bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Akt inhibitor, triciribine, ameliorates chronic hypoxia‐induced vascular pruning and TGFβ‐induced pulmonary fibrosis
Authors: Abdalla Maha , Sabbineni Harika , Prakash Roshini , Ergul Adviye , Fagan Susan C , Somanath Payaningal R 
Published: May 2015

Background and PurposeInterstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt‐mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.Experimental ApproachWe investigated the role of the Akt‐mTOR pathway and its downstream molecular mechanisms in chronic hypoxia‐ and TGFβ‐induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice.Key ResultsAkt1−/− mice were protected from chronic hypoxia‐induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFβ‐induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia‐ and TGFβ‐induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1−/− mice lungs expressed less TSP1. Moreover, TSP1−/− mice were resistant to adMyrAkt1‐induced pulmonary fibrosis.Conclusions and ImplicationsOur study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.
Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells
Authors: Shayhidin Elnur Elyar , Forcellini Elsa , Boulanger Marie‐Chloé , Mahmut Ablajan , Dautrey Sébastien , Barbeau Xavier , Lagüe Patrick , Sévigny Jean , Paquin Jean‐François , Mathieu Patrick 
Published: May 2015

Background and PurposeEctonucleotide pyrophosphatase/PDE1 (NPP1) is an ectoenzyme, which plays a role in several disorders including calcific aortic valve disease (CAVD). So far, compounds that have been developed as inhibitors of NPP1 lack potency and specificity. Quinazoline‐4‐piperidine sulfamides (QPS) have been described as potent inhibitors of NPP1. However, their mode of inhibition as well as their selectivity and capacity to modify biological processes have not been investigated.Experimental ApproachIn the present series of experiments, we have evaluated the efficacy of two derivatives, QPS1‐2, in inhibiting human NPP1, and we have evaluated the effect of the most potent derivative (QPS1) on other ectonucleotidases as well as on the ability of this compound to prevent phosphate‐induced mineralization of human primary aortic valve interstitial cells (VICs).Key ResultsThe QPS1 derivative is a potent (Ki 59.3 ± 5.4 nM) and selective non‐competitive inhibitor of human NPP1. Moreover, QPS1 also significantly inhibited the K121Q NPP1 gene variant (Ki 59.2 ± 14.5 nM), which is prevalent in the general population. QPS1 did not significantly alter the activity of other nucleotide metabolizing ectoenzymes expressed at the cell surface, namely NPP3, NTPDases (1–3), ecto‐5′‐nucleotidase and ALP. Importantly, QPS1 in the low micromolar range (≤10 μM) prevented phosphate‐induced mineralization of VICs and lowered the rise of osteogenic genes as expected for NPP1 inhibition.Conclusions and ImplicationsWe have provided evidence that QPS1 is a potent and selective non‐competitive inhibitor of NPP1 and that it prevented pathological mineralization in a cellular model.
Sex hormones regulate cerebral drug metabolism via brain miRNAs: down‐regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol
Authors: Li Jie , Xie Mengmeng , Wang Xiaoshuang , Ouyang Xiufang , Wan Yu , Dong Guicheng , Yang Zheqiong , Yang Jing , Yue Jiang 
Published: May 2015

Background and PurposeBrain cytochrome P450 2D (CYP2D) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP2D can be regulated in an organ‐specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNAs in the selective regulation of brain CYP2D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone.Experimental ApproachThe regulation of CYP2D and brain‐enriched miRNAs by testosterone was investigated using SH‐SY5Y cells, U251 cells, and HepG2 cells as well as orchiectomized growth hormone receptor knockout (GHR‐KO) mice and rats. Concentration–time curves of tramadol in rat brain were determined using a microdialysis technique. The analgesic action of tramadol was assessed by the tail‐flick test in rats.Key ResultsmiR‐101 and miR‐128‐2 bound the 3′‐untranslated region of the CYP2D6 mRNA and decreased its level. Testosterone decreased CYP2D6 catalytic function via the up‐regulation of miR‐101 and miR‐128‐2 in SH‐SY5Y and U251 cells, but not in HepG2 cells. Orchiectomy decreased the levels of miR‐101 and miR‐128‐2 in the hippocampus of male GHR‐KO mice, indicating that androgens regulate miRNAs directly, not via the alteration of growth hormone secretion patterns. Changes in the pharmacokinetic and pharmacodynamic profiles of tramadol by orchiectomy was attenuated by either testosterone supplementation or a specific brain CYP2D inhibitor.Conclusions and ImplicationsThe selective regulation of brain CYP2D via brain‐enriched miRNAs, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances.
Long‐term isolation and endemicity of Neotropical aquatic insects limit the community responses to recent amphibian decline
Authors: Múrria Cesc , Rugenski Amanda T. , Whiles Matt R. , Vogler Alfried P. 
Published: May 2015

AbstractAimNeotropical highland streams have shown diminished ecosystem functioning after amphibian extirpation infected by the chytrid fungus Batrachochytrium dendrobatidis. The loss of amphibians could affect communities of aquatic insects co‐occurring in these streams in various ways. We examined patterns of species and genetic diversity of these communities and their evolutionary history along the chytrid expansion gradient to elucidate potential community responses.LocationSix streams over a 320‐km transect in Panama affected by chytrid expansion from west to east for up to 14 years, and two apparently chytrid‐free streams in the east.MethodsPatterns of α‐ and β‐diversity were investigated at three hierarchical levels: genus, species and haplotypes. Genus identification was based on morphology, and putative species were inferred by grouping the DNA barcodes (749 cox1 sequences) with the GMYC method on all collected individuals of Ephemeroptera, Trichoptera, Coleoptera and Plecoptera.ResultsA total of 96 genera in 43 families (9 orders) of insects were encountered. Genus‐level α‐diversity was higher in the easternmost streams, possibly due to a separate biogeographical history, whereas β‐diversity was constant along the chytrid expansion gradient. Community DNA barcoding resulted in 426 cox1 haplotypes and 154 putative species, most of them limited to single sites. High β‐diversity along the gradient at both species and haplotype levels argues against community homogenization by migration in the wake of amphibian declines. In contrast, phylo‐β‐diversity was low, indicating community similarity at deep levels.Main conclusionsAquatic insect communities in this region are influenced by long‐term limited dispersion that generated high endemicity. The pattern persists mostly unperturbed after disease‐driven amphibian declines; hence, if indeed insects fill the niches vacated by tadpoles, they would originate from local communities rather than immigration. Given the unique evolutionary history and physical isolation of local assemblages, the ecosystem deterioration carries the risk of losing unique diversity.
Women with an HbA1c of 41–49 mmol/mol (5.9–6.6%): a higher risk subgroup that may benefit from early pregnancy intervention
Authors: Rowan J. A. , Budden A. , Ivanova V. , Hughes R. C. , Sadler L. C. 
Published: May 2015

AbstractAimsTo examine whether women with an HbA1c of 41–49 mmol/mol (5.9–6.6%) at diagnosis of gestational diabetes are higher risk than women with an HbA1c of < 41 mmol/mol (5.9%) and whether pregnancy outcomes are improved if treated at < 24 weeks' gestation.MethodsThis was an observational study of women with gestational diabetes diagnosed by early HbA1c screening or subsequent oral glucose tolerance test at < 34 weeks' gestation who delivered at National Women's Health, Auckland, from July 2012 to June 2014. Data were extracted from the hospital database. Women with HbA1c 41–49 mmol/mol (5.9–6.6%) were divided into those seen < 24 weeks (Early, n = 134) and those seen ≥ 24 weeks (Later, n = 151). Those with HbA1c < 41 mmol/mol (5.9%) were labelled Other GDM (n = 661).ResultsThe Early and Later groups, compared with Other GDM, had more Polynesian and fewer (non‐Indian) Asian women, higher BMI and more required medication (P < 0.001). More were smokers (P = 0.007, 0.02) and more had chronic hypertension (P < 0.001, 0.02). There were higher rates of adverse outcomes in the Later group than the Other GDM group (pre‐eclampsia 8.0% vs. 2.4%, P = 0.001, preterm birth 16.6% vs. 8.2%, P = 0.002, neonatal admission 15.5% vs. 9.2%, P = 0.02). Outcomes were similar between the Early group and Other GDM group (pre‐eclampsia 1.5% vs. 2.4%, P = 0.5, preterm birth 10.5% vs. 8.2% P = 0.4, neonatal admission 13.6% vs. 9.2%, P = 0.12). Comparing the Early and Later groups, the Early group had less pre‐eclampsia, 1.5% vs. 8.0%, adjusted P = 0.03. Other outcomes were not statistically different.ConclusionsAn HbA1c of 41–49 mmol/mol (5.9–6.7%) identifies a higher‐risk group of women with gestational diabetes. Overall, our data support early treatment of women with an HbA1c ≥ 41 mmol/mol (5.9%).
Low density lipoprotein receptor related protein 1 and 6 gene variants and ischaemic stroke risk
Authors: Harriott A. M. , Heckman M. G. , Rayaprolu S. , Soto‐Ortolaza A. I. , Diehl N. N. , Kanekiyo T. , Liu C.‐C. , Bu G. , Malik R. ,   the METASTROKE Consortium, Cole J. W. , Meschia J. F. , Ross O. A. 
Published: May 2015

Background and purposeLow density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS).MethodsA Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke.ResultsIn the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non‐carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006).ConclusionsThe results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted.
Risk of Parkinson's disease following anxiety disorders: a nationwide population‐based cohort study
Authors: Lin C.‐H. , Lin J.‐W. , Liu Y.‐C. , Chang C.‐H. , Wu R.‐M. 
Published: May 2015

Background and purposeAnxiety is potentially a pre‐motor symptom of Parkinson's disease (PD). Our aim was to investigate the association between anxiety and subsequent PD risk in a population‐based sample.MethodsA total of 174 776 participants, who were free of prior PD, dementia and stroke, were enrolled from Taiwan National Health Insurance Research Database between 1 January 2005 and 31 December 2005. The association between anxiety at the beginning of the study and the incidence of PD was examined using a Cox regression model. Information regarding comorbidities, especially depression, and concomitant medication use was adjusted in the proportional hazards models.ResultsOver an average follow‐up of 5.5 years, 2258 incident PD cases were diagnosed. After adjusting for age, sex, comorbidities and concomitant medication use, patients with anxiety were more likely to develop PD than subjects without anxiety [adjusted hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.26–1.51]. Anxiety severity was dose‐dependently associated with increased likelihood of PD: crude HR 1.27 (95% CI 1.11–1.44) for mild anxiety, 1.35 (95% CI 1.19–1.53) for moderate anxiety and 2.36 (95% CI 2.13–2.62) for severe anxiety (P < 0.0001). Results were similar after adjustment for age, sex, comorbid depression and other PD risk factors, and in the sensitivity analyses excluding participants with comorbid depression or with a PD diagnosis <3 years after anxiety diagnosis, and controlling for Charlson's scores.ConclusionsThe likelihood of developing PD was greater amongst patients with anxiety than patients without anxiety, and the severity of anxiety correlated with risk of PD.
Midazolam as an anticonvulsant antidote for organophosphate intoxication—A pharmacotherapeutic appraisal
Authors: Reddy Sandesh D. , Reddy Doodipala Samba 
Published: May 2015

SummaryObjectiveThis review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication.MethodsBenzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action.ResultsMidazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic γ‐aminobutyric acid (GABA)A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings.SignificanceIn experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence.
Antiepileptic drugs alter the expression of placental carriers: An in vitro study in a human placental cell line
Authors: Rubinchik‐Stern Miriam , Shmuel Miri , Eyal Sara 
Published: May 2015

SummaryObjectiveAntiepileptic drugs (AEDs) affect the expression of carriers for drugs and nutrients at several blood‐tissue barriers, but their impact on placental carriers is largely unknown. Our aim was to study the effects of AEDs in human placental cells on the expression of carriers for hormones, nutrients, and drugs: folate placental uptake carriers (reduced folate carrier, RFC; folate receptor α, FRα) and efflux transporters (breast cancer resistance protein, BCRP and multidrug resistance protein 2) and thyroid hormone uptake transporters (l‐type amino acid transporter‐LAT1 and organic anion transporting polypeptides‐OATPs).MethodsThe human trophoblast BeWo cells were incubated with phenytoin (PHT), valproic acid (VPA), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), or their vehicles at concentrations that mostly represent their therapeutic range. RT‐PCR and western blot analysis were utilized to study the effects of AEDs on carriers’ mRNA and protein expression, respectively. The activity of BCRP was evaluated by accumulation studies.ResultsCompared with controls, VPA‐treated cells displayed half the levels of RFC mRNA and protein (p < 0.05) and up to 2.7‐fold increases in BCRP mRNA and protein expression (p < 0.05), together with enhanced BCRP activity. PHT increased the expression of BCRP and LAT1 by 2.9‐fold and 2.5‐fold, respectively (p < 0.01). LTG modulated the levels of FRα transcript and protein, whereas LEV altered those of RFC, LAT1, and OATPs 1A2 and 4A1. CBZ affected carrier expression at the mRNA but not the protein level. All the AEDs altered to a modest extent the transcription of nuclear receptors known to regulate transporter expression.SignificanceThese findings suggest a possible effect of AEDs on placental transport mechanisms for folate and thyroid hormones as well as those involved in the elimination of potential toxins from the fetus. Identification of AED effects on the placental barrier could be a first step toward a more rational pharmacotherapy and supplemental therapy in pregnant women with epilepsy.
Evolutionary biology and genetic techniques for insect control
Authors: Leftwich Philip T. , Bolton Michael , Chapman Tracey 
Published: May 2015

AbstractThe requirement to develop new techniques for insect control that minimize negative environmental impacts has never been more pressing. Here we discuss population suppression and population replacement technologies. These include sterile insect technique, genetic elimination methods such as the release of insects carrying a dominant lethal (RIDL), and gene driving mechanisms offered by intracellular bacteria and homing endonucleases. We also review the potential of newer or underutilized methods such as reproductive interference, CRISPR technology, RNA interference (RNAi), and genetic underdominance. We focus on understanding principles and potential effectiveness from the perspective of evolutionary biology. This offers useful insights into mechanisms through which potential problems may be minimized, in much the same way that an understanding of how resistance evolves is key to slowing the spread of antibiotic and insecticide resistance. We conclude that there is much to gain from applying principles from the study of resistance in these other scenarios – specifically, the adoption of combinatorial approaches to minimize the spread of resistance evolution. We conclude by discussing the focused use of GM for insect pest control in the context of modern conservation planning under land‐sparing scenarios.
Skeletal muscle mass assessed by computed tomography correlates to muscle strength and physical performance at a liver‐related hospital experience
Authors: Itoh Shinji , Shirabe Ken , Yoshizumi Tomoharu , Takeishi Kazuki , Harimoto Norifumi , Ikegami Toru , Kawanaka Hirofumi , Nishie Akihiro , Kamishima Takahide , Maehara Yoshihiko 
Published: May 2015

AimWe aimed to evaluate whether skeletal muscle mass measured by computed tomography (CT) or bioelectrical impedance analysis (BIA) correlated to muscle strength and physical performance in liver‐related hospital cases.MethodsWe prospectively conducted this study in 120 liver‐related hospital cases. Skeletal muscle mass was measured by CT scan and BIA. Muscle strength was determined by hand grip strength and physical performance by usual gait speed.ResultsSkeletal muscle mass measured using CT significantly correlated to usual gait speed (r2 = 0.17, P < 0.0001) and hand grip strength (r2 = 0.66, P < 0.0001), but the correlations were lower using BIA (r2 = 0.1, P = 0.0005; r2 = 0.54, P < 0.0001). With regard to liver function, the relationship between skeletal muscle mass measured by CT and BIA and two muscle function parameters in the Child–Pugh A group were significant. In contrast, skeletal muscle mass measured by BIA in the Child–Pugh B or C group was not significantly related to usual gait speed.ConclusionSkeletal muscle mass measured by CT was significantly correlated to hand grip strength and usual gait speed, with higher correlations compared with BIA. Moreover, skeletal muscle mass measured by CT significantly correlated with two muscle functions, even in patients with Child–Pugh B or C.
Domestic Violence and the Law: The 1976 Act and its Aftermath
Authors: Maidment Susan 
Published: May 2015

This paper examines the parliamentary response to domestic violence as represented in three pieces of legislation: the Domestic Violence and Matrimonial Proceedings Act 1976, the Domestic Proceedings and Magistrates' Courts Act 1978 and the Housing (Homeless Persons) Act 1977. There is also briefer consideration of the role of criminal law, divorce and the possibility of using wardship procedures and actions in tort. The author maintains that the most important need of battered women is the provision of alternative permanent accommodation, and that this must be the criterion by which the efficacy of the present law is judged. With this in mind, the provisions of the three major Acts are described and evaluated, with most attention going to the 1976 Act. Maidment's general conclusion is that the promises held out by the legislative reforms ‘do not appear to have been fulfilled in practice’. The legal remedies are available, but the ways in which they are interpreted and implemented mean that battered women are inadequately protected. Violence against women has to be seen in the context of a patriarchal family system and the subordinate status of women. The law, on its own, cannot change deep-seated public attitudes, although it may have an important symbolic and educative role to play in contributing to such a change.