. Y. , Chan Cecilia L. W. 
Published: July 2021

Abstract
Background
Physical activity (PA) has been positively associated with health-related quality of life (HRQoL) among cancer patients and family caregivers. However, there has been no relevant research for patient-caregiver dyads.

Methods
Path analysis, based on the actor–partner interdependence model (APIM), was used to examine the relationship between physical activity and health-related quality of life and explore the mediating role of emotional distress in 233 dyads.

Results
In both patients and caregivers, physical activity had a direct positive effect on physical quality of life (QoL) but not on mental. There was a significant indirect effect of physical activity on health-related quality of life via emotional distress for both dyad members. Patients’ and caregivers’ confidence in fighting cancer was negatively associated with their own emotional distress. Caregivers’ confidence in fighting cancer was positively associated with their physical activity and also negatively associated with patients’ emotional distress.

Conclusions
Physical activity may be considered as a possible behavioral and rehabilitation strategy for improving health-related quality of life in patient-caregiver dyads and reducing negative symptoms. Future research and intervention may consider cancer patient-family caregiver dyad as a unit of care.
Innovative trial approaches in immune-mediated inflammatory diseases: current use and future potential
Authors: Grayling Michael J. , Bigirumurame Theophile , Cherlin Svetlana , Ouma Luke , Zheng Haiyan , Wason James M. S. 
Published: July 2021

AbstractBackgroundDespite progress that has been made in the treatment of many immune-mediated inflammatory diseases (IMIDs), there remains a need for improved treatments. Randomised controlled trials (RCTs) provide the highest form of evidence on the effectiveness of a potential new treatment regimen, but they are extremely expensive and time consuming to conduct. Consequently, much focus has been given in recent years to innovative design and analysis methods that could improve the efficiency of RCTs. In this article, we review the current use and future potential of these methods within the context of IMID trials.MethodsWe provide a review of several innovative methods that would provide utility in IMID research. These include novel study designs (adaptive trials, Sequential Multi-Assignment Randomised Trials, basket, and umbrella trials) and data analysis methodologies (augmented analyses of composite responder endpoints, using high-dimensional biomarker information to stratify patients, and emulation of RCTs from routinely collected data). IMID trials are now well-placed to embrace innovative methods. For example, well-developed statistical frameworks for adaptive trial design are ready for implementation, whilst the growing availability of historical datasets makes the use of Bayesian methods particularly applicable.To assess whether and how these innovative methods have been used in practice, we conducted a review via PubMed of clinical trials pertaining to any of 51 IMIDs that were published between 2018 and 20 in five high impact factor clinical journals.ResultsAmongst 97 articles included in the review, 19 (19.6%) used an innovative design method, but most of these were relatively straightforward examples of innovative approaches. Only two (2.1%) reported the use of evidence from routinely collected data, cohorts, or biobanks. Eight (9.2%) collected high-dimensional data.ConclusionsApplication of innovative statistical methodology to IMID trials has the potential to greatly improve efficiency, to generalise and extrapolate trial results, and to further personalise treatment strategies. Currently, such methods are infrequently utilised in practice. New research is required to ensure that IMID trials can benefit from the most suitable methods.
Thoracoscopic T2-T3 versus T4 sympathectomy for primary palmar hyperhidrosis in children and adolescents: a randomized comparative study
Authors: Elhalaby Ismael Essam , Mansour Mohamed Awad , Tawfik Ahmed Mohamed Ismail , Aly Hisham Fayad 
Published: July 2021

Abstract
Background
Controversy exists regarding the appropriate level of sympathectomy for primary palmar hyperhidrosis (PH) as different levels are associated with variable postoperative patients’ satisfaction and potential complications. The aim of this study was to investigate the safety, efficacy, and outcome of T2-T3 thoracoscopic sympathectomy (TS) versus T4 TS in this age group.

Results
This prospective study included 32 patients (17 males and 15 females) with primary PH treated at the department of pediatric surgery, in our institution during the period from February 2019 to February 2020. Inclusion criteria included moderate and/or severe degrees of PH not responding to conservative measures. The patients were divided randomly into two groups: group I treated by T2-T3 TS and group II underwent only T4 TS. All patients were evaluated regarding operative details and postoperative outcome. Follow-up ranged from 6 to 24 months. Group I included 18 patients (14 operated on both sides and 4 operated on one side), and group II included 14 patients (11 operated on both sides and 3 operated on one side). The ages ranged between 5 and 18 years (mean 14.25 ± 3.14 years). The difference in mean age among both groups (14.5 versus 13.9 years) was not statistically significant. The mean operative time was significantly longer in group I (22.4 versus 17.2 min, p value 0.046). The hospital stay (1 day) was similar for both groups. Postoperative compensatory hyperhidrosis (CH) was more frequent in group I (n=7, 50% versus n=5, 45.5%), but the difference was not statistically significant. Postoperative over dryness occurred in 5 patients in group I (28.6%) and temporary Horner’s syndrome in one patient (7.14%). No over dryness or Horner’s syndrome occurred in any patient in group II. The QOL score has improved in both groups; the degree of improvements was better in group II.

Conclusion
Both T2-T3 TS and T4 TS are effective in treating primary palmar hyperhidrosis in children and adolescents. T4 TS is preferred than T2-3 TS due to less frequent postoperative complications and better patients’ satisfaction.
Can the botanical azadirachtin replace phased-out soil insecticides in suppressing the soil insect pest Diabrotica virgifera virgifera?
Authors: Toepfer Stefan , Toth Szabolcs , Szalai Mark 
Published: July 2021

AbstractBackgroundDue to recent bans on the use of several soil insecticides and insecticidal seed coatings, soil-dwelling insect pests are increasingly difficult to manage. One example is the western corn rootworm (Diabrotica virgifera virgifera, Coleoptera: Chrysomelidae), a serious root-feeder of maize (Zea mays). We investigated whether the less problematic botanical azadirachtin, widely used against above-ground insects, could become an option for the control of this soil insect pest.MethodsArtificial diet-based bioassays were implemented under standard laboratory conditions to establish dose response curves for the pest larvae. Then, potted-plant experiments were implemented in greenhouse to assess feasibility and efficacy of a novel granular formulation of azadirachtin under more natural conditions and in relation to standard insecticides.ResultsBioassays in three repetitions revealed a 3-day LD50of 22.3 µg azadirachtin/ml which corresponded to 0.45 µg/neonate ofD. v. virgiferaand a 5-day LD50of 19.3 µg/ml or 0.39 µg/first to second instar larva. No sublethal effects were observed. The three greenhouse experiments revealed that the currently proposed standard dose of a granular formulation of 38 g azadirachtin/hectare for in-furrow application at sowing is not enough to controlD. v. virgiferaor to prevent root damage. At 10× standard-dose total pest control was achieved as well as the prevention of most root damage. This was better than the efficacy achieved by cypermethrin-based granules and comparable to tefluthrin-granules, or thiamethoxam seed coatings. The ED50for suppressing larval populations were estimated at 92 g azadirachtin/ha, for preventing heavy root damage 52 g/ha and for preventing general root damage 220 g/ha.ConclusionsThere seems clear potential for the development of neem-based botanical soil insecticides for arable crops such as maize. They might become, if doses are increased and more soil insecticides phased out, a promising, safer solution as part of the integrated pest management toolkit against soil insects.
Aging, Cardiovascular Risk, and SHBG Levels in Men and Women From the General Population
Authors: Aribas Elif , Kavousi Maryam , Laven Joop S E , Ikram M Arfan , Roeters van Lennep Jeanine E 
Published: July 2021

Abstract

Aims
Prior studies have reported inconsistent results for the association between sex hormone-binding globulin (SHBG) and cardiovascular disease among men and women. Although it is suggested that SHBG levels change with aging, the exact trend of SHBG across age and cardiovascular risk and the underlying mechanisms of these changes remain to be elucidated.

Methods
Using data of 3264 men and women from a large population-based cohort study, we first visualized the distribution of serum SHBG levels across age. Second, we computed a cardiovascular risk factor sum score and investigated the mean SHBG levels across categories of the risk factor sum score and stratified per age-category. Next, linear regression models were used to investigate the associations between serum SHBG levels and age and potential regulators of SHBG, including body mass index (BMI), fasting insulin, sex steroids, thyroxine, and triglycerides.

Results
Among men, a linear increase in SHBG levels with age and among women a U-shaped pattern was observed. Participants with larger number of cardiovascular risk factors had lower SHBG levels. When stratified by age, older participants had higher SHBG levels. A multivariate model including total testosterone and triglyceride levels in men and total testosterone, triglycerides, BMI, and fasting insulin in women explained, respectively, 46.2% and 31.8% of the variance in SHBG levels.

Conclusion
We observed a clear sex-specific pattern for SHBG levels with age. Our findings highlight the importance of taking into account the age-related changes in SHBG levels to avoid controversial results in the assessment of the cardiovascular risk associated with SHBG.
Growing Up in the Shadow of Confederate Monuments
Authors: Bynum Caroline Walker 
Published: July 2021

Abstract
Drawing on her memories of growing up in a racially segregated South, the author argues not so much for the removal and erasure of Confederate memorials as for mutilating them or retaining a version of their presence glossed with an explanation for their rejection. Connecting the southern anti-Semitism and anti-Black racism of her youth, she explains the parallels and differences between German efforts to come to terms with the Holocaust and American efforts, southern and northern, to move beyond and make reparation for both slavery and continuing twentieth- and twenty-first-century racism.
Jan van Eyck at London in 1428
Authors: Richmond Colin 
Published: July 2021

Abstract
On the basis of reports that Jan van Eyck visited England (he was well traveled in the service of Philip the Good, duke of Burgundy), this essay speculates freely on what the diplomat and painter actually did in and around London for three weeks in 1428. The essay claims, for example, that van Eyck went to the village of Foots Cray to buy watercresses to use as models when painting greenery on the Ghent Altarpiece of the Mystic Lamb (which he completed in 1432). The recently erected gateway to the palace at Greenwich is said likewise to be the model for a towered gateway depicted on the altarpiece. After providing local detail about relevant parts of England in 1428, the essay closes with speculation (although the author writes, “The facts are known”) about the origin of a harp, of a purportedly Welsh variety, appearing on the altarpiece in the hands of an angel. The author argues that it was the instrument of an itinerant Breton musician whom van Eyck had heard in recital at the Poor Clares convent of the Holy Trinity at the Minories in Aldgate. The harpist subsequently murdered his Stepney landlady and was himself killed by enraged local housewives. Van Eyck is said to have purchased the man's harp when his worldly goods were posthumously sold.
scRNA sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development in mouse
Authors: Wittmann Marie-Theres , Katada Sayako , Sock Elisabeth , Kirchner Philipp , Ekici Arif B. , Wegner Michael , Nakashima Kinichi , Lie Dieter Chichung , Reis André 
Published: July 2021

ABSTRACT
Transcription factor 4 (TCF4) is a crucial regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability and schizophrenia. As a class I bHLH transcription factor (TF), it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify TF partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs, we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implicated in this process. In addition to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TF networks in neurodevelopmental processes.
Srsf3 mediates alternative RNA splicing downstream of PDGFRα signaling in the facial mesenchyme
Authors: Dennison Brenna J. C. , Larson Eric D. , Fu Rui , Mo Julia , Fantauzzo Katherine A. 
Published: July 2021

ABSTRACTSignaling through the platelet-derived growth factor receptor alpha (PDGFRα) is crucial for mammalian craniofacial development, although the mechanisms by which the activity of downstream intracellular effectors is regulated to mediate gene expression changes have not been defined. We find that the RNA-binding protein Srsf3 is phosphorylated at Akt consensus sites downstream of PI3K-mediated PDGFRα signaling in mouse palatal mesenchyme cells, leading to its nuclear translocation. We further demonstrate that ablation of Srsf3 in the mouse neural crest lineage leads to facial clefting due to defective cranial neural crest cell proliferation and survival. Finally, we show that Srsf3 regulates the alternative RNA splicing of transcripts encoding protein kinases in the mouse facial process mesenchyme to regulate PDGFRα-dependent intracellular signaling. Collectively, our findings reveal that alternative RNA splicing is an important mechanism of gene expression regulation downstream of PI3K/Akt-mediated PDGFRα signaling in the facial mesenchyme and identify Srsf3 as a critical regulator of craniofacial development.
The initial expansion of the C. elegans syncytial germ line is coupled to incomplete primordial germ cell cytokinesis
Authors: Bauer Jack , Poupart Vincent , Goupil Eugénie , Nguyen Ken C. Q. , Hall David H. , Labbé Jean-Claude 
Published: July 2021

ABSTRACT
The C. elegans germline is organized as a syncytium in which each germ cell possesses an intercellular bridge that is maintained by a stable actomyosin ring and connected to a common pool of cytoplasm, termed the rachis. How germ cells undergo cytokinesis while maintaining this syncytial architecture is not completely understood. Here, we use live imaging to characterize primordial germ cell (PGC) division in C. elegans first-stage larvae. We show that each PGC possesses a stable intercellular bridge that connects it to a common pool of cytoplasm, which we term the proto-rachis. We further show that the first PGC cytokinesis is incomplete and that the stabilized cytokinetic ring progressively moves towards the proto-rachis and eventually integrates with it. Our results support a model in which the initial expansion of the C. elegans syncytial germline occurs by incomplete cytokinesis, where one daughter germ cell inherits the actomyosin ring that was newly formed by stabilization of the cytokinetic ring, while the other inherits the pre-existing stable actomyosin ring. We propose that such a mechanism of iterative cytokinesis incompletion underpins C. elegans germline expansion and maintenance.
Vacuolar H+-ATPase dysfunction rescues intralumenal vesicle cargo sorting in yeast lacking PI(3,5)P2 or Doa4
Authors: Wilson Zachary N. , Buysse Dalton , West Matt , Ahrens Daniel , Odorizzi Greg 
Published: July 2021

ABSTRACT
Endosomes undergo a maturation process highlighted by a reduction in lumenal pH, a conversion of surface markers that prime endosome–lysosome fusion and the sequestration of ubiquitylated transmembrane protein cargos within intralumenal vesicles (ILVs). We investigated ILV cargo sorting in mutant strains of the budding yeast Saccharomyces cerevisiae that are deficient for either the lysosomal/vacuolar signaling lipid PI(3,5)P2 or the Doa4 ubiquitin hydrolase that deubiquitylates ILV cargos. Disruption of PI(3,5)P2 synthesis or Doa4 function causes a defect in sorting of a subset of ILV cargos. We show that these cargo-sorting defects are suppressed by mutations that disrupt Vph1, a subunit of vacuolar H+-ATPase (V-ATPase) complexes that acidify late endosomes and vacuoles. We further show that Vph1 dysfunction increases endosome abundance, and disrupts vacuolar localization of Ypt7 and Vps41, two crucial mediators of endosome–vacuole fusion. Because V-ATPase inhibition attenuates this fusion and rescues the ILV cargo-sorting defects in yeast that lack PI(3,5)P2 or Doa4 activity, our results suggest that the V-ATPase has a role in coordinating ILV cargo sorting with the membrane fusion machinery.
This article has an associated First Person interview with the first author of the paper.