bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials
Authors: Nunez Derek J. , Alexander Myriam , Yerges-Armstrong Laura , Singh Gurparkash , Byttebier Geert , Fabbrini Elisa , Waterworth Dawn , Meininger Gary , Galwey Nicholas , Wallentin Lars , White Harvey D. , Vannieuwenhuyse Bart , Alazawi William , Kendrick Stuart , Sattar Naveed , Ferrannini Ele 
Published: November 2018

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy (“STABILITY”) trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A1clevels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min−1·1.73 m−2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA1con ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials.NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.
Impact of cervical spinal cord contusion on the breathing pattern across the sleep-wake cycle in the rat
Authors: Lee Kun-Ze 
Published: November 2018

The present study was designed to investigate breathing patterns across the sleep-wake state following a high cervical spinal injury in rats. The breathing patterns (e.g., respiratory frequency, tidal volume, and minute ventilation), neck electromyogram, and electroencephalography of unanesthetized adult male rats were measured at the acute (i.e., 1 day), subchronic (i.e., 2 wk), and/or chronic (i.e., 6 wk) injured stages after unilateral contusion of the second cervical spinal cord. Cervical spinal cord injury caused a long-term reduction in the tidal volume but did not influence the sleep-wake cycle duration. The minute ventilation during sleep was usually lower than that during the wake period in uninjured animals due to a decrease in respiratory frequency. However, this sleep-induced reduction in respiratory frequency was not observed in contused animals at the acute injured stage. By contrast, the tidal volume was significantly lower during sleep in contused animals but not uninjured animals from the acute to the chronic injured stage. Moreover, the frequency of sigh and postsigh apnea was elevated in acutely contused animals. These results indicated that high cervical spinal contusion is associated with exacerbated sleep-induced attenuation of the tidal volume and higher occurrence of sleep apnea, which may be detrimental to respiratory functional recovery after cervical spinal cord injury. NEW & NOTEWORTHY Cervical spinal injury is usually associated with sleep-disordered breathing. The present study investigated breathing patterns across sleep-wake state following cervical spinal injury in the rat. Unilateral cervical spinal contusion significantly impacted sleep-induced alteration of breathing patterns, showing a blunted frequency response and exacerbated attenuated tidal volume and occurrence of sleep apnea. The result enables us to investigate effects of cervical spinal injury on the pathogenesis of sleep-disordered breathing and evaluate potential therapies to improve respiration.
PRL-3 Promotes Ubiquitination and Degradation of AURKA and Colorectal Cancer Progression via Dephosphorylation of FZR1
Authors: Zhang Cheng , Qu Like , Lian Shenyi , Meng Lin , Min Li , Liu Jiafei , Song Qian , Shen Lin , Shou Chengchao 
Published: November 2018

Abstract

The oncogenic phosphatase PRL-3 is highly expressed in metastatic colorectal cancer but not in nonmetastatic colorectal cancer or noncolorectal cancer metastatic cancers. Although the proinvasive capacity of PRL-3 has been validated in multiple types of cancer, its impact on colorectal cancer progression and the underlying mechanisms remain poorly understood. Here, we report that overexpressed PRL-3 stimulates G2–M arrest, chromosomal instability (CIN), self-renewal, and growth of colorectal cancer cells in xenograft models, while colorectal cancer cell proliferation is decreased. PRL-3–induced G2–M arrest was associated with decreased expression of Aurora kinase A (AURKA). PRL-3–promoted slow proliferation, CIN, self-renewal, and growth in xenografts were counteracted by ectopic expression of AURKA. Conversely, knockdown of PRL-3 resulted in low proliferation, S-phase arrest, impaired self-renewal, increased apoptosis, and diminished xenograft growth independently of AURKA. Analysis of colorectal cancer specimens showed that expression of PRL-3 was associated with high status of CIN and poor prognosis, which were antagonized by expression of AURKA. PRL-3 enhanced AURKA ubiquitination and degradation in a phosphatase-dependent fashion. PRL-3 interacted with AURKA and FZR1, a regulatory component of the APC/CFZR1 complex. Destabilization of AURKA by PRL-3 required PRL-3-mediated dephosphorylation of FZR1 and assembly of the APC/CFZR1 complex. Our study suggests that PRL-3–regulated colorectal cancer progression is collectively determined by distinct malignant phenotypes and further reveals PRL-3 as an essential regulator of APC/CFZR1 in controlling the stability of AURKA.

Significance:
Dephosphorylation of FZR1 by PRL-3 facilitates the activity of APC/CFZR1 by destabilizing AURKA, thus influencing aggressive characteristics and overall progression of colorectal cancer.
Birth Weight and Risk of Type 2 Diabetes Mellitus, Cardiovascular Disease, and Hypertension in Adults: A Meta‐Analysis of 7 646 267 Participants From 135 Studies
Authors: Knop Marianne Ravn , Geng Ting‐Ting , Gorny Alexander Wilhelm , Ding Renyu , Li Changwei , Ley Sylvia H. , Huang Tao 
Published: November 2018

Background
Low birth weight has been associated with increased risk of type 2 diabetes mellitus, cardiovascular disease, and hypertension, but the risk at high birth weight levels remains uncertain. This systematic review and meta‐analysis aimed to clarify the shape of associations between birth weight and aforementioned diseases in adults and assessed sex‐specific risks.

Methods and Results

We systematically searched PubMed,
EMBASE
, and Web of Science for studies published between 1980 and October 2016. Studies of birth weight and type 2 diabetes mellitus (T2
DM
), cardiovascular disease (
CVD
), and hypertension were included. Random‐effects models were used to derive the summary relative risks and corresponding 95% confidence intervals.We identified 49 studies with 4 053 367 participants assessing the association between birth weight and T2
DM
, 33 studies with 5 949 477 participants for
CVD
, and 53 studies with 4 335 149 participants for hypertension and high blood pressure. Sex‐specific binary analyses showed that only females had an increased risk of T2
DM
and
CVD
at the upper tail of the birth weight distribution. While categorical analyses of 6 birth weight groups and dose‐response analyses showed J‐shaped associations of birth weight with T2
DM
and
CVD
, the association was inverse with hypertension. The lowest risks for T2
DM
,
CVD
, and hypertension were observed at 3.5 to 4.0, 4.0 to 4.5, and 4.0 to 4.5 kg, respectively.

Conclusions

These findings indicate that birth weight is associated with risk of T2
DM
and
CVD
in a J‐shaped manner and that this is more pronounced among females.
Caspase Cleavage of Gelsolin Is an Inductive Cue for Pathologic Cardiac Hypertrophy
Authors: Putinski Charis , Abdul‐Ghani Mohammad , Brunette Steve , Burgon Patrick G. , Megeney Lynn A. 
Published: November 2018

Background
Cardiac hypertrophy is an adaptive remodeling event that may improve or diminish contractile performance of the heart. Physiologic and pathologic hypertrophy yield distinct outcomes, yet both are dependent on caspase‐directed proteolysis. This suggests that each form of myocardial growth may derive from a specific caspase cleavage event(s). We examined whether caspase 3 cleavage of the actin capping/severing protein gelsolin is essential for the development of pathologic hypertrophy.

Methods and Results
Caspase targeting of gelsolin was established through protein analysis of hypertrophic cardiomyocytes and mass spectrometry mapping of cleavage sites. Pathologic agonists induced late‐stage caspase‐mediated cleavage of gelsolin. The requirement of caspase‐mediated gelsolin cleavage for hypertrophy induction was evaluated in primary cardiomyocytes by cell size analysis, monitoring of prohypertrophy markers, and measurement of hypertrophy‐related transcription activity. The in vivo impact of caspase‐mediated cleavage was investigated by echo‐guided intramyocardial injection of adenoviral‐expressed gelsolin. Expression of the N‐terminal gelsolin caspase cleavage fragment was necessary and sufficient to cause pathologic remodeling in isolated cardiomyocytes and the intact heart, whereas expression of a noncleavable form prevents cardiac remodeling. Alterations in myocardium structure and function were determined by echocardiography and end‐stage cardiomyocyte cell size analysis. Gelsolin secretion was also monitored for its impact on naïve cells using competitive antibody trapping, demonstrating that hypertrophic agonist stimulation of cardiomyocytes leads to gelsolin secretion, which induces hypertrophy in naïve cells.

Conclusions
These results suggest that cell autonomous caspase cleavage of gelsolin is essential for pathologic hypertrophy and that cardiomyocyte secretion of gelsolin may accelerate this negative remodeling response.
Logical reasoning by a Grey parrot? A case study of the disjunctive syllogism
Authors: Pepperberg Irene M. , Gray Suzanne L. , Mody Shilpa , Cornero Francesca M. , Carey Susan 
Published: November 2018

Abstract
In Call’s (2004) 2-cups task, widely used to explore logical and causal reasoning across species and early human development, a reward is hidden in one of two cups, one is shown to be empty, and successful subjects search for the reward in the other cup. Infants as young as 17-months and some individuals of almost all species tested succeed. Success may reflect logical, propositional thought and working through a disjunctive syllogism (A or B; not A, therefore B). It may also reflect appreciation of the modal concepts “necessity” and “possibility”, and the epistemic concept “certainty”. Mody & Carey’s (2016) results on 2-year-old children with 3- and 4-cups versions of this task converge with studies on apes in undermining this rich interpretation of success. In the 3-cups version, one reward is hidden in a single cup, another in one of two other cups, and the participant is given one choice, thereby tracking the ability to distinguish a certain from an uncertain outcome. In the 4-cups procedure, a reward is hidden in one cup of each pair (e.g., A, C); one cup (e.g., B) is then shown to be empty. Successful subjects should conclude that the reward is 100% likely in A, only 50% likely in either C or D, and accordingly choose A, thereby demonstrating modal and logical concepts in addition to epistemic ones. Children 2 1/2 years of age fail the 4-cups task, and apes fail related tasks tapping the same constructs. Here we tested a Grey parrot (Psittacus erithacus), Griffin, on the 3- and 4-cups procedures. Griffin succeeded on both tasks, outperforming even 5-year-old children. Controls ruled out that his success on the 4-cups task was due to a learned associative strategy of choosing the cup next to the demonstrated empty one. These data show that both the 3- and 4-cups tasks do not require representational abilities unique to humans. We discuss the competences on which these tasks are likely to draw, and what it is about parrots, or Griffin in particular, that explains his better performance than either great apes or linguistically competent preschool children on these and conceptually related tasks.
An Alternative History of Medieval Empathy: The Scholastics and compassio
Authors: Ruys Juanita Feros 
Published: November 2018

Abstract
This essay contributes to the alternative history of empathy by complicating the current state of scholarship placing the birthplace of modern Western empathy in the European Middle Ages. In counterpoint, the essay argues that there endured throughout the Middle Ages a suspicion of empathy as a feeling state and a prompt to right action. This position was inherited from the ancient Stoics and was particularly expressed by the medieval philosopher-theologians known as the Scholastics. In making this case, the essay focuses on the Medieval Latin term compassio and takes as its material the writings of Bonaventure, scholastic exegesis of the Christian foundation myths of the fall of humans and the evil angels, and scholastic analyses of almsgiving.
Morphological and molecular studies of a new species of the root mealybug genus Ripersiella Tinsley (Hemiptera: Coccoidea: Rhizoecidae) from greenhouses in The Netherlands and a first incursion of the American root mealybug Rhizoecus keysensis Hambleton in Europe
Authors: Jansen Maurice , Westenberg Marcel 
Published: November 2018

Ripersiella emarai is described from Ficus cyathistipula Warburg, Ficus lyrata Warburg and Dieffenbachia sp. from Dutch greenhouses. The immature stages are described based on microscopic features and a key to the stages is provided for their separation. This species description is actuated by the necessity to distinguish the new species from the root mealybug Ripersiella hibisci (Kawai & Takagi), which is occasionally imported and shares host plants with the new species. An identification key to adults of the Dutch greenhouse species and species intercepted during import inspections based on microscopic morphological characters is given. A key to distinguish the nymphal stages is provided and keys are given to the identification of first, second and third instar nymphs of Ripersiella multiporifera Jansen, R. hibisci (Kawai & Takagi) and R. emarai Jansen. Rhizoecus advenoides Takagi & Kawai, 1971 is found to be a junior synonym of Rh. amorphophalli Betrem, 1940.
Oral anticoagulation is preferable to injected, but only if it is safe and effective: An interview study of patient and carer experience of oral and injected anticoagulant therapy for cancer-associated thrombosis in the select-d trial
Authors: Hutchinson Ann , Rees Sophie , Young Annie , Maraveyas Anthony , Date Kathryn , Johnson Miriam J 
Published: November 2018

Background: Cancer patients have a four- to fivefold greater risk of thrombosis than the general population. Recommended treatment for cancer-associated thrombosis is 3–6 months of low-molecular-weight heparin. The ‘select-d’ trial is an open-label, randomised, multi-centre pilot trial in patients with cancer-associated thrombosis, utilising dalteparin (low-molecular-weight heparin) versus rivaroxaban (a direct oral anticoagulant), to assess effectiveness and safety. Aim: To explore patient and informal carers’ experiences of cancer-associated thrombosis and their experience and understanding of the risk–benefit of thrombosis treatment. Design: Qualitative substudy of the select-d trial, using semi-structured interviews. Interviews were audio-recorded and transcribed. Data were analysed using Framework Analysis. Participants: Participants were purposively sampled ( n = 37 patients; 46% male; age 40–89; 9 with carer present). Results: Three themes were found: experience of cancer-associated thrombosis, experience of anticoagulation and risk–benefit balance of the two modes of administration. Some were shocked by their thrombosis diagnosis (most were unaware of their risk), but others found it insignificant compared with cancer. Most patients found tablets more convenient, but injections were acceptable in the context of having cancer. While most were happy to follow medical advice, others weighed preference on the basis of effectiveness. Conclusion: Lack of awareness of thrombosis risk is concerning; cancer patients must be informed to enable prompt help-seeking. Tablets could provide a welcome choice for patients if there is equivalent risk–benefit to injected anticoagulants. Patients trust their clinicians to tailor their treatment. Future research could explore the effect of routine information giving about the risk of thrombosis.
Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine
Authors: Highland Jaclyn N , Morris Patrick J , Zanos Panos , Lovett Jacqueline , Ghosh Soumita , Wang Amy Q , Zarate Carlos A , Thomas Craig J , Moaddel Ruin , Gould Todd D 
Published: November 2018

Background: ( R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, ( 2R,6R)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine’s adverse effects and abuse potential, in rodents. Methods: We evaluated the oral bioavailability of ( 2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of ( 2R,6R)-hydroxynorketamine in mice. Oral administration of ( 2R,6R)-hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests. Results: ( 2R,6R)-hydroxynorketamine had absolute bioavailability between 46–52% in mice, 42% in rats, and 58% in dogs. Compared to intraperitoneal injection in mice, the relative oral bioavailability of ( 2R,6R)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, ( 2R,6R)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67–1.2 in mice and rats. Oral administration of ( 2R,6R)-hydroxynorketamine to mice did not alter locomotor activity or precipitate behaviors associated with discomfort, sickness, or stereotypy up to a dose of 450 mg/kg. Oral ( 2R,6R)-hydroxynorketamine reduced forced-swim test immobility time (15–150 mg/kg) and reversed learned helplessness (50–150 mg/kg) in mice. Conclusions: These results demonstrate that ( 2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.
Chronic antipsychotic treatment targets GIRK current suppression, loss of long-term synaptic depression and behavioural sensitization in a mouse model of amphetamine psychosis
Authors: Groos Dominik , Zheng Fang , Rauh Manfred , Quinger Benedikt , Kornhuber Johannes , Müller Christian P , Alzheimer Christian 
Published: November 2018

Background: Antipsychotic drugs (APDs) are the mainstay of the pharmacological treatment of psychotic disorders like schizophrenia. While the clinical efficacy of APDs has long since been established, the neurobiological mechanisms underlying their therapeutic benefits are still not well understood. Methods: Here, we used an escalating amphetamine regimen to induce a psychosis-like state in mice. To achieve clinically relevant drug concentrations in amphetamine-pretreated mice, the typical APD haloperidol or the atypical APD olanzapine were chronically administered via subcutaneously implanted osmotic mini-pumps. Results: Demonstrating their therapeutic efficacy, both drugs dampened amphetamine-induced hyperlocomotion and restored normal behaviour in the light-induced activity test. Whole-cell recordings from dopaminergic neurons of the ventral tegmental area (VTA) in ex vivo brain slices revealed two pronounced aberrations associated with the psychosis-like state: Strongly enhanced spontaneous firing and a substantial loss of G protein-gated inwardly rectifying potassium (GIRK) current upon activation of GABAB receptors with baclofen. Chronic haloperidol and olanzapine restored normal firing and partially rescued the GIRK current response to baclofen. In ex vivo slices containing the nucleus accumbens, which receives a dopaminergic projection from the VTA, abrogation of long-term synaptic depression (LTD) and enhanced excitatory drive onto medium spiny neurons were identified as synaptic consequences of amphetamine-induced psychosis. Again, both alterations proved amenable to chronic APD treatment. Conclusion: Our data provide evidence for aberrant neuronal function and plasticity in the mesolimbic dopamine system during an induced psychotic state and identify these alterations as targets of chronic APD treatment.
Awareness of and attitudes toward translational medicine among health personnel in hospitals in Shanghai, China
Authors: Meina Li , Wenya Yu , Feng Ye , Tao Ding , Lulu Zhang 
Published: November 2018

Objective The study aim was to evaluate the knowledge and attitudes of hospital health personnel toward translational medicine. Methods We conducted a cross-sectional survey from July 2013 to September 2013 with a representative sample of 1690 health personnel from 13 large comprehensive or specialized hospitals in Shanghai, China. Results The results showed that awareness of and attitudes toward translational medicine significantly differed by gender, age, highest level of education, profession, and professional rank. Health personnel showed a highly positive attitude toward translational medicine; however, their knowledge of translational medicine was low. Conclusion Effective measures are needed to improve health personnel’s awareness of and attitudes toward translational medicine.