bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypothermia protects brain mitochondrial function from hypoxemia in a murine model of sepsis
Authors: Chisholm Kim I , Ida Keila K , Davies Andrew L , Tachtsidis Ilias , Papkovsky Dmitri B , Dyson Alex , Singer Mervyn , Duchen Michael R , Smith Kenneth J 
Published: December 2015

Sepsis is commonly associated with brain dysfunction, but the underlying mechanisms remain unclear, although mitochondrial dysfunction and microvascular abnormalities have been implicated. We therefore assessed whether cerebral mitochondrial dysfunction during systemic endotoxemia in mice increased mitochondrial sensitivity to a further bioenergetic insult (hyoxemia), and whether hypothermia could improve outcome. Mice (C57bl/6) were injected intraperitoneally with lipopolysaccharide (LPS) (5 mg/kg; n = 85) or saline (0.01 ml/g; n = 47). Six, 24 and 48 h later, we used confocal imaging in vivo to assess cerebral mitochondrial redox potential and cortical oxygenation in response to changes in inspired oxygen. The fraction of inspired oxygen (FiO2) at which the cortical redox potential changed was compared between groups. In a subset of animals, spontaneous hypothermia was maintained or controlled hypothermia induced during imaging. Decreasing FiO2 resulted in a more reduced cerebral redox state around veins, but preserved oxidation around arteries. This pattern appeared at a higher FiO2 in LPS-injected animals, suggesting an increased sensitivity of cortical mitochondria to hypoxemia. This increased sensitivity was accompanied by a decrease in cortical oxygenation, but was attenuated by hypothermia. These results suggest that systemic endotoxemia influences cortical oxygenation and mitochondrial function, and that therapeutic hypothermia can be protective.
Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury
Authors: Han Xiaoning , Lan Xi , Li Qiang , Gao Yufeng , Zhu Wei , Cheng Tian , Maruyama Takayuki , Wang Jian 
Published: December 2015

Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68+ microglia, but increased the number of Ym-1+ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase–mediated cytotoxicity and proinflammatory responses.
Cannabinoid receptor activation in the juvenile rat brain results in rapid biomechanical alterations: Neurovascular mechanism as a putative confounding factor
Authors: Chatelin Simon , Humbert-Claude Marie , Garteiser Philippe , Ricobaraza Ana , Vilgrain Valérie , Van Beers Bernard E , Sinkus Ralph , Lenkei Zsolt 
Published: December 2015

We have recently reported cannabinoid-induced rapid changes in the structure of individual neurons. In order to investigate the presence of similar effects at the regional level, measures of brain tissue biomechanics are required. However, cannabinoids are known to alter cerebral blood flow (CBF), putatively resulting in presently unexplored changes in cerebral tissue biomechanics. Here we used magnetic resonance elastography (MRE) and flow-sensitive alternating inversion recovery (FAIR) imaging to measure in vivo alterations of mechanical properties and CBF, respectively, in the rat hippocampus, a brain region with a high density of type-1 cannabinoid receptors (CB1R). Systemic injection of the cannabinoid agonist CP55,940 (0.7 mg/kg) induced a significant stiffness decrease of 10.5 ± 1.2% at 15 minutes. FAIR imaging indicated a comparable decrease (11.3 ± 1.9%) in CBF. Both effects were specific to CB1R activation, as shown by pretreatment with the CB1R-specific antagonist AM251. Strikingly, similar rapid parallel changes of brain elasticity and CBF were also observed after systemic treatment with the hypotensive drug nicardipine. Our results reveal important drug-induced parallel changes in CBF and brain mechanical characteristics, and show that blood flow-dependent tissue softening has to be considered as an important putative confounding factor when cerebral viscoelastic changes are investigated.
Microvascular basis for growth of small infarcts following occlusion of single penetrating arterioles in mouse cortex
Authors: Taylor Zachary J , Hui Edward S , Watson Ashley N , Nie Xingju , Deardorff Rachael L , Jensen Jens H , Helpern Joseph A , Shih Andy Y 
Published: December 2015

Small cerebral infarcts, i.e. microinfarcts, are common in the aging brain and linked to vascular cognitive impairment. However, little is known about the acute growth of these minute lesions and their effect on blood flow in surrounding tissues. We modeled microinfarcts in the mouse cortex by inducing photothrombotic clots in single penetrating arterioles. The resultant hemodynamic changes in tissues surrounding the occluded vessel were then studied using in vivo two-photon microscopy. We were able to generate a spectrum of infarct volumes by occluding arterioles that carried a range of blood fluxes. Those resulting from occlusion of high-flux penetrating arterioles (flux of 2 nL/s or higher) exhibited a radial outgrowth that encompassed unusually large tissue volumes. The gradual expansion of these infarcts was propagated by an evolving insufficiency in capillary flow that encroached on territories of neighboring penetrating arterioles, leading to the stagnation and recruitment of their perfusion domains into the final infarct volume. Our results suggest that local collapse of microvascular function contributes to tissue damage incurred by single penetrating arteriole occlusions in mice, and that a similar mechanism may add to pathophysiology induced by microinfarcts of the human brain.
A novel quantitative high-throughput screen identifies drugs that both activate SUMO conjugation via the inhibition of microRNAs 182 and 183 and facilitate neuroprotection in a model of oxygen and glucose deprivation
Authors: Bernstock Joshua D , Lee Yang-ja , Peruzzotti-Jametti Luca , Southall Noel , Johnson Kory R , Maric Dragan , Volpe Giulio , Kouznetsova Jennifer , Zheng Wei , Pluchino Stefano , Hallenbeck John M 
Published: December 2015

The conjugation/de-conjugation of Small Ubiquitin-like Modifier (SUMO) has been shown to be associated with a diverse set of physiologic/pathologic conditions. The clinical significance and ostensible therapeutic utility offered via the selective control of the global SUMOylation process has become readily apparent in ischemic pathophysiology. Herein, we describe the development of a novel quantitative high-throughput screening (qHTS) system designed to identify small molecules capable of increasing SUMOylation via the regulation/inhibition of members of the microRNA (miRNA)-182 family. This assay employs a SHSY5Y human neuroblastoma cell line stably transfected with a dual firefly-Renilla luciferase reporter system for identification of specific inhibitors of either miR-182 or miR-183. In this study, we have identified small molecules capable of inducing increased global conjugation of SUMO in both SHSY5Y cells and rat E18-derived primary cortical neurons. The protective effects of a number of the identified compounds were confirmed via an in vitro ischemic model (oxygen/glucose deprivation). Of note, this assay can be easily repurposed to allow high-throughput analyses of the potential drugability of other relevant miRNA(s) in ischemic pathobiology.
Pharmacologic manipulation of lysosomal enzyme transport across the blood–brain barrier
Authors: Urayama Akihiko , Grubb Jeffrey H , Sly William S , Banks William A 
Published: December 2015

The adult blood–brain barrier, unlike the neonatal blood–brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, enzyme transport can be re-induced with alpha-adrenergics. Here, we examined agents that are known to alter the blood–brain barrier transport of large molecules or to induce lysosomal enzyme transport across the blood–brain barrier ((±)epinephrine, insulin, retinoic acid, and lipopolysaccharide) in 2-week-old and adult mice. In 2-week-old adolescent mice, all these pharmacologic agents increased brain and heart uptake of phosphorylated human β-glucuronidase. In 8-week-old adult mice, manipulations with (±)epinephrine, insulin, and retinoic acid were significantly effective on uptake by brain and heart. The increased uptake of phosphorylated human β-glucuronidase was inhibited by mannose 6-phosphate for the agents (±)epinephrine and retinoic acid and by L-NG-nitroarginine methyl ester for the agent lipopolysaccharide in neonatal and adult mice. An in situ brain perfusion study revealed that retinoic acid directly modulated the transport of phosphorylated human β-glucuronidase across the blood–brain barrier. The present study indicates that there are multiple opportunities to at least transiently induce phosphorylated human β-glucuronidase transport at the adult blood–brain barrier.
Ion channel networks in the control of cerebral blood flow
Authors: Longden Thomas A , Hill-Eubanks David C , Nelson Mark T 
Published: December 2015

One hundred and twenty five years ago, Roy and Sherrington made the seminal observation that neuronal stimulation evokes an increase in cerebral blood flow.1 Since this discovery, researchers have attempted to uncover how the cells of the neurovascular unit—neurons, astrocytes, vascular smooth muscle cells, vascular endothelial cells and pericytes—coordinate their activity to control this phenomenon. Recent work has revealed that ionic fluxes through a diverse array of ion channel species allow the cells of the neurovascular unit to engage in multicellular signaling processes that dictate local hemodynamics. In this review we center our discussion on two major themes: (1) the roles of ion channels in the dynamic modulation of parenchymal arteriole smooth muscle membrane potential, which is central to the control of arteriolar diameter and therefore must be harnessed to permit changes in downstream cerebral blood flow, and (2) the striking similarities in the ion channel complements employed in astrocytic endfeet and endothelial cells, enabling dual control of smooth muscle from either side of the blood–brain barrier. We conclude with a discussion of the emerging roles of pericyte and capillary endothelial cell ion channels in neurovascular coupling, which will provide fertile ground for future breakthroughs in the field.
Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels
Authors: He Tongrong , Santhanam Anantha Vijay R , Lu Tong , d'Uscio Livius V , Katusic Zvonimir S 
Published: December 2015

We tested hypothesis that activation of the prostacyclin (PGI2) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI2, iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APPα (sAPPα). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor δ (PPARδ) in human brain microvascular endothelial cells. PPARδ-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPARδ) upregulated ADAM10 and increased production of sAPPα. Genetic deletion of endothelial PPARδ (ePPARδ−/−) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPPα. In vivo treatment with GW501516 increased sAPPα content in hippocampus of wild type mice but not in hippocampus of ePPARδ−/− mice. Our findings identified previously unrecognized role of IP-PPARδ signal transduction pathway in the production of sAPPα in cerebral microvasculature.
Quantitative assessment of microvasculopathy in arcAβ mice with USPIO-enhanced gradient echo MRI
Authors: Klohs Jan , Deistung Andreas , Ielacqua Giovanna D , Seuwen Aline , Kindler Diana , Schweser Ferdinand , Vaas Markus , Kipar Anja , Reichenbach Jürgen R , Rudin Markus 
Published: December 2015

Magnetic resonance imaging employing administration of iron oxide-based contrast agents is widely used to visualize cellular and molecular processes in vivo. In this study, we investigated the ability of [Formula: see text] and quantitative susceptibility mapping to quantitatively assess the accumulation of ultrasmall superparamagnetic iron oxide (USPIO) particles in the arcAβ mouse model of cerebral amyloidosis. Gradient-echo data of mouse brains were acquired at 9.4 T after injection of USPIO. Focal areas with increased magnetic susceptibility and [Formula: see text] values were discernible across several brain regions in 12-month-old arcAβ compared to 6-month-old arcAβ mice and to non-transgenic littermates, indicating accumulation of particles after USPIO injection. This was concomitant with higher [Formula: see text] and increased magnetic susceptibility differences relative to cerebrospinal fluid measured in USPIO-injected compared to non-USPIO-injected 12-month-old arcAβ mice. No differences in [Formula: see text] and magnetic susceptibility were detected in USPIO-injected compared to non-injected 12-month-old non-transgenic littermates. Histological analysis confirmed focal uptake of USPIO particles in perivascular macrophages adjacent to small caliber cerebral vessels with radii of 2–8 µm that showed no cerebral amyloid angiopathy. USPIO-enhanced [Formula: see text] and quantitative susceptibility mapping constitute quantitative tools to monitor such functional microvasculopathies.
Headaches in patients with previous head injuries: A population-based historical cohort study (HUNT)
Authors: Nordhaug Lena Hoem , Vik Anne , Hagen Knut , Stovner Lars Jacob , Pedersen Torunn , Gravdahl Gøril Bruvik , Linde Mattias 
Published: December 2015

Background Headache attributed to head injury is claimed to be among the most common secondary headache disorders, yet available epidemiological evidence is scarce. We evaluated the prevalence of headache among individuals previously exposed to head injury by a comparison to an uninjured control group. Methods This population-based historical cohort study used data from hospital records on previous exposure to head injury linked to a large epidemiological survey with data on headache occurrence. Participants without head injury, according to hospital records, were used as controls. The head injuries were classified according to the Head Injury Severity Scale (HISS) and the International Classification of Headache Disorders (ICHD-3 beta). Binary logistic regression was performed to investigate the association between headache and head injury, controlling for potential confounders. Results The exposed group consisted of 940 individuals and the control group of 38,751 individuals. In the multivariate analyses, adjusting for age, sex, anxiety, depression and socioeconomic status, there were significant associations between mild head injury and any headache, migraine, chronic daily headache and medication overuse headache. Conclusion Headache was more likely among individuals previously referred to a hospital for a mild head injury compared to uninjured controls.
Screen time exposure and reporting of headaches in young adults: A cross-sectional study
Authors: Montagni Ilaria , Guichard Elie , Carpenet Claire , Tzourio Christophe , Kurth Tobias 
Published: December 2015

Objective The objective of this article is to investigate whether excessive screen time exposure is associated with non-migraine headache and migraine in young adults. Background Increased levels of television time have been associated with increased risk of headache. However, time spent using newer electronic devices with a screen (smartphone, tablet) has not been examined yet. Methods We conducted a cross-sectional study among 4927 participants of the French i-Share cohort. Demographic characteristics, screen time exposure (computers, tablets, smartphones and television) as well as headache/migraine symptoms were recorded in a standardized questionnaire. Multinomial logistic regression models were used to evaluate the association between screen time exposure and headache status. Results Participants had a mean age of 20.8 years and 75.5% were female. The multivariable model showed that students in the highest screen time exposure quintile had an increased risk for migraine. The odds ratio (OR) (95% confidence interval (CI)) was 1.37 (1.14 to 1.66) for migraine when compared with students without headache and with low screen time exposure. This association was somewhat stronger for migraine without aura (OR = 1.50, 95% CI 1.19 to 1.89). We found no significant association between screen time exposure and non-migraine headache. Conclusion High levels of screen time exposure are associated with migraine in young adults. No significant association was found with non-migraine headache.
Refractory chronic spontaneous urticaria and permanent atrial fibrillation associated with dental infection: Mere coincidence or something more to it?
Authors: Kasperska-Zajac Alicja , Grzanka Alicja , Kowalczyk Jacek , Wyszyńska-Chłap Magdalena , Lisowska Grażyna , Kasperski Jacek , Jarząb Jerzy , Misiołek Maciej , Kalarus Zbigniew 
Published: December 2015

Controversy surrounds the role of dental infection/inflammation in the oral cavity in chronic spontaneous urticaria (CSU) and atrial fibrillation (AF), which is mainly due to scarce literature in this area. Therefore, this case report and review of literature illustrate a possible association between the acute-phase response (APR) and clinical conditions, such as CSU and dental infection/inflammation of oral cavity and AF. We describe a 36-year-old man with an 8-year history of difficult-to-treat, uncontrolled CSU, co-existent with dental infection/inflammatory processes of oral cavity and permanent atrial fibrillation (AF). In the presented case, the most likely triggering or aggravating/maintaining factor of the symptoms was the inflammation/dental infection of the oral cavity because of rapid reduction of the urticarial symptoms, drug doses, and serum CRP levels after the dental therapy. Dental treatment may have a beneficial effect on the systemic inflammatory response, reducing/normalizing the circulating levels of APR markers. APR activation appears to worsen CSU course, early identification and treatment of infectious/inflammatory foci in the oral cavity would form the mainstay of supportive therapy for CU probably through reduction of the systemic inflammatory burden. APR associated with infectious/inflammatory foci in the oral cavity could be taken into account as a predisposing agents to AF.
Breastfeeding Duration and Authoritative Feeding Practices in First-Time Mothers
Authors: Jansen Elena , Mallan Kimberley M. , Byrne Rebecca , Daniels Lynne A. , Nicholson Jan M. 
Published: December 2015

Background: Longer breastfeeding duration appears to have a protective effect against childhood obesity. This effect may be partially mediated by maternal feeding practices during the first years of life. However, the few studies that have examined links between breastfeeding duration and subsequent feeding practices have yielded conflicting results. Objective: Using a large sample of first-time mothers and a newly validated, comprehensive measure of maternal feeding (the Feeding Practices and Structure Questionnaire), this study examined associations between breastfeeding duration and maternal feeding practices at child age 24 months. Methods: Mothers (n = 458) enrolled in the NOURISH trial provided data on breastfeeding at child age 4, 14, and 24 months, and on feeding practices at 24 months. Structural equation modeling was used to examine associations between breastfeeding duration and 5 nonresponsive and 4 structure-related “authoritative” feeding practices, adjusting for a range of maternal and child characteristics. Results: The model showed acceptable fit (χ2/df = 1.68; root mean square error of approximation = .04, comparative fit index = .91, and Tucker-Lewis index = .89) and longer breastfeeding duration was negatively associated with 4 out of 5 nonresponsive feeding practices and positively associated with 3 out of 4 structure-related feeding practices. Overall, these results suggest that mothers who breastfeed longer reported using more appropriate feeding practices. Conclusion: These data demonstrate an association between longer breastfeeding duration and authoritative feeding practices characterized by responsiveness and structure, which may partly account for the apparent protective effect of breastfeeding on childhood obesity.
Preliminary evaluation of a brief mindfulness-based stress reduction intervention for mental health professionals
Authors: Dobie Alana , Tucker Alison , Ferrari Madeleine , Rogers Jeffrey M 
Published: December 2015

Objectives: Mental health professionals are particularly susceptible to occupational stress; however, there are limited formal programmes to address the problem. This paper discusses the preliminary results of a brief mindfulness-based stress reduction (MBSR) programme for practising professionals in a public hospital mental health unit. Method: A mixed-group of nine mental health professionals participated in eight weeks of daily 15-minute MBSR training interspersed with three 30-minute education sessions developed by the authors (AD and AT). Levels of psychological distress and mindfulness skill were measured before and immediately after participation. Results: Following the brief MBSR programme, quantitative and qualitative participant feedback revealed a perceived reduction in psychological distress. Conclusions: A brief MBSR programme can be incorporated into the full-time workloads of practicing mental health professionals, potentially addressing a significant unmet workplace need.