bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of Ras/MAPK pathway gene variants in Chilean patients with Cryptorchidism
Authors: Rodríguez F. , Vallejos C. , Ponce D. , Unanue N. , Hernández M. I. , Célis S. , Arcos K. , Belmar F. , López M. T. , Cassorla F.
Published: May 2018

Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty‐nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high‐resolution melting (HRM) analysis followed by sequencing. Restriction or allele‐specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.
Antenatal risk factors associated with neonatal morbidity in large‐for‐gestational‐age infants: an international prospective cohort study
Authors: Vieira Matias C. , McCowan Lesley M.E. , North Robyn A. , Myers Jenny E. , Walker James J. , Baker Philip N. , Dekker Gustaaf A. , Kenny Louise C. , Poston Lucilla , Pasupathy Dharmintra ,   the SCOPE consortium
Published: May 2018

Introduction

Large‐for‐gestational‐age infants are associated with increased risk of neonatal morbidity and mortality. However, most of them will not have adverse outcomes. Our aim was to identify antenatal clinical factors associated with neonatal morbidity in large‐for‐gestational‐age infants.

Material and methods

Nulliparous women from the Screening for Pregnancy Endpoints (SCOPE) study were included. We compared maternal and fetal factors between large‐for‐gestational‐age infants (birthweight >90th customized centile) with and without neonatal morbidity, defined as admission to a neonatal intensive care unit or severe neonatal morbidity. Factors were selected based on a priori hypotheses of association and included maternal demography, anthropometric measures and self‐reported physical activity (15 and 20 weeks), fetal biometry (20 weeks), and clinical information. Multivariable logistic regression was used to identify risk factors. Stratified analyses were performed by maternal obesity and physical activity.

Results

Among term pregnancies, prevalence of large‐for‐gestational‐age infants was 9.3% (491/5255), with 11.8% (58/491) prevalence of neonatal morbidity. Random glucose at 20 weeks (odds ratio 1.52; 95% confidence interval 1.17–1.97, per 1 mmol/L increase) and no regular physical activity at 20 weeks (odds ratio 3.93; 95% confidence interval 1.75–8.83) were associated with increased risk of neonatal morbidity after adjustment for birthweight, gestational age at delivery and gestational diabetes. The increased risk associated with higher glucose levels was not evident in women with regular physical activity or without obesity.

Conclusions

Regular physical activity in mid‐pregnancy is associated with lower risk for neonatal morbidity in large‐for‐gestational‐age infants and seems to offer protection against the increased risk associated with higher maternal glucose levels.
Maternal diabetes alters the development of ductus venosus shunting in the fetus
Authors: Lund Agnethe , Ebbing Cathrine , Rasmussen Svein , Kiserud Torvid , Kessler Jörg
Published: May 2018

Introduction

Despite adequate glycemic control, the risks of fetal macrosomia and perinatal complications are increased in diabetic pregnancies. Adjustments of the umbilical venous distribution, including increased ductus venosus shunting, can be important fetal compensatory mechanisms, but the impact of pregestational diabetes on umbilical venous and ductus venosus flow is not known.

Material and methods

In this prospective study, 49 women with pregestational diabetes mellitus underwent monthly ultrasound examinations from gestational week 20 to 36. The blood velocity and the mean diameters of the umbilical vein and ductus venosus were used for calculating blood flow volumes. The development of the umbilical venous flow, ductus venosus flow and ductus venosus shunt fraction (% of umbilical venous blood shunted through the ductus venosus) was compared with a reference population, and the effect of HbA1c on the ductus venosus flow was assessed.

Results

The umbilical venous flow was larger in pregnancies with pregestational diabetes mellitus than in low‐risk pregnancies (p < 0.001) but smaller when normalized for fetal weight (p = 0.036). The distributional pattern of the ductus venosus flow developed differently in diabetic pregnancies, particularly during the third trimester, being smaller (p = 0.007), also when normalized for fetal weight (p < 0.001). Correspondingly, the ductus venosus shunt fraction was reduced (p < 0.0001), most prominently at 36 weeks. There were negative relations between the maternal HbA1c and the ductus venosus flow velocity, flow volume and shunt fraction.

Conclusions

In pregnancies with pregestational diabetes mellitus, prioritized umbilical venous distribution to the fetal liver and lower ductus venosus shunt capacity reduce the compensatory capability of the fetus and may represent an augmented risk during hypoxic challenges during late pregnancy and birth.
Endometriosis and adenomyosis are associated with increased risk of preterm delivery and a small‐for‐gestational‐age child: a systematic review and meta‐analysis
Authors: Bruun Mette R. , Arendt Linn H. , Forman Axel , Ramlau‐Hansen Cecilia H.
Published: May 2018

Introduction

The objective of this systematic review and meta‐analysis was to evaluate the risk of preterm delivery and having a small‐for‐gestational‐age (SGA) child in women with endometriosis and adenomyosis compared with women without these two diseases.

Material and methods

Studies on endometriosis or adenomyosis and risk of preterm delivery and/or SGA infant were included. The systematic search was conducted for all published articles in PubMed and Embase published from 1950 to 2017 using specific search terms. After duplicates were removed, two authors independently reviewed all studies, initially based on title and subsequently based on abstract. Studies considered relevant were read in full text by both reviewers to identify if studies met the inclusion criteria.

Results

The search found 21 studies on a total of 2 517 516 women meeting the inclusion criteria. Women with endometriosis had an increased odds of preterm delivery [odds ratio (OR) 1.47, 95% CI 1.28–1.69] and SGA infant (OR 1.26, 95% CI 1.04–1.549). Compared with endometriosis, adenomyosis implied an even higher odds of both preterm delivery (OR 3.09, 95% CI 1.88–5.09) and SGA infant (OR 3.23, 95% CI 1.71–6.09) as well.

Conclusions

Women with endometriosis or adenomyosis had a higher odds of preterm delivery and having a child that was SGA compared with women without endometriosis or adenomyosis. The odds of both adverse birth outcomes was highest among women with adenomyosis. The results suggest a closer prenatal monitoring among pregnant women with endometriosis or adenomyosis.
National treatment guidelines decreased the use of racemic adrenaline for bronchiolitis in four Finnish university hospitals
Authors: Palmu Sauli , Mecklin Minna , Heikkilä Paula , Backman Katri , Peltola Ville , Renko Marjo , Korppi Matti
Published: May 2018

Aim

Inhaled racemic adrenaline was used for bronchiolitis in many hospitals in Finland prior to new national current care guidelines for bronchiolitis in 2014, which limited its recommendations to on‐demand rescue therapy. We studied the drug's use before and after the new guidelines to gauge changes in prescribing habits.

Methods

This 2012–2016 study analysed how many 0.5 mL doses of racemic adrenaline were used for children by emergency rooms, paediatric wards and paediatric intensive care units at four university hospitals and estimated drug and staff costs.

Results

There were substantial differences in the yearly consumption of racemic adrenaline between the hospitals before and after the bronchiolitis guidelines were published, with reductions in drug costs and staff time. The overall use more than halved during the study period, particularly in two hospitals where baseline consumptions were highest, but not in a third where baseline consumption was already low. In the fourth, the baseline consumption was modest and there was a constant decrease during the study years.

Conclusion

The current care guidelines for bronchiolitis had some impact on clinical practice, as the overall use of racemic adrenaline more than halved, but considerable differences remained in the four study hospitals after their publication.
Elevated anti‐tissue transglutaminase antibodies in children newly diagnosed with type 1 diabetes do not always indicate coeliac disease
Authors: Rinawi Firas , Badarneh Basel , Tanous Osama , Bashir Husam , Tennenbaum‐Rakover Yardena , Peleg Sarit
Published: May 2018

Aim

Elevated levels of anti‐tissue transglutaminase (anti‐tTG) antibody may spontaneously normalise in children with newly diagnosed type 1 diabetes, even if they eat gluten. The prevalence of this phenomenon and predictors of a subsequent coeliac disease (CD) diagnosis were determined.

Methods

The medical records of children diagnosed with type 1 diabetes at Ha'Emek Medical Centre, Israel, from 2007 to 2015, were retrospectively reviewed for elevated anti‐tTG antibody levels. Demographic, clinical, laboratory and histological findings were compared between CD patients and those with transient coeliac serology.

Results

Of 425 patients with new onset type 1 diabetes, 34 (8%) had elevated anti‐tTG antibodies: CD was diagnosed in 14, anti‐tTG normalisation occurred in 13 and duodenal biopsies did not suggest CD in seven without anti‐tTG antibody normalisation. Protective factors for a subsequent CD diagnosis were older age (p = 0.009) and mildly elevated anti‐tTG antibody levels at the time of the type 1 diabetes diagnosis (p = 0.007), and decreased anti‐tTG levels within six months of diagnosis (p = 0.03).

Conclusion

Serological follow‐up of a diet containing gluten is recommended for children who have newly diagnosed type 1 diabetes and slightly elevated anti‐tTG antibodies with no symptoms that suggest CD.
Peritoneal and Systemic Responses of Obese TypeIIDiabetic Rats to Chronic Exposure to a Hyperbranched Polyglycerol‐Based Dialysis Solution
Authors: La Han Bo , Guan Qiunong , Chafeeva Irina , Mendelson Asher A. , da Roza Gerald , Liggins Richard , Kizhakkedathu Jayachandran N. , Du Caigan
Published: May 2018

Metabolic syndrome (MetS) is commonly observed among peritoneal dialysis (PD) patients, and hyperbranched polyglycerol (HPG) is a promising glucose‐sparing osmotic agent forPD. However, the biocompatibility of aHPG‐basedPDsolution (HPG) in subjects with MetS has not been investigated. This study compared the local and systemic effects of aHPGsolution with conventional physioneal (PYS) and icodextrin (ICO)PDsolutions in rats with MetS. Obese type 2 diabeticZSF1 rats received a daily intraperitoneal injection ofPDsolutions (10 mL) for 3 months. The peritoneal membrane (PM) function was determined by ultrafiltration (UF), and the systemic responses were determined by profiling blood metabolic substances, cytokines and oxidative status. Tissue damage was assessed by histology. At the end of the 3‐month treatment withPDsolutions,PMdamage andUFloss in both thePYSandICOgroups were greater than those in theHPGgroup. Blood analyses showed that compared to the baseline control, the rats in theHPGgroup exhibited a significant decrease only in serum albumin andIL‐6 and a minor glomerular injury, whereas in both thePYSandICOgroups, there were more significant decreases in serum albumin, antioxidant activity,IL‐6,KC/GRO(CXCL1) andTNF‐α (inICOonly) as well as a more substantial glomerular injury compared to theHPGgroup. Furthermore,PYSincreased serum creatinine, serum glucose and urine production. In conclusion, compared toPYSorICOsolutions, theHPGsolution had less adverse effects locally on thePMand systemically on distant organs (e.g. kidneys) and the plasma oxidative status in rats with MetS.
Potentially Inappropriate Prescribing to Older Patients: Criteria, Prevalence and an Intervention to Reduce It: The Prescription Peer Academic Detailing (Rx‐PAD) Study – A Cluster‐Randomized, Educational Intervention in Norwegian General Practice
Authors: Rognstad Sture , Brekke Mette , Gjelstad Svein , Straand Jørund , Fetveit Arne
Published: May 2018

Potentially inappropriate prescriptions (PIP) is drug treatment, which in general, at the group level for a median/mean patient, can be considered unfavourable meaning that the risks commonly may outweigh the benefits. This MiniReview reports and discusses the main findings in a large cluster‐randomized educational intervention in Norwegian general practice, aimed at reducing the prevalence of PIPs to patients ≥70 years (The Rx‐PAD study). Targets for the intervention were general practitioners (GPs) in continuing medical education (CME) groups receiving educational outreach visits (i.e. peer academic detailing). A Delphi consensus process, with a panel of medical experts, was undertaken to elaborate a list of explicit criteria defining PIPs for patients ≥70 years in general practice. Agreement was achieved for 36 explicit PIP criteria, the so‐called Norwegian General Practice (NorGeP) criteria. Using a selection (n = 24) of these criteria during a 1‐year baseline period on the prescribing practice of 454 GPs (i.e. those enrolled to participate in the intervention trial), we found a prevalence rate of 24.7 PIPs per 100 patients ≥70 years per year. In the Rx‐PAD study, 449 GPs completed an educational intervention (96.6% of the included GPs), 250 in the intervention group and 199 in the control arm. Following the intervention, PIPs were reduced by 13% (95% CI 8.6–17.3), and the number of patients who were no longer exposed to one or more PIPs was reduced by 1173 (8.1%). The GPs who responded most strongly to the educational intervention were the oldest GPs (57–68 years), and these were the GPs with the highest prevalence of PIPs at baseline before the intervention.
Allosteric and Orthosteric Activators of mGluR8 Differentially Affect the Chemotherapeutic‐Induced Human Neuroblastoma SH‐SY5Y Cell Damage: The Impact of Cell Differentiation State
Authors: Jantas Danuta , Grygier Beata , Zatorska Justyna , Lasoń Władysław
Published: May 2018

The participation of group III metabotropic glutamate receptors (mGluRs) in cancer growth and progression is still an understudied issue. Based on our recent data on high expression of mGluR8 in human neuroblastoma SH‐SY5Y cells, in this study, we evaluated the effect of an mGluR8‐specific positive allosteric modulator (PAM: AZ12216052) and orthosteric agonist [(S)‐3,4‐DCPG ((S)‐3,4‐dicarboxyphenylglycine)] on chemotherapeutic (doxorubicin, irinotecan or cisplatin)‐evoked cell damage in undifferentiated (UN‐) and retinoic acid‐differentiated (RA‐) SH‐SY5Y cells. The data showed that AZ12216052 as well as a group III mGluR antagonist (UBP1112) but not (S)‐3,4‐DCPG partially inhibited the cell damage evoked by doxorubicin, irinotecan or cisplatin in UN‐SH‐SY5Y cells. In RA‐SH‐SY5Y, we observed only a modest protective effect of mGluR8 PAM. In contrast, both types of mGluR8 activators significantly enhanced toxic effects of doxorubicin and irinotecan in RA‐SH‐SY5Y cells. These data suggest that in undifferentiated neuroblastoma malignant cells, some mGluR8 modulators can decrease cytotoxic effects of chemotherapeutics which exclude them from the group of putative anticancer agents. On the other hand, in SH‐SY5Y cells differentiated to a more mature neuron‐like phenotype, that is non‐malignant cells, the mGluR8 activators can aggravate the chemotherapeutic neurotoxicity which is a well‐known undesired effect of these drugs. Our pharmacological data add new observations to the unexplored field of research on the role of mGluR8 in cancer, pointing to complexity of response which could be mediated by particular types of mGluR8 ligands at least in neuroblastoma cells.
One‐carbon cycle support rescues sperm damage in experimentally induced varicocoele in rats
Authors: Mohammadi Parisa , Hassani‐Bafrani Hassan , Tavalaee Marziyeh , Dattilo Maurizio , Nasr‐Esfahani Mohammad H.
Published: May 2018

Objectives

To investigate whether micronutrients in support of the one‐carbon cycle and glutathione synthesis are effective in improving sperm damage after surgical varicocoele induction in rats and whether any effect is achieved without a rebound reductive stress as seen with oral antioxidants.

Materials and Methods

Surgical varicocoele was induced in adult male Wistar rats and resulted in significant damage to the testis and sperm cells measured at 2 and 4 months after surgery. At 2 months after surgery, rats received a 2‐month oral supplementation in support of the one‐carbon cycle containing B vitamins (B2, B3, B6, folic acid and B12), N‐acetyl‐cysteine, zinc, small amounts of vitamin E, and a natural source of betalains and quercetine (Condensyl®; Parthenogen SAGL, Lugano, Switzerland and Nurilia SARL, Lyon, France).

Results

One‐carbon cycle supplementation, compared to untreated controls, significantly improved the morphometric characteristics of testis (P < 0.05), sperm concentration, motility and abnormal morphology (P < 0.001), sperm chromatin condensation (aniline blue staining, P < 0.05), sperm DNA damage (acridine orange staining, P < 0.05) and sperm lipid peroxidation (BODIPY C11, P < 0.001). The improvement in both nuclear condensation and DNA damage and the lack of excessive inhibition of lipid peroxidation confirmed that no reductive stress had occurred.

Conclusions

Micronutrients in support of the one‐carbon cycle are effective in the treatment of surgically induced varicocoele in rats, probably by activating natural antioxidant defences and epigenetics. These results support the idea that essential micronutrients including B vitamins may also have a positive influence in clinical varicocoele, which should be tested in prospective clinical trials.
Systematic review of ureteral access sheaths: facts and myths
Authors: De Coninck Vincent , Keller Etienne Xavier , Rodríguez‐Monsalve María , Audouin Marie , Doizi Steeve , Traxer Olivier
Published: May 2018

The aim of the present paper was to review the literature on all available ureteral access sheaths (UASs) with their indications, limitations, risks, advantages and disadvantages in current modern endourological practice. Two authors searched Medline, Scopus, Embase and Web of Science databases to identify studies on UASs published in English. No time period restriction was applied. All original articles reporting outcomes or innovations were included. Additional articles identified through references lists were also included. Case reports, editorials, letters, review articles and meeting abstracts were excluded. A total of 754 abstracts were screened, 176 original articles were assessed for eligibility and 83 articles were included in the review. Based on a low level of evidence, UASs increase irrigation flow during flexible ureteroscopy and decrease intrapelvic pressure and probably infectious complications. Data were controversial and sparse on the impact of UASs on multiple reinsertions and withdrawals of a ureteroscope, stone‐free rates, ureteroscope protection or damage, postoperative pain, risk of ureteral strictures, and also on its cost‐effectiveness. Studies on the benefit of UASs in paediatrics and in patients with a coagulopathy were inconclusive. In the absence of good randomized data, the true impact of UASs on surgery outcome remains unclear. The present review may contribute to the evidence‐based decision‐making process at the individual patient level regarding whether or not a UAS should be used.
IDH‐mutated astrocytomas with 19q‐loss constitute a subgroup that confers better prognosis
Authors: Otani Ryohei , Uzuka Takeo , Higuchi Fumi , Matsuda Hadzki , Nomura Masashi , Tanaka Shota , Mukasa Akitake , Ichimura Koichi , Kim Phyo , Ueki Keisuke
Published: May 2018

IDH‐mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II‐IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next‐generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH‐mutated gliomas, 12 were 1p‐intact/19q‐intact (anaplastic astrocytomas [AA]), 7 were 1p‐intact/19q‐loss (AA), and 23 showed 1p/19q‐codeletion (anaplastic oligodendrogliomas). Of the 88 IDH‐wild type glioblastomas (GBMs), 14 showed 1p‐intact/19q‐loss status. All of the seven 1p‐intact/19q‐loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q‐loss AAs had regions presenting oligodendroglioma‐like morphology, and were associated with significantly longer overall survival compared to 19q‐intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q‐loss GBM and 19q‐intact GBM (P = .4). In a case of 19q‐loss AA, both oligodendroglial morphology and 19q‐loss disappeared after recurrence, possibly indicating correlation between 19q‐loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH‐mutated astrocytomas harboring 19q‐loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q‐intact astrocytomas.
Subcutaneous immunotherapy suppresses Th2 inflammation and induces neutralizing antibodies, but sublingual immunotherapy suppresses airway hyperresponsiveness in grass pollen mouse models for allergic asthma
Authors: Hesse L. , Brouwer U. , Petersen A. H. , Gras R. , Bosman L. , Brimnes J. , Oude Elberink J. N. G. , van Oosterhout A. J. M. , Nawijn M. C.
Published: May 2018

Background

Both subcutaneous and sublingual allergen immunotherapy (SCIT and SLIT) have been shown to effectively suppress allergic manifestations upon allergen exposure, providing long‐term relief from symptoms in allergic disorders including allergic asthma. Clinical studies directly comparing SCIT and SLIT report a different kinetics and magnitude of immunological changes induced during treatment. Comparative studies into the mechanisms underlying immune suppression in SCIT and SLIT are lacking.

Objective

We aimed to establish an experimental model for grass pollen (GP) SCIT and SLIT that would allow a head‐to‐head comparison of the two treatments.

Methods

BALB/c mice were sensitized with GP extract, followed by SCIT and SLIT treatments with various GP dosages. Subsequently, we challenged mice with GP and measured airway responsiveness (AHR), GP‐specific immunoglobulins, ear swelling tests (EST), eosinophilic inflammation in bronchoalveolar lavage fluid (BALF), and T cell cytokine release after restimulation of lung cells (IL‐5, IL‐10, and IL‐13).

Results

We find that SLIT treatment was able to suppress allergen‐induced AHR, while allergic inflammation was not effectively suppressed even at the highest GP dose in this model. In contrast, SCIT treatment induced higher levels of GP‐specific IgG1, while SLIT was superior in inducing a GP‐specific IgG2a response, which was associated with increased Th1 activity in lung tissue after SLIT, but not SCIT treatment. Interestingly, SCIT was able to suppress Th2‐type cytokine production in lung cell suspensions, while SLIT failed to do so.

Conclusions and clinical relevance

In conclusion, GP‐SCIT suppresses Th2 inflammation and induced neutralizing antibodies, while GP‐SLIT suppresses the clinically relevant lung function parameters in an asthma mouse model, indicating that the two application routes depend on partially divergent mechanisms of tolerance induction. Interestingly, these data mirror observations in clinical studies, underscoring the translational value of these mouse models.
Experimental approach in research of Guillain–Barré syndrome: A range of pathogeneses mediated by molecular mimicry
Authors: Koga Michiaki
Published: May 2018

Molecular mimicry between microbial antigens and host tissue is a highly attractive explanation for the pathogenesis of many autoimmune diseases. Among them, Guillain–Barré syndrome (GBS) is an excellent model to show the causal pathogenesis of molecular mimicry, because the epidemiological association of GBS with several infections has been established. The present review describes recent findings regarding the causative role of molecular mimicry in GBS that arises after infection with several different bacteria and viruses, including Campylobacter jejuni, Mycoplasma pneumoniae, cytomegalovirus, Haemophilus influenzae, Epstein–Barr virus, hepatitis E virus and Zika virus. Although many issues must be resolved to fully understand GBS pathogenesis, molecular mimicry is highly likely to be involved in the development of C. jejuni‐associated GBS and probably of M. pneumoniae‐associated GBS. Candidate autoantibodies that are generated in cytomegalovirus‐ and H. influenzae‐associated GBS types can also provide clues to the causal role of molecular mimicry. For other diseases associated with antecedent infections, clarification of pathogeneses is premature and warrants further research on molecular mimicry, as well as other autoimmune‐triggering mechanisms.
Retinoic acid‐inducible gene‐I, melanoma differentiation‐associated gene 5 and C‐X‐C motif chemokine ligand 10 are induced by a Toll‐like receptor 3 agonist in human brain microvascular endothelial cells
Authors: Imaizumi Tadaatsu , Arai Akine , Kawaguchi Shogo , Hayakari Ryo , Matsumiya Tomoh , Seya Kazuhiko , Yoshida Hidemi , Tanaka Hiroshi
Published: May 2018

Objective

Brain microvascular endothelial cells (BMEC) are the major component of the blood–brain barrier, and play a critical role in protecting the brain from pathogens. Although Toll‐like receptor 3 (TLR3) is known as an important pattern‐recognition receptor against viral double‐stranded RNA, the downstream reactions of TLR3 in human BMEC are not fully characterized. The purpose of the present study was to investigate the role of TLR3 signaling in the expression of retinoic acid‐inducible gene‐I (RIG‐I), melanoma differentiation‐associated gene 5 (MDA5) and C‐X‐C motif chemokine ligand 10 (CXCL10) in human BMEC.

Methods

The hCMEC/D3 cells, a human BMEC cell line, were cultured and stimulated with polyinosinic‐polycytidylic acid, a synthetic TLR3 agonist. Quantitative real‐time reverse transcription polymerase chain reaction, western blotting and enzyme‐linked immunosorbent assay were used to examine the expression of interferon‐β, RIG‐I and CXCL10. RNA interference against TLR3, interferon‐β, RIG‐I or MDA5 was also carried out.

Results

Expression of RIG‐I, MDA5 and CXCL10 were induced by polyinosinic‐polycytidylic acid, and this was inhibited by knockdown of either TLR3 or interferon‐β. Knockdown of RIG‐I or MDA5 did not affect the CXCL10 expression in the early phase (4 h), but decreased the CXCL10 induction in the late phase (8 or 24 h).

Conclusions

RIG‐I, MDA5 and CXCL10 are induced through TLR3 activation in hCMEC/D3 cells, and RIG‐I and MDA5 might function to enhance and/or prolong the reactions mediated by CXCL10. These molecules might play a distinct role in innate immune reactions against double‐stranded RNA viruses in human BMEC.
Perineal closure following extralevator abdominoperineal excision for cancer of the rectum
Authors: Barrie J. , Haque A. , Evans D. A.
Published: May 2018

Aim

Extralevator abdominoperineal resection (ELAPE) may be complicated by perineal wound healing problems and herniation. We report a consecutive series of 38 such patients with selective use of a fasciocutaneous V‐Y buttock advancement flap (BAF).

Method

Data were collected on a series of patients undergoing ELAPE for rectal malignancy between August 2011 and July 2017. Demographics, management and outcomes were recorded prospectively. Perineal wound problems were considered as ‘major’ if they required packing; otherwise, they were classed as ‘minor’.

Results

Thirty‐eight patients [eight female and 30 male; median age 63 (range: 35–89) years] underwent ELAPE. Thirty‐seven had an adenocarcinoma of the rectum and one had a malignant melanoma. The median tumour height (from the anal verge) was 30 (range: 0–80) mm. Sixteen patients had a BAF. The median length of stay was 10 (range: 6–25) days. Primary perineal healing occurred in 18 (47%) patients. Major wound breakdown occurred in three (10%) patients and minor wound breakdown in 17 (45%). Two of the 16 patients having a BAF had major wound breakdown: one wound took 9 weeks to heal completely and the other took 9 months. Of the 22 patients who did not have a BAF, one had a major wound breakdown which closed by 3 months. There were no perineal fistulae or chronic sinuses. There were two perineal herniae that were successfully repaired by perineal insertion of biological mesh (Permacol™; Covidien, Dublin, Ireland).

Conclusions

Selective use of a BAF for perineal closure can give good results in terms of healing and an acceptably low early perineal herniation rate.
Prognostic impact of interhospital variation in adjuvant chemotherapy for patients with Stage II/III colorectal cancer: a nationwide study
Authors: Arakawa K. , Kawai K. , Tanaka T. , Hata K. , Sugihara K. , Nozawa H.
Published: May 2018

Aim

Clinical guidelines recommend adjuvant chemotherapy for high‐risk patients with Stage II–III colorectal cancer. However, chemotherapeutic administration rates differ significantly between hospitals. We assessed the prognostic benefit of adjuvant chemotherapy in patients with Stage IIb/c colorectal cancer, and the prognostic impact of interhospital variations in the administration of adjuvant chemotherapy for Stage II–III colorectal cancer.

Method

We conducted a multicentre, retrospective study of 17 757 patients with Stage II–III colorectal cancer treated between 1997 and 2008 in 23 hospitals in Japan. Hospitals were classified as high‐rate (rate > 42.8%) or low‐rate (rate ≤ 42.8%), chemotherapy prescribing clinics.

Results

The 5‐year overall survival (OS) of patients with Stage II–III colorectal cancer receiving adjuvant chemotherapy was significantly higher than for those not receiving adjuvant chemotherapy (85.7% vs 79.2%, P < 0.01 and 79.9% vs 72.5%, P < 0.01, respectively). For patients with Stage II disease, adjuvant chemotherapy was an independent factor for longer OS (P < 0.01, hazard ratio = 0.71). Both adjuvant chemotherapy and high‐rate hospital independently improved OS for patients with Stage III colorectal cancer (both P < 0.01; hazard ratio = 0.68 and 0.87, respectively).

Conclusion

Significant prognostic benefit was found for patients with Stage IIb/c colorectal cancer who received adjuvant chemotherapy, with patients who were treated in hospitals with high adjuvant chemotherapy rates demonstrating better prognoses.
Slow treatment promotes control of harmful species by multiple agents
Authors: Lampert Adam , Hastings Alan , Sanchirico James N.
Published: May 2018

The management of harmful species, including invasive species, pests, parasites, and diseases, is a major, global challenge. Harmful species cause severe damage to ecosystems, biodiversity, agriculture, and human health. The control of harmful species is challenging and often requires cooperation among multiple agents, such as land‐owners, agencies, and countries. Agents may have incentives to contribute less, leaving more work for other agents, which can result in inefficient treatment. Here we present a dynamic game theory model and we show that slow treatment may promote a stable solution (Markovian Nash equilibrium) where all agents cooperate to remove the harmful species. The efficiency of this solution depends critically on the life history of the harmful species that determines the speed of optimal treatment. Furthermore, this cooperative equilibrium may coexist with other Nash equilibria, including one dictating no treatment of the harmful species, which implies that coordination among agents is critical for successful control.
The difficulty in interpreting gene expression profiling in BAP‐negative melanocytic tumors
Authors: Fischer Andrew S. , High Whitney A.
Published: May 2018

Background

BAP‐negative melanocytic tumors were unrecognized in the medical literature until 2011. While the clinical significance of these tumors is poorly understood, there is concern such lesions represent processes in transition, and malignant degeneration is a concern. We investigated use of a 23‐gene expression profiling (23‐GEP) test for distinction from melanoma with the aim of better characterizing the biologic potential of such tumors.

Methods

Twenty BAP‐negative melanocytic tumors, subjected to 23‐GEP (Myriad Genetic Laboratories, Inc. [Salt Lake City, Utah]) testing, were retrospectively analyzed.

Results

Tumors exhibited varying degrees of atypia and aberrant immunohistochemical profiles. 23‐GEP testing revealed a “malignant” genetic signature in four cases, a “benign” signature in 15 cases, and an “indeterminate” signature in one case. Array‐based comparative genomic hybridization (aCGH) testing was performed for two cases with a “malignant” 23‐GEP signature, but the aCGH result conflicted with 23‐GEP, and supported benignity. Conversely, in one case with a “benign” 23‐GEP result, aCGH testing supported assessment as melanoma. Moreover, evolving melanoma could not be wholly excluded by histopathological analysis in 2 “benign” cases.

Conclusions

BAP‐negative melanocytic tumors remain a diagnostic dilemma for dermatopathologists. A widely marketed 23‐GEP test may not be useful in distinguishing these tumors from spitzoid melanoma, at least in comparison to aCGH technology.
Adenodermatofibroma possessing dilated glandular structures with eccrine features: A case study
Authors: Muto Ikko , Kuwahara Fumi , Shintani Takako , Saruta Hiroshi , Nakama Takekuni , Ohata Chika
Published: May 2018

Adenodermatofibroma is a newly recognized variant of dermatofibroma characterized by dense proliferation of fibroblasts and histiocytes admixed with dilated glandular structures showing apocrine secretion. Only five cases of adenodermatofibroma have been reported to date. We report an additional case of adenodermatofibroma on the back of a 67‐year‐old female. In addition to the dilated glandular structures, nondilated eccrine units were present at the upper periphery of the lesion, above which the normal eccrine glands reside. Although decapitation secretion was observed in the nondilated eccrine units at the upper periphery of the lesion, this was not observed in the dilated glandular structures. The inner cells of the dilated glandular structures were S‐100 positive, similar to those of the secretory portion of eccrine glands. We considered the glandular structures in our patient were derived from the entrapped eccrine units. We suggest that the term “apocrine metaplasia” be applied to eccrine units showing decapitation secretion.
Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro
Authors: Breining Peter , Jensen Jonas B. , Sundelin Elias I. , Gormsen Lars C. , Jakobsen Steen , Busk Morten , Rolighed Lars , Bross Peter , Fernandez‐Guerra Paula , Markussen Lasse K. , Rasmussen Nanna E. , Hansen Jacob B. , Pedersen Steen B. , Richelsen Bjørn , Jessen Niels
Published: May 2018

Aims

To test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [11C]‐metformin tracer in mice and studying in vitro effects of metformin on cultured human brown adipocytes.

Materials and methods

Tissue‐specific uptake of metformin was assessed in mice by PET/CT imaging after injection of [11C]‐metformin. Human brown adipose tissue was obtained from elective neck surgery and metformin transporter expression levels in human and murine BAT were determined by qPCR. Oxygen consumption in metformin‐treated human brown adipocyte cell models was assessed by Seahorse XF technology.

Results

Injected [11C]‐metformin showed avid uptake in the murine interscapular BAT depot. Metformin exposure in BAT was similar to hepatic exposure. Non‐specific inhibition of the organic cation transporter (OCT) protein by cimetidine administration eliminated BAT exposure to metformin, demonstrating OCT‐mediated uptake. Gene expression profiles of OCTs in BAT revealed ample OCT3 expression in both human and mouse BAT. Incubation of a human brown adipocyte cell models with metformin reduced cellular oxygen consumption in a dose‐dependent manner.

Conclusion

These results support BAT as a putative metformin target.
Roles of the right temporo‐parietal and premotor cortices in self‐location and body ownership
Authors: Convento Silvia , Romano Daniele , Maravita Angelo , Bolognini Nadia
Published: May 2018

In the rubber hand illusion (RHI), the feeling that a fake hand belongs to oneself can be induced by the simultaneous, congruent touch of the fake visible hand and one's own hidden hand. This condition is also associated with a recalibration of the perceived location of the real hand. A cortical network, including premotor and temporo‐parietal areas, has been proposed as the basis of the RHI. However, the causal contribution of these areas to the discrete illusory components remains unclear. We used transcranial direct current stimulation (tDCS) to assess the contribution of the right premotor cortex (rPMc) and the right temporo‐parietal junction (rTPJ) to the RHI and explored the role of these areas in modulating the subjective experience of embodiment and the misperception of the hand position. We found that anodal tDCS of both rPMc and rTPJ increased the misjudgement of the real hand location towards the fake hand. Crucially, the difference in proprioceptive displacement evoked by the congruent and incongruent visuo‐tactile stroking was minimised when tDCS was applied over the rPMc, while it was amplified when the rTPJ was targeted. The parietal effects of tDCS also extended to the self‐report components of the RHI. These findings suggest that the tDCS of rTPJ modulates the RHI depending on the temporal congruency of the visuo‐tactile stimulation, while the tDCS of rPMc induces a general recalibration of hand coordinates, regardless of the visuo‐tactile congruency. The present results are discussed in the view of a multicomponent model of the RHI.
Distinct neural mechanisms for reading Arabic vs. verbal numbers: An ERP study
Authors: Proverbio Alice Mado , Bianco Marco , De Benedetto Francesco
Published: May 2018

In this electroencephalogram/event‐related potential (EEG/ERP) study, 16 volunteers were asked to compare the numerical equality of 360 pairs of multidigit numbers presented in Arabic or verbal format. Behavioural data showed faster and more accurate responses for digit targets, with a right hand/left hemisphere advantage only for verbal numerals. Occipito‐temporal N1, peaking at approximately 180 ms, was strongly left‐lateralized during verbal number processing and bilateral during digit processing. A LORETA (low‐resolution electromagnetic tomography) source reconstruction performed at the N1 latency stage (155–185 ms) revealed greater brain activation during coding of Arabic than of verbal stimuli. Digit perceptual coding was associated with the activation of the right angular gyrus (rAG), the left fusiform gyrus (FG,BA37), and left and right superior and medial frontal areas. N1 sources for verbal numerals included the left FG (BA37), the precuneus (BA31), the parahippocampal area and a small right prefrontal activation. In addition, verbal numerals elicited a late frontocentral negativity, possibly reflecting stimulus unfamiliarity or complexity. Overall, the data suggest distinct mechanisms for number reading through ciphers (digits) or words. Information about quantity was accessed earlier and more accurately if numbers were in a nonlinguistic code. Indeed, it can be speculated that numerosity processing would involve circuits originally involved in processing space (i.e., rAG/rIPS).
Soluble urokinase‐type plasminogen activator receptor is associated with signs of periodontitis in adolescents
Authors: Skottrup Peter D. , Dahlén Gunnar , Baelum Vibeke , Lopez Rodrigo
Published: May 2018

Owing to its molecular stability in body fluids, soluble urokinase‐type plasminogen activator receptor (suPAR) is used as a biomarker for the level of systemic inflammation. This study compares the suPAR levels in serum with those in the saliva of adolescents and evaluates their association with the periodontal conditions. Adolescents identified as screen positive (n = 87) or screen negative (n = 73) for periodontitis had saliva and serum samples taken, along with subgingival plaque samples. The concentrations of suPAR were determined in saliva and serum, and 18 microbial species and the immunoglobulin response to them was evaluated. Factor analyses were used to reduce the number of variables within each of the domains of clinical, microbiological, and immunological findings. The median salivary suPAR concentration was 13.18 [(interquartile range (IQR): 6.20–23.36] μg l−1 and was not associated with the serum suPAR levels (median 2.05; IQR: 1.62–2.46 μg l−1). Linear regression analysis showed that the log10(salivary suPAR concentration) was statistically significantly positively associated with the clinical phenotype ‘Periodontitis Extent’ (β = 0.28; 95% CI: 0.16–0.39) along with ‘Putative periodontopathogens’ (β = 0.65; 95% CI: 0.51–0.79). The study represents the first determination of salivary suPAR concentration in a larger well‐defined adolescent population. Our results suggest the potential for clinical use of suPAR in saliva as an inflammatory risk indicator/biomarker of periodontitis.
Valproic acid inhibits ATP‐triggered Ca2+ release via a p38‐dependent mechanism in bEND.3 endothelial cells
Authors: Leong Iat‐Lon , Tsai Tien‐Yao , Wong Kar‐Lok , Shiao Lian‐Ru , Cheng Ka‐Shun , Chan Paul , Leung Yuk‐Man
Published: May 2018

Valproic acid (VA) is currently used to treat epilepsy and bipolar disorder. It has also been demonstrated to promote neuroprotection and neurogenesis. Although beneficial actions of VA on brain blood vessels have also been demonstrated, the effects of VA on brain endothelial cell (EC) Ca2+ signaling are hitherto unreported. In this report, we examined the effects of VA on agonist‐triggered Ca2+ signaling in mouse cortical bEND.3 EC. While VA (100 μm) did not cause an acute inhibition of ATP‐triggered Ca2+ signaling, a 30‐min VA treatment strongly suppressed ATP‐triggered intracellular Ca2+ release; however, such treatment did not affect Ca2+ release triggered by cyclopiazonic acid, an inhibitor of SERCA Ca2+ pump, suggesting there was no reduction in Ca2+ store size. VA‐activated p38 signaling, and VA‐induced inhibition of ATP‐triggered Ca2+ release was prevented by SB203580, a p38 inhibitor, suggesting VA caused the inhibition by activating p38. Remarkably, VA treatment did not affect acetylcholine‐triggered Ca2+ release, suggesting VA may not inhibit inositol 1,4,5‐trisphosphate‐induced Ca2+ release per se, and may not act directly on Gq or phospholipase C. Taken together, our results suggest VA treatment, via a p38‐dependent mechanism, led to an inhibition of purinergic receptor‐effector coupling.
Cannabis smoking impairs driving performance on the simulator and real driving: a randomized, double‐blind, placebo‐controlled, crossover trial
Authors: Micallef Joëlle , Dupouey Julien , Jouve Elisabeth , Truillet Romain , Lacarelle Bruno , Taillard Jacques , Daurat Agnès , Authié Colas , Blin Olivier , Rascol Olivier , Philip Pierre , Mestre Daniel
Published: May 2018

Driving experiments in real conditions are considered as a ‘gold standard’ to evaluate the effects of drugs on driving performance. Several constraints are difficult to manage in these conditions, so driving simulation appears as the best alternative. A preliminary comparison is crucial before being able to use driving simulation as a valid evaluation method. The aim of this study was to design a driving simulation method for assessing drug effects on driving. We used cannabis (THC) as a positive control and assessed whether THC affects driving performance in simulation conditions and whether these effects are consistent with performance in real driving conditions. A double‐blind, placebo‐controlled, two successive two‐way crossover design was performed using cigarettes containing 20 mg of THC. Healthy occasional users of THC, aged 25–35 years, who had a consistent driving experience were included. The first two sessions were realized in simulation conditions, and the last two sessions were in real driving conditions. Driving performance was estimated through inappropriate line crossings (ILC) and the standard deviation of the vehicle's lateral position. Participants felt significantly drowsier and more tired after THC, whatever the driving condition. Driving stability was significantly impaired after THC, both in simulated and real driving conditions. We also found that ILC were significantly more numerous in driving simulation conditions, as compared to real driving. In conclusion, the driving simulator was proven to be more sensitive for demonstrating THC‐induced effects on driving performances. Driving simulation appears to be a good qualitative predictor of driving safety after drug intake.
Effects of Intraborehole Flow on Purging and Sampling Long‐Screened or Open Wells
Authors: Poulsen David L. , Cook Peter G. , Simmons Craig T. , McCallum James L. , Dogramaci Shawan
Published: May 2018

Hydraulic head differences across the screened or open interval of a well significantly influence the sampled water mixture. Sample bias can occur due to an insufficient pumping rate and/or due to native groundwater displacement by intraborehole flow (IBF). Proper understanding of the sampled water mixture is crucial for accurate interpretation of environmental tracers and groundwater chemistry data, and hence groundwater characterization. This paper uses numerical modeling to quantify sample bias caused by IBF in an un‐pumped high‐yield well, and the influence of pumping rate and heterogeneity on the volume of pumpage required to purge an IBF plume. The results show that (1) the pumping rate must be at least an order of magnitude greater than the IBF rate to achieve permeability‐weighted yield, (2) purge volume was 2.2 to 20.6 times larger than the IBF plume volume, with the ratio depending on plume location relative to hydraulic conductivity and head distributions, and (3) after an example 1000‐day un‐pumped period, purging required removal of at least three orders of magnitude more water than the common practice of three to five well volumes. These results highlight the importance of knowing the borehole flow regime to identify IBF inflow and outflow zones, estimate IBF rates, and to develop a strategic sampling approach.