bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamate modulates the firing rate in oculomotor nucleus motoneurons as a function of the recruitment threshold current
Authors: Torres‐Torrelo Julio , Rodríguez‐Rosell David , Nunez‐Abades Pedro , Carrascal Livia , Torres Blas 
Published: May 2012

Key points
This study deals with the cellular mechanisms involved in firing rate modulation in vivo in the oculomotor system where there are requirements for high firing rates by motoneurons.
The study demonstrates that glutamate effects depend on the recruitment threshold and, presumably, motoneuron size.
Mid‐ and high‐threshold motoneurons in response to glutamate decrease their voltage threshold and strengthened the tonic and phasic components of the firing rate.
In a functional context, motoneurons could be recruited at lower recruitment threshold and could generate a strong muscle contraction under glutamate modulation to perform saccadic eye movements with different velocities and/or to maintain the eye in different eccentric positions in the orbit.
Our results suggest that the recruitment and firing behaviour of ocular motoneurons can be modified in vivo by glutamatergic synaptic inputs. It provides a link between cellular function and behavioural motoneuron output.
Abstract  Studies in alert preparations have demonstrated that ocular motoneurons exhibit a phasic–tonic firing rate related to eye velocity and position, respectively. The slopes of these relationships are higher in motoneurons with higher recruitment threshold and have been proposed to depend upon synaptic input. To investigate this hypothesis, motoneurons of the rat oculomotor nucleus were recorded in a brain slice preparation in control conditions and during glutamate (5 μm) application to the bath. Glutamate did not affect membrane potential or input resistance, but produced a decrease in rheobase and depolarization voltage as a function of the current needed for generating a maintained repetitive discharge (recruitment threshold current). In addition, glutamate compressed the range of recruitment threshold current (0.1–0.4 nA) as compared to the control (0.15–0.7 nA). Glutamate exposed motoneurons showed an increase in the tonic frequency gain and the peak frequency. Such increments depended on the recruitment threshold current and the last recruited motoneurons almost doubled the tonic frequency gain (35.2 vs. 57.9 spikes s−1 nA−1) and the peak frequency (52.4 vs. 102.6 spikes s−1). Finally, glutamate increased the spike frequency adaptation due to a significant increase in the phasic firing component as compared to the tonic one. In conclusion, glutamate modulates tonic and phasic discharge properties as a function of the recruitment threshold current and, presumably, motoneuron size. These findings contribute to understand the link between cellular functions and motoneuron discharge during oculomotor behaviour.
Translational evidence that impaired autophagy contributes to arterial ageing
Authors: LaRocca Thomas J. , Henson Grant D. , Thorburn Andrew , Sindler Amy L. , Pierce Gary L. , Seals Douglas R. 
Published: May 2012

Key points
Advancing age is the major risk factor for the development of cardiovascular diseases.
Arterial endothelial dysfunction, characterized by impaired endothelium‐dependent dilatation (EDD), is a key antecedent to age‐associated clinical cardiovascular disease.
We tested the hypothesis that changes in autophagy, the process by which cells recycle damaged biomolecules, may be an underlying cause of the age‐related reduction in EDD.
We show that autophagy is impaired in arteries of older humans and mice with reduced EDD, and that enhancing autophagy restores EDD by reducing superoxide‐dependent oxidative stress and inflammation, and increasing nitric oxide bioavailability.
Our results identify impaired autophagy as a potential cause of age‐related arterial dysfunction and suggest that boosting autophagy may be a novel strategy for the treatment of arterial endothelial dysfunction and prevention of cardiovascular diseases with ageing.
Abstract  Ageing causes arterial endothelial dysfunction that increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. The aim of the present study was to determine the role of autophagy, the cellular process of recycling damaged biomolecules, in endothelial dysfunction with ageing. In older humans, expression of autophagy markers in arterial endothelial cells was impaired by ∼50% (P < 0.05) and was associated with an ∼30% (P < 0.05) reduction in arterial endothelium‐dependent dilatation (EDD). Similarly, in C57BL/6 control mice ageing was associated with an ∼40% decrease (P < 0.05) in arterial markers of autophagy and an ∼25% reduction (P < 0.05) in EDD. In both humans and mice, impaired EDD was mediated by reduced nitric oxide (NO) bioavailability and was associated with increased oxidative stress and inflammation (P < 0.05). In old mice, treatment with the autophagy‐enhancing agent trehalose restored expression of autophagy markers, rescued NO‐mediated EDD by reducing oxidative stress, and normalized inflammatory cytokine expression. In cultured endothelial cells, inhibition of autophagy increased oxidative stress and reduced NO production, whereas trehalose enhanced NO production via an autophagy‐dependent mechanism. These results provide the first evidence that autophagy is impaired with ageing in vascular tissues. Our findings also suggest that autophagy preserves arterial endothelial function by reducing oxidative stress and inflammation and increasing NO bioavailability. Autophagy‐enhancing strategies may therefore have therapeutic efficacy for ameliorating age‐associated arterial dysfunction and preventing CVD.
Acetylcholine is released from taste cells, enhancing taste signalling
Authors: Dando Robin , Roper Stephen D. 
Published: May 2012

Key points
Acetylcholine (ACh), a classical neurotransmitter, stimulates M3 muscarinic receptors on Receptor (Type II) taste bud cells
ACh is synthesized by, and released from Receptor (Type II) taste bud cells during gustatory stimulation.
This muscarinic autocrine feedback amplifies taste‐evoked Ca2+ signals and enhances afferent neurotransmitter (ATP) release from Receptor (Type II) cells.
Taste Receptor cells in mice lacking M3 muscarinic receptors display depressed sensitivity to gustatory stimulation
The findings highlight a new signalling pathway in taste buds and may explain taste disturbances (i.e. side effects) associated with certain anticholinergic drugs.
Abstract  Acetylcholine (ACh), a candidate neurotransmitter that has been implicated in taste buds, elicits calcium mobilization in Receptor (Type II) taste cells. Using RT‐PCR analysis and pharmacological interventions, we demonstrate that the muscarinic acetylcholine receptor M3 mediates these actions. Applying ACh enhanced both taste‐evoked Ca2+ responses and taste‐evoked afferent neurotransmitter (ATP) secretion from taste Receptor cells. Blocking muscarinic receptors depressed taste‐evoked responses in Receptor cells, suggesting that ACh is normally released from taste cells during taste stimulation. ACh biosensors confirmed that, indeed, taste Receptor cells secrete acetylcholine during gustatory stimulation. Genetic deletion of muscarinic receptors resulted in significantly diminished ATP secretion from taste buds. The data demonstrate a new role for acetylcholine as a taste bud transmitter. Our results imply specifically that ACh is an autocrine transmitter secreted by taste Receptor cells during gustatory stimulation, enhancing taste‐evoked responses and afferent transmitter secretion.
Identification of Anaplastic Lymphoma Kinase as a Potential Therapeutic Target in Ovarian Cancer
Authors: Ren Hong , Tan Zhi-Ping , Zhu Xin , Crosby Katherine , Haack Herbert , Ren Jian-Min , Beausoleil Sean , Moritz Albrecht , Innocenti Gregory , Rush John , Zhang Yi , Zhou Xin-Min , Gu Ting-Lei , Yang Yi-Feng , Comb Michael J. 
Published: May 2012

Abstract
Ovarian cancer is the leading cause of death from gynecologic cancer. Improvement in the clinical outcome of patients is likely to be achieved by the identification of molecular events that underlie the oncogenesis of ovarian cancer. Here we show that the anaplastic lymphoma kinase (ALK) is aberrantly activated in ovarian cancer. Using an unbiased and global phosphoproteomic approach, we profiled 69 Chinese primary ovarian tumor tissues and found ALK to be aberrantly expressed and phosphorylated in 4 tumors. Genetic characterization of these ALK-positive tumors indicated that full-length ALK expression in two serous carcinoma patients is consistent with ALK gene copy number gain, whereas a stromal sarcoma patient carries a novel transmembrane ALK fusion gene: FN1-ALK. Biochemical and functional analysis showed that both full-length ALK and FN1-ALK are oncogenic, and tumors expressing ALK or FN1-ALK are sensitive to ALK kinase inhibitors. Furthermore, immunohistochemical analysis of ovarian tumor tissue microarray detected aberrant ALK expression in 2% to 4% serous carcinoma patients. Our findings provide new insights into the pathogenesis of ovarian cancer and identify ALK as a potential therapeutic target in a subset of serous ovarian carcinoma and stromal sarcoma patients. Cancer Res; 72(13); 3312–23. ©2012 AACR.
Genetic Variants, Prediagnostic Circulating Levels of Insulin-like Growth Factors, Insulin, and Glucose and the Risk of Colorectal Cancer: The Multiethnic Cohort Study
Authors: Ollberding Nicholas J. , Cheng Iona , Wilkens Lynne R. , Henderson Brian E. , Pollak Michael N. , Kolonel Laurence N. , Le Marchand Loïc 
Published: May 2012

AbstractBackground: Increased exposure of colonic and rectal epithelial cells to the promitotic and antiapoptotic effects of insulin and insulin-like growth factors (IGF) is hypothesized to increase colorectal cancer risk.Methods: In a case–control study nested within the Multiethnic Cohort, we attempted to replicate associations for five genetic variants associated with IGF system biomarkers, insulin, or glucose and to examine their association with the risk of colorectal cancer. In a subset of participants, the association between circulating biomarkers and colorectal cancer risk was examined. Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CI) for genetic variants (1,954 cases/2,587 controls) and serum biomarkers (258 cases/1,701 controls).Results: Associations with circulating biomarkers were replicated in the Multiethnic Cohort for IGF1 rs35767 and for IGFBP3 rs2854744, rs2854746, and rs3110697 (P &lt; 0.05). Homozygous carriers of the glucokinase regulator (GCKR) rs780094 variant T-allele were at a decreased risk of colorectal cancer (OR, 0.77; 95% CI, 0.64–0.92). In risk factor–adjusted models, participants with the highest prediagnostic IGF-II levels were at an increased risk [OR (T1 vs. T3), 1.58; 95% CI, 1.09–2.28; Ptrend = 0.011] and participants with the highest prediagnostic IGF-binding protein (IGFBP)-3 levels were at a decreased risk of colorectal cancer (OR, 0.53; 95% CI, 0.34–0.83; Ptrend = 0.003).Conclusion: These data provide further support for a role of prediagnostic IGF and insulin levels in the etiology of colorectal cancer.Impact: Future studies attempting to replicate the association between the GCKR rs780094 variant and the risk of colorectal cancer are warranted. Cancer Epidemiol Biomarkers Prev; 21(5); 810–20. ©2012 AACR.
Genetic Polymorphisms in Oxidative Stress Pathway Genes and Modification of BMI and Risk of Non-Hodgkin Lymphoma
Authors: Kim Christopher , Zheng Tongzhang , Lan Qing , Chen Yingtai , Foss Francine , Chen Xuezhong , Holford Theodore , Leaderer Brian , Boyle Peter , Chanock Stephen J. , Rothman Nathaniel , Zhang Yawei 
Published: May 2012

Abstract
Background: Being overweight and obese increases oxidative stress in the body. To test the hypothesis that genetic variations in oxidative stress pathway genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL), we conducted a population-based case–control study in Connecticut women.
Methods: Individuals who were overweight/obese (BMI ≥ 25) were compared with normal and underweight individuals (BMI &lt; 25), and their risk of NHL stratified assuming a dominant allele model for each oxidative stress pathway single-nucleotide polymorphism.
Results: Polymorphisms in AKR1A1, AKR1C1, AKR1C3, CYBA, GPX1, MPO, NCF2, NCF4, NOS1, NOS2A NOS3, OGG1, ATG9B, SOD1, SOD2, SOD3, RAC1, and RAC2 genes after false discovery rate adjustment did not modify the association between BMI and risk of NHL overall and histologic subtypes.
Conclusions: The results suggest that common genetic variations in oxidative stress genes do not modify the relationship between BMI and risk of NHL.
Impact: Studies of BMI and oxidative stress independently may elevate NHL risk, but this study suggests no interaction of the two risk factors. Future studies with larger study populations may reveal interactions. Cancer Epidemiol Biomarkers Prev; 21(5); 866–8. ©2012 AACR.
Does Electric Light Stimulate Cancer Development in Children?
Authors: Stevens Richard G. 
Published: May 2012

AbstractIncidence of cancer in children has increased in recent decades, and known risk factors can account for only a small minority of cases. Gestation and early childhood are particularly vulnerable periods in human development and an important aspect of development is in circadian rhythmicity. Emerging evidence implicates the molecular circadian mechanism in a vast array of other physiologic functions including metabolism, DNA damage response and cell-cycle regulation. Electric light exposure at night can disrupt circadian rhythms and, thereby, many other physiologic processes that are under circadian control. On this basis, it is proposed that ill-timed electric light exposure to pregnant women, to neonates, infants, and small children may increase cancer risk in those children. There are practical implications and interventions that accrue from this idea should it later be confirmed to be true. Cancer Epidemiol Biomarkers Prev; 21(5); 701–4. ©2012 AACR.
Appropriateness of Percutaneous Coronary Interventions in Washington State
Authors: Bradley Steven M. , Maynard Charles , Bryson Chris L. 
Published: May 2012

Background—
In anticipation of applying Appropriate Use Criteria for percutaneous coronary intervention (PCI) quality improvement, we determined the prevalence of appropriate, uncertain, and inappropriate PCIs stratified by indication for all PCIs performed in the state of Washington.

Methods and Results—

Within the Clinical Outcomes Assessment Program, we assigned appropriateness ratings to all PCIs performed in 2010 in accordance with published Appropriate Use Criteria. Of 13 291 PCIs, we successfully mapped the clinical scenario to the Appropriate Use Criteria in 9924 (75%) cases. Of the 3367 PCIs not classified, common failures to map to the criteria included nonacute PCI without prior noninvasive stress results (n = 1906; 57%) and unstable angina without high-risk features (n = 902; 27%). Of mapped PCIs, 8010 (71%) were for acute indications, with 7887 (98%) rated as appropriate, 39 (<1%) as uncertain, and 84 (1%) as inappropriate. Of 1914 mapped nonacute indications, 847 (44%) were rated as appropriate, 748 (39%) as uncertain, and 319 (17%) as inappropriate. Assuming results for noninvasive stress tests when data were missing, in the best-case scenario, 319 (8%) of nonacute PCIs were classified as inappropriate compared with 1459 (38%) in the worst-case scenario. Variation in inappropriate PCIs by facility was greatest for mapped nonacute indications (median = 14%; 25
th
to 75
th
percentiles = 9% to 24%) and nonacute indications with missing data precluding appropriateness classification (median = 54%; 25
th
to 75
th
percentiles = 35% to 66%).

Conclusions—
In a complete cohort of PCIs performed in Washington state, 1% of PCIs for acute indications and 17% of PCIs for nonacute indications were classified as inappropriate. Missing data on noninvasive stress tests present a challenge in the application of the criteria for quality improvement.
Improving Blood Pressure Control Through a Clinical Pharmacist Outreach Program in Patients With Diabetes Mellitus in 2 High-Performing Health Systems
Authors: Heisler Michele , Hofer Timothy P. , Schmittdiel Julie A. , Selby Joe V. , Klamerus Mandi L. , Bosworth Hayden B. , Bermann Martin , Kerr Eve A. 
Published: May 2012

Background—
Even in high-performing health systems, some patients with diabetes mellitus have poor blood pressure (BP) control because of poor medication adherence and lack of medication intensification. We examined whether the Adherence and Intensification of Medications intervention, a pharmacist-led intervention combining elements found in efficacy studies to lower BP, improved BP among patients with diabetes mellitus with persistent hypertension and poor refill adherence or insufficient medication intensification in 2 high-performing health systems.

Methods and Results—

We conducted a prospective, multisite cluster randomized pragmatic trial with randomization of 16 primary care teams at 5 medical centers (3 Veterans Affairs and 2 Kaiser Permanente) to the Adherence and Intensification of Medications intervention or usual care. The primary outcome was relative change in systolic BP (SBP), comparing 1797 intervention with 2303 control team patients, from 6 months preceding to 6 months after the 14-month intervention period. We examined shorter-term changes in SBP as a secondary outcome. The mean SBP decrease from 6 months before to 6 months after the intervention period was ≈9 mm Hg in both arms. Mean SBPs of eligible intervention patients were 2.4 mm Hg lower (95% CI: −3.4 to −1.5;
P
<0.001) immediately after the intervention than those achieved by control patients.

Conclusions—
The Adherence and Intensification of Medications program more rapidly lowered SBPs among intervention patients, but usual-care patients achieved equally low SBP levels by 6 months after the intervention period. These findings show the importance of evaluating in different real-life clinical settings programs found in efficacy trials to be effective before urging their widespread adoption in all settings.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT00495794.
Ethnic Differences in Carotid Intima-Media Thickness Between UK Children of Black African-Caribbean and White European Origin
Authors: Whincup Peter H. , Nightingale Claire M. , Owen Christopher G. , Rapala Alicja , Bhowruth Devina J. , Prescott Melanie H. , Ellins Elizabeth A. , Donin Angela S. , Masi Stefano , Rudnicka Alicja R. , Sattar Naveed , Cook Derek G. , Deanfield John E. 
Published: May 2012

Background and Purpose—
UK black African-Caribbean adults have higher risks of stroke than white Europeans and have been shown to have increased carotid intima-media thickness (cIMT). We examined whether corresponding ethnic differences in cIMT were apparent in childhood and, if so, whether these could be explained by ethnic differences in cardiovascular risk markers.

Methods—
We conducted a 2-stage survey of 939 children (208 white European, 240 black African-Caribbean, 258 South Asian, 63 other Asian, 170 other ethnicity), who had a cardiovascular risk assessment and measurements of cIMT at mean ages of 9.8 and 10.8 years, respectively.

Results—

Black African-Caribbean children had a higher cIMT than white Europeans (mean difference, 0.014 mm; 95% CI, 0.008–0.021 mm;
P
<0.0001). cIMT levels in South Asian and other Asian children were however similar to those of white Europeans. Among all children, cIMT was positively associated with age, systolic and diastolic blood pressure and inversely with combined skinfold thickness and serum triglyceride. Mean triglyceride was lower among black African-Caribbeans than white Europeans; blood pressure and skinfold thickness did not differ appreciably. However, adjustment for these risk factors had little effect on the cIMT difference between black African-Caribbeans and white Europeans.

Conclusions—
UK black African-Caribbean children have higher cIMT levels in childhood; the difference is not explained by conventional cardiovascular risk markers. There may be important opportunities for early cardiovascular prevention, particularly in black African-Caribbean children.
Bevacizumab Attenuates VEGF-Induced Angiogenesis and Vascular Malformations in the Adult Mouse Brain
Authors: Walker Espen J. , Su Hua , Shen Fanxia , Degos Vincent , Amend Gregory , Jun Kristine , Young William L. 
Published: May 2012

Background and Purpose—

Vascular endothelial growth factor (VEGF) expression is elevated in human brain arteriovenous malformations (bAVM). We have developed a bAVM model in the adult mouse by focal
Alk1
gene deletion and human VEGF stimulation. We hypothesized that once the abnormal vasculature has been established, tonic VEGF stimulation is necessary to maintain the abnormal phenotype, and VEGF antagonism by bevacizumab (Avastin) would reduce vessel density and attenuate the dysplastic vascular phenotype.

Methods—

Angiogenesis and bAVM were induced by injection of adeno-associated viral vector expressing human VEGF alone into the brain of wild-type mice or with adenoviral vector expressing Cre recombinase (Ad-Cre) into

Alk1
2f/2f

mice. Six weeks later, bevacizumab or trastuzumab (Herceptin, bevacizumab control) was administered. Vessel density, dysplasia index, vascular cell proliferation and apoptosis, and human IgG were assessed (n=6/group).

Results—

Compared with trastuzumab (15 mg/kg), administration of 5, 10, and 15 mg/kg of bevacizumab to adeno-associated viral vector expressing human VEGF treated wild-type mice reduced focal vessel density (
P
<0.05); administration of 5 mg/kg bevacizumab decreased proliferating vascular cells (
P
=0.04) and increased TUNEL-positive vascular cells (
P
=0.03). More importantly, bevacizumab (5 mg/kg) treatment reduced both vessel density (
P
=0.01) and dysplasia index (
P
=0.02) in our bAVM model. Human IgG was detected in the vessel wall and in the parenchyma in the angiogenic foci of bevacizumab-treated mice.

Conclusions—
We provide proof-of-principle that, once abnormal AVM vessels have formed, VEGF antagonism may reduce the number of dysplastic vessels and should be evaluated further as a therapeutic strategy for the human disease.
Moral Values Are Associated with Individual Differences in Regional Brain Volume
Authors: Lewis Gary J. , Kanai Ryota , Bates Timothy C. , Rees Geraint 
Published: May 2012

Abstract
Moral sentiment has been hypothesized to reflect evolved adaptations to social living. If so, individual differences in moral values may relate to regional variation in brain structure. We tested this hypothesis in a sample of 70 young, healthy adults examining whether differences on two major dimensions of moral values were significantly associated with regional gray matter volume. The two clusters of moral values assessed were “individualizing” (values of harm/care and fairness) and “binding” (deference to authority, in-group loyalty, and purity/sanctity). Individualizing was positively associated with left dorsomedial pFC volume and negatively associated with bilateral precuneus volume. For binding, a significant positive association was found for bilateral subcallosal gyrus and a trend to significance for the left anterior insula volume. These findings demonstrate that variation in moral sentiment reflects individual differences in brain structure and suggest a biological basis for moral sentiment, distributed across multiple brain regions.