bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2′,2′‐difluorodeoxyuridine and their nucleotides
Authors: Derissen Ellen J. B. , Huitema Alwin D. R. , Rosing Hilde , Schellens Jan H. M. , Beijnen Jos H. 
Published: February 2018

AimsGemcitabine (2′,2′‐difluoro‐2′‐deoxycytidine; dFdC) is a prodrug that has to be phosphorylated within the tumour cell to become active. Intracellularly formed gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) are considered responsible for the antineoplastic effects of gemcitabine. However, a major part of gemcitabine is converted into 2′,2′‐difluoro‐2′‐deoxyuridine (dFdU) by deamination. In the cell, dFdU can also be phosphorylated to its monophosphate (dFdUMP), diphosphate (dFdUDP) and triphosphate (dFdUTP). In vitro data suggest that these dFdU nucleotides might also contribute to the antitumour effects, although little is known about their intracellular pharmacokinetics (PK). Therefore, the objective of the present study was to gain insight into the intracellular PK of all dFdC and dFdU nucleotides formed during gemcitabine treatment.MethodsPeripheral blood mononuclear cell (PBMC) samples were collected from 38 patients receiving gemcitabine, at multiple time points after infusion. Gemcitabine, dFdU and their nucleotides were quantified in PBMCs. In addition, gemcitabine and dFdU plasma concentrations were monitored. The individual PK parameters in plasma and in PBMCs were determined.ResultsBoth in plasma and in PBMCs, dFdU was present in higher concentrations than gemcitabine [mean intracellular area under the concentration–time curve from time zero to 24 h (AUC0–24 h) 1650 vs. 95 μM*h]. However, the dFdUMP, dFdUDP and dFdUTP concentrations in PBMCs were much lower than the dFdCDP and dFdCTP concentrations. The mean AUC0–24 h for dFdUTP was 312 μM*h vs. 2640 μM*h for dFdCTP.ConclusionsThe study provides the first complete picture of all nucleotides that are formed intracellularly during gemcitabine treatment. Low intracellular dFdU nucleotide concentrations were found, which calls into question the relevance of these nucleotides for the cytotoxic effects of gemcitabine.
Shortcomings in the management of undescended testis: guideline intention vs reality and the underlying causes – insights from the biggest German cohort
Authors: Boehme Philip , Geis Berit , Doerner Johannes , Wirth Stefan , Hensel Kai O. 
Published: February 2018

ObjectivesTo assess the implementation of the current guideline and identify potential underlying causes for late surgery in children with undescended testis (UDT) in Germany. UDT is the most common surgical issue in paediatric urology and to avoid malignant degeneration and subfertility current guidelines recommend orchidopexy during the first year of life; however, this seems not to be implemented in practice.Patients and MethodsIn all, 5 547 patients with cryptorchidism at 16 hospitals nationwide were studied regarding age at orchidopexy between 2003 and 2016. Multivariate analysis was performed to identify factors influencing timing of surgery. Additionally, a survey on knowledge of UDT management was conducted amongst physicians treating boys and final‐year medical students.ResultsBetween 2003 and 2008 only 4% of boys with UDT underwent surgery before the age of 1 year. After the guideline update from 2009, this figure was 5% from 2010 to 2012, and 8% from 2013 to 2016. The presence of a specialised department for paediatric surgery, as well as a high UDT case‐to‐year ratio positively influenced the timing of orchidopexy. The survey revealed discipline‐specific differences in the levels of knowledge about UDT management. One‐third of respondents did not know the guideline recommendations and 61% felt insufficiently informed. International comparisons revealed significant differences in the age at surgery of boys with UDT, with Germany and Great Britain ranging in the middle of the field.ConclusionsCurrently, only a small proportion of boys with UDT are operated upon during their first year of life. The level of knowledge in attending physicians remains in need of improvement. This should be actively addressed, i.e. by campaigns and educational programmes. Further studies are needed to investigate the underlying causes of late orchidopexy in UDT.
GPCRs in context: sexual dimorphism in the cardiovascular system
Authors: Mouat Margaret A , Coleman James L J , Smith Nicola J 
Published: February 2018

Cardiovascular disease (CVD) remains the largest cause of mortality worldwide, and there is a clear gender gap in disease occurrence, with men being predisposed to earlier onset of CVD, including atherosclerosis and hypertension, relative to women. Oestrogen may be a driving factor for female‐specific cardioprotection, though androgens and sex chromosomes are also likely to contribute to sexual dimorphism in the cardiovascular system (CVS). Many GPCR‐mediated processes are involved in cardiovascular homeostasis, and some exhibit clear sex divergence. Here, we focus on the G protein‐coupled oestrogen receptor, endothelin receptors ETA and ETB and the eicosanoid G protein‐coupled receptors (GPCRs), discussing the evidence and potential mechanisms leading to gender dimorphic responses in the vasculature. The use of animal models and pharmacological tools has been essential to understanding the role of these receptors in the CVS and will be key to further delineating their sex‐specific effects. Ultimately, this may illuminate wider sex differences in cardiovascular pathology and physiology.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc
Mechanisms of imidazoline I2 receptor agonist‐induced antinociception in rats: involvement of monoaminergic neurotransmission
Authors: Siemian Justin N , Wang Kaixuan , Zhang Yanan , Li Jun‐Xu 
Published: February 2018

Background and PurposeAlthough the antinociceptive efficacies of imidazoline I2 receptor agonists have been established, the exact post‐receptor mechanisms remain unknown. This study tested the hypothesis that monoaminergic transmission is critical for I2 receptor agonist‐induced antinociception.Experimental Approachvon Frey filaments were used to assess antinociceptive effects of two I2 receptor agonists, 2‐BFI and CR4056 on chronic constriction injury (CCI)‐induced neuropathic pain or complete Freund's adjuvant (CFA)‐induced inflammatory pain in rats. Rectal temperature was measured to assess hypothermic effects of 2‐BFI. A two‐lever drug discrimination paradigm in which rats were trained to discriminate 5.6 mg·kg−1 2‐BFI (i.p.) from its vehicle was used to examine the discriminative stimulus effects of 2‐BFI. In each experiment, pharmacological mechanisms were investigated by combining 2‐BFI or CR4056 with various pharmacological manipulations of the monoaminergic system including selective reuptake inhibition, monoamine depletion and monoamine receptor antagonism.Key ResultsIn the CCI model, selective reuptake inhibitors of 5‐HT (fluoxetine) or noradrenaline (desipramine), but not dopamine (GBR12909), enhanced 2‐BFI‐induced antinociception. Selective depletion of 5‐HT or noradrenaline almost abolished 2‐BFI‐induced antinociception. 5‐HT1A, 5‐HT2A and α1‐adrenoceptor antagonists, but not other monoaminergic antagonists, attenuated 2‐BFI and CR4056‐induced antinociception in CCI and/or CFA models. However, none of these monoamine receptor antagonists significantly altered 2‐BFI‐induced hypothermia or discriminative stimulus effects.Conclusions and ImplicationsAntinociception induced by I2 receptor agonists was mediated by serotonergic and noradrenergic mechanisms with 5‐HT1A, 5‐HT2A and α1‐adrenoceptor being particularly important. In contrast, the hypothermic and discriminative stimulus effects of I2 receptor agonists were mediated by distinct, independent mechanisms.
Severity of cerebral palsy and likelihood of adverse events after botulinum toxin A injections
Authors: Swinney Caitlyn M , Bau Karen , Burton Karen L Oakley , O'Flaherty Stephen J , Bear Natasha L , Paget Simon P 
Published: February 2018

AimTo determine the incidence of common adverse events after botulinum toxin A (BoNT‐A) injections in children with cerebral palsy (CP) and to identify whether the severity of CP influences the incidence of adverse events.MethodThis was an observational study of patients attending a BoNT‐A clinic at a tertiary paediatric hospital (2010–2014). Data examined included procedural adverse events at the time of injection and at follow‐up. Systemic adverse events were defined as lower respiratory tract illnesses, generalized weakness, dysphagia, and death. Severity of CP was categorized by the Gross Motor Function Classification System (GMFCS). The relationships between GMFCS and adverse events were analysed using negative binomial regression models.ResultsIn total, 591 children underwent 2219 injection episodes. Adverse events were reported during the procedure (130 [6%] injection episodes) and at follow‐up (492 [22%] injection episodes). There were significantly increased rates of systemic adverse events in injection episodes involving children in GMFCS level IV (incidence rate ratio [IRR] 3.92 [95% confidence interval] 1.45–10.57]) and GMFCS level V (IRR 7.37 [95% confidence interval 2.90–18.73]; p<0.001).InterpretationAdverse events after BoNT‐A injections are common but mostly mild and self‐limiting. Children in GMFCS levels IV and V are at increased risk of systemic adverse events. The relationship between CP severity and BoNT‐A adverse events is complex and further research is required to better understand this relationship.What this paper adds

Adverse events reported at the time of botulinum toxin A injection occurred in 6% of injection episodes.

Adverse events were reported at follow‐up in 22% of injection episodes.

Children in Gross Motor Function Classification System (GMFCS) levels IV and V have increased rates of systemic adverse events.

Children in GMFCS levels IV and V report less local weakness and pain.
Intrinsic changes of left ventricular function in patients with Behçet disease and comparison according to systemic disease activity
Authors: Sun Byung Joo , Park Jae‐Hyeong , Yoo Su‐Jin , Park Yunseon , Kim Yeon Ju , Lee In Suk , Kim Jinhyun , Yoo In Seol , Shim Seung Cheol , Kang Seong Wook , Kim Jun‐Hyung , Lee Jae‐Hwan , Choi Si Wan , Jeong Jin‐Ok , Seong In‐Whan 
Published: February 2018

PurposeAlthough cardiac manifestation of Behçet disease (BD) has been described in sporadic reports, its timely diagnosis remains difficult. The objective of this study was to describe early cardiac manifestations of BD. We also performed a comprehensive classification of systemic BD activity and compared their cardiac manifestations.MethodsA prospective screening using speckle tracking echocardiography was performed in 85 patients with BD who had no history of heart disease. After excluding subjects with left ventricular (LV) ejection fraction (LVEF) <50% (n = 1), atrial fibrillation (n = 2), or inadequate echocardiographic images (n = 1), we analyzed their clinical and echocardiographic parameters including LV global longitudinal strains (GLS) and compared them with those of an age‐ and gender‐matched control group (n = 145). Systemic BD activity was classified as minimal (Group A), controlled (Group B), and active (Group C).ResultsIn 81 study patients (59 females, age of 51 ± 11 years), echocardiography revealed a mean LVEF of 64 ± 5% without any significant valvular dysfunction or aortic aneurysm. Although there was no difference in LVEF between the control group and the patient group, the patient group showed significant reduction in GLS (‐17.1 ± 2.9% vs ‐20.8 ± 2.2%, P < .001). Groups A (n = 21, 26%), B (n = 47, 58%), and C (n = 13, 58%) consistently showed reduction in GLS compared with the control group. However, there was no significant difference in cardiac manifestations among these groups according to systemic disease activity.ConclusionPatients with BD present intrinsic LV dysfunction despite no apparent abnormality on routine echocardiography. However, their cardiac manifestations are not proportional to systemic BD activity.
Cortical projections to the superior colliculus in grey squirrels (Sciurus carolinensis)
Authors: Baldwin Mary K. L. , Young Nicole A. , Matrov Denis , Kaas Jon H. 
Published: February 2018

AbstractThe superior colliculus is an important midbrain structure involved with integrating information from varying sensory modalities and sending motor signals to produce orienting movements towards environmental stimuli. Because of this role, the superior colliculus receives a multitude of sensory inputs from a wide variety of subcortical and cortical structures. Proportionately, the superior colliculus of grey squirrels is among the largest in size of all studied mammals, suggesting the importance of this structure in the behavioural characteristics of grey squirrels. Yet, our understanding of the connections of the superior colliculus in grey squirrels is lacking, especially with respect to possible cortical influences. In this study, we placed anatomical tracer injections within the medial aspect of the superior colliculus of five grey squirrels (Sciurus carolinensis) and analysed the areal distribution of corticotectal projecting cells in flattened cortex. V1 projections to the superior colliculus were studied in two additional animals. Our results indicate that the superior colliculus receives cortical projections from visual, higher order somatosensory, and higher order auditory regions, as well as limbic, retrosplenial and anterior cingulate cortex. Few, if any, corticotectal projections originate from primary motor, primary somatosensory or parietal cortical regions. This distribution of inputs is similar to the distribution of inputs described in other rodents such as rats and mice, yet the lack of inputs from primary somatosensory and motor cortex is features of corticotectal inputs more similar to those observed in tree shrews and primates, possibly reflecting a behavioural shift from somatosensory (vibrissae) to visual navigation.
Efficacy and safety of eslicarbazepine acetate monotherapy in patients converting from carbamazepine
Authors: Pazdera Ladislav , Sperling Michael R. , Harvey Jay H. , Sam Maria C. , Strom Laura A. , Blum David , Grinnell Todd , Cheng Hailong 
Published: February 2018

SummaryObjectiveTo evaluate the influence of prior use of carbamazepine (CBZ) and other antiepileptic drugs (AEDs) with a putatively similar mechanism of action (inhibition of voltage‐gated sodium channels;VGSCs) on seizure outcomes and tolerability when converting to eslicarbazepine acetate (ESL), using data pooled from 2 controlled conversion‐to‐ESLmonotherapy trials (studies: 093‐045, 093‐046).MethodsAdults with treatment‐resistant focal (partial‐onset) seizures were randomized 2:1 toESL1600 or 1200 mg once daily. The primary efficacy endpoint was study exit (meeting predefined exit criteria related to worsening seizure control) versus an historical control group. Other endpoints included change in seizure frequency, responder rate, and tolerability. Endpoints were analyzed for subgroups of patients who receivedCBZ(or anyVGSCinhibitor [VGSCi]) during baseline versus those who received otherAEDs.ResultsOf 365 patients in the studies, 332 were evaluable for efficacy. The higher risk of study exit in the subgroups that receivedCBZ(or anyVGSCi) during baseline, versus otherAEDs, was not statistically significant (hazard ratios were 1.49 for +CBZvs −CBZ[P= .10] and 1.27 for +VGSCi vs. −VGSCi [P= .33]). Reductions in seizure frequency and responder rates were lower in patients who converted fromCBZor otherVGSCi compared with those who converted from otherAEDs. There were no notable differences in overall tolerability between subgroups, but the incidence of some adverse events (eg, dizziness, somnolence, nausea) differed between subgroups and/or between treatment periods.SignificanceBaseline use ofCBZor other major putativeVGSCinhibitors did not appear to significantly increase the risk of study exit due to worsening seizure control, or to increase the frequency of side effects when converting toESLmonotherapy. However, bigger improvements in efficacy may be possible in patients converting toESLmonotherapy from anAEDregimen that does not include aVGSCinhibitor.
Primary sebocytes and sebaceous gland cell lines for studying sebaceous lipogenesis and sebaceous gland diseases
Authors: Schneider Marlon R. , Zouboulis Christos C. 
Published: February 2018

AbstractSebocytes, the major cell type in sebaceous glands, are differentiated epithelial cells that gradually accumulate lipids and eventually disrupt, releasing their content (sebum) in a secretory process known as holocrine secretion. Via the hair canal, sebum reaches the skin surface, where it has several known or postulated functions, including pheromonal, thermoregulatory, antimicrobial and antioxidant activities. Altered sebum secretion and/or structural sebaceous gland changes have also been involved in the pathogenesis of skin diseases, such as acne vulgaris and some forms of alopecia. Here, we assess how recent work employing primary sebocytes and sebaceous gland cell lines contributed for our understanding of sebaceous lipogenesis and its role in skin health and disease.
Decreased anterior cingulate activation in a motor task in youths with bipolar disorder
Authors: King Jace B. , Anderson Jeffrey S. , Yurgelun‐Todd Deborah A. , Subramaniam Punitha , Ehrler Marie R. , Lopez‐Larson Melissa P. 
Published: February 2018

BackgroundBipolar disorder (BP) is characterized by abnormal shifts in mood between episodes of mania and severe depression, both of which have been linked with psychomotor disturbances. This study compares brain activation patterns in motor networks between euthymic youths with BP and healthy controls (HC) during the completion of a simple motor task.MethodsThirty‐five youths with BP and 35 HC (aged 10–19) completed a self‐paced sequential bilateral finger‐tapping task, consisting of a 4‐minute scan block with alternating 20‐second periods of either the tapping task (six blocks) or rest (six blocks), while undergoing functional magnetic resonance imaging. Clinical and behavioral symptoms were assessed using the Child Behavior Checklist (CBCL). A between‐group whole‐brain analysis compared activation pattern differences while controlling for effects of age and sex. Clusters meeting whole‐brain false discovery rate (FDR) correction (qFDR < .05) were considered statistically significant. Post hoc analyses evaluating comorbid attention‐deficit/hyperactivity disorder (ADHD) in the BP group were also conducted.ResultsSignificantly decreased activation was found in the anterior cingulate cortex (ACC) in youths with BP compared to HC. Furthermore, ACC activation was negatively correlated with CBCL mood dysregulation profile scores in the BP group. No significant differences in functional activation patterns were found between youths with BP and comorbid ADHD and those with only BP.ConclusionsThese findings suggest a potential common mechanism of impaired ACC modulation between emotion dysregulation and motor processing in youths with BP.
Identification and characterization of Cucurbita gummy stem blight fungi in Northeast China
Authors: Zhao Qian , Wu Jianzhong , Zhang Liyan , Xu Lizhen , Yan Chao , Gong Zhenping 
Published: February 2018

AbstractCucurbita maxima (pumpkin) is a typical cucurbit that is susceptible to gummy stem blight. In recent years, this major fungal disease has decimated pumpkin yields in Northeast China (Heilongjiang Province) in increasingly numerous outbreaks with more rapid spread in recent years. After culturing fungi on potato dextrose agar medium, we conducted a systematic study of the growth and morphological characteristics of various purified strains of Cucurbita gummy stem blight (GSB) fungus from across Northeast China. Subsequently, DNA samples of 30 isolates with distinct hyphal variations were subjected to internal transcribed spacer (ITS) sequencing. Sequence analysis resulted in identification of the isolates as Stagonosporopsis cucurbitacearum and demonstrated that this is a dominant and widely distributed fungal species in this region. Subsequently, multi‐site phylogenetic analysis assigned the 30 aforementioned strains to two genotypes that aligned to seven phenotypic types of Cucurbita GSB fungi. By analysing ITS conserved sequences of these phenotypically diverse groups, we found that Cucurbita GSB pathogens broadly shared two motifs that contained sequence variations unique to two groups in addition to common identical motifs. Ultimately, this study provided useful data for rapid and accurate identification of S. cucurbitacearum and diagnosis in early symptoms of Cucurbita GSB. This work also provides tools to explore the distribution and regularity of GSB outbreaks spatially and temporally across Northeast China.
Transitions in sex determination and sex chromosomes across vertebrate species
Authors: Pennell Matthew W. , Mank Judith E. , Peichel Catherine L. 
Published: February 2018

AbstractDespite the prevalence of sexual reproduction across eukaryotes, there is a remarkable diversity of sex‐determination mechanisms. The underlying causes of this diversity remain unclear, and it is unknown whether there are convergent trends in the directionality of turnover in sex‐determination mechanisms. We used the recently assembled Tree of Sex database to assess patterns in the evolution of sex‐determination systems in the remarkably diverse vertebrate clades of teleost fish, squamate reptiles and amphibians. Contrary to theoretical predictions, we find no evidence that the evolution of separate sexes is irreversible, as transitions from separate sexes to hermaphroditism occur at higher rates than the reverse in fish. We also find that transitions from environmental sex determination to genetic sex determination occur at higher rates than the reverse in both squamates and fish, suggesting that genetic sex determination is more stable. However, our data are not consistent with the hypothesis that heteromorphic sex chromosomes are an “evolutionary trap.” Rather, we find similar transition rates between homomorphic and heteromorphic sex chromosomes in both fish and amphibians, and to environmental sex determination from heteromorphic vs. homomorphic sex chromosome systems in fish. Finally, we find that transitions between male and female heterogamety occur at similar rates in amphibians and squamates, while transitions to male heterogamety occur at higher rates in fish. Together, these results provide the most comprehensive view to date of the evolution of vertebrate sex determination in a phylogenetic context, providing new insight into long‐standing questions about the evolution of sexual reproduction.