Assessment of minimally invasive direct coronary artery bypass grafting of the left internal thoracic artery by means of magnetic resonance imaging

ObjectivesWe sought to evaluate graft patency, flow, and flow reserve in patients with minimally invasive direct coronary artery bypass surgery of internal thoracic artery grafts by a combined magnetic resonance protocol with a phase-contrast technique and magnetic resonance angiography.MethodsAt 1.5 T (Magnetom Sonata, Siemens), 30 symptomatic patients with 30 left internal thoracic artery grafts were examined 6 years after minimally invasive surgical intervention. Navigator-gated magnetic resonance angiography and contrast-enhanced FLASH-3D magnetic resonance angiography (0.2 mmol gadopentate–diethylene triamine pentetic acid [Gd-DTPA]/kg body weight) was used to assess bypass patency. Phase-contrast flow measurements with retrospective gating were performed in the internal thoracic artery grafts at rest and after stress induction with dipyridamole (0.57 mg/kg body weight). Graft patency was evaluated by means of multidetector computed tomography (Sensation 16, Siemens).ResultsInternal thoracic artery grafts were occluded in 5 of 30 patients. In 6 patients the anastomosis to the left anterior descending artery was highly stenotic (>70%) at multidetector computed tomography. In patients with regular grafts (multidetector computed tomography), a significant improvement of graft flow (P < .001) and diastolic/systolic peak velocity ratio (P < .001) after stress induction was detected. Magnetic resonance angiography combined with flow reserve measurements could differentiate between occluded-stenotic and regular minimally invasive direct coronary artery bypass grafts.ConclusionsMagnetic resonance imaging allows a combined assessment of bypass patency and flow with flow reserve in patients after the minimally invasive direct coronary artery bypass operation. The protocol of this study might be applicable for the evaluation of graft status in symptomatic patients after revascularization

Responses of Arctic cyclones to biogeophysical feedbacks under future warming scenarios in a regional Earth system model

Arctic cyclones, as a prevalent feature in the coupled dynamics of the Arctic climate system, have large impacts on the atmospheric transport of heat and moisture and deformation and drifting of sea ice. Previous studies based on historical and future simulations with climate models suggest that Arctic cyclogenesis is affected by the Arctic amplification of global warming, for instance, a growing land-sea thermal contrast. We thus hypothesize that biogeophysical feedbacks (BF) over the land, here mainly referring to the albedo-induced warming in spring and evaporative cooling in summer, may have the potential to significantly change cyclone activity in the Arctic. Based on a regional Earth system model (RCA-GUESS) which couples a dynamic vegetation model and a regional atmospheric model and an algorithm of cyclone detection and tracking, this study assesses for the first time the impacts of BF on the characteristics of Arctic cyclones under three IPCC Representative Concentration Pathways scenarios (i.e. RCP2.6, RCP4.5 and RCP8.5). Our analysis focuses on the spring- and summertime periods, since previous studies showed BF are the most pronounced in these seasons. We find that BF induced by changes in surface heat fluxes lead to changes in land-sea thermal contrast and atmospheric stability. This, in turn, noticeably changes the atmospheric baroclinicity and, thus, leads to a change of cyclone activity in the Arctic, in particular to the increase of cyclone frequency over the Arctic Ocean in spring. This study highlights the importance of accounting for BF in the prediction of Arctic cyclones and the role of circulation in the Arctic regional Earth system

Response of cyanobacteria and phytoplankton abundance to warming, extreme rainfall events and nutrient enrichment

Cyanobacterial blooms are an increasing threat to water quality and global water security caused by the nutrient enrichment of freshwaters. There is also a broad consensus that blooms are increasing with global warming, but the impacts of other concomitant environmental changes, such as an increase in extreme rainfall events, may affect this response. One of the potential effects of high rainfall events on phytoplankton communities is greater loss of biomass through hydraulic flushing. Here we used a shallow lake mesocosm experiment to test the combined effects of: warming (ambient vs. +4°C increase), high rainfall (flushing) events (no events vs. seasonal events) and nutrient loading (eutrophic vs. hypertrophic) on total phytoplankton chlorophyll‐a and cyanobacterial abundance and composition. Our hypotheses were that: (a) total phytoplankton and cyanobacterial abundance would be higher in heated mesocosms; (b) the stimulatory effects of warming on cyanobacterial abundance would be enhanced in higher nutrient mesocosms, resulting in a synergistic interaction; (c) the recovery of biomass from flushing induced losses would be quicker in heated and nutrient‐enriched treatments, and during the growing season. The results supported the first and, in part, the third hypotheses: total phytoplankton and cyanobacterial abundance increased in heated mesocosms with an increase in common bloom‐forming taxa—Microcystis spp. and Dolichospermum spp. Recovery from flushing was slowest in the winter, but unaffected by warming or higher nutrient loading. Contrary to the second hypothesis, an antagonistic interaction between warming and nutrient enrichment was detected for both cyanobacteria and chlorophyll‐a demonstrating that ecological surprises can occur, dependent on the environmental context. While this study highlights the clear need to mitigate against global warming, oversimplification of global change effects on cyanobacteria should be avoided; stressor gradients and seasonal effects should be considered as important factors shaping the response

Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling.

ABSTRACT Increased expression of drug efflux transporters at the bloodbrain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders. Up to 40% of epileptic patients respond poorly if at all to conventional pharmacotherapy, and impaired drug uptake into the brain is considered to be one important contributor to therapeutic failure The present study is concerned with mechanistic links that connect seizure activity to increased P-glycoprotein expression. Our goals are to identify therapeutic targets that can be manipulated to prevent seizure-induced transporter overexpression and to improve pharmacotherapy with antiepileptic drugs. The combined in vitro/in vivo experiments are focuse

Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling.

ABSTRACT Increased expression of drug efflux transporters at the bloodbrain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders. Up to 40% of epileptic patients respond poorly if at all to conventional pharmacotherapy, and impaired drug uptake into the brain is considered to be one important contributor to therapeutic failure The present study is concerned with mechanistic links that connect seizure activity to increased P-glycoprotein expression. Our goals are to identify therapeutic targets that can be manipulated to prevent seizure-induced transporter overexpression and to improve pharmacotherapy with antiepileptic drugs. The combined in vitro/in vivo experiments are focuse

Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling.

ABSTRACT Increased expression of drug efflux transporters at the bloodbrain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders. Up to 40% of epileptic patients respond poorly if at all to conventional pharmacotherapy, and impaired drug uptake into the brain is considered to be one important contributor to therapeutic failure The present study is concerned with mechanistic links that connect seizure activity to increased P-glycoprotein expression. Our goals are to identify therapeutic targets that can be manipulated to prevent seizure-induced transporter overexpression and to improve pharmacotherapy with antiepileptic drugs. The combined in vitro/in vivo experiments are focuse

International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy

Common criteria for the diagnosis of drug resistance and the assessment of outcome are needed urgently as a prerequisite for standardized evaluation and reporting of individual therapeutic responses in canine epilepsy. Thus, we provide a proposal for the definition of drug resistance and partial therapeutic success in canine patients with epilepsy. This consensus statement also suggests a list of factors and aspects of outcome, which should be considered in addition to the impact on seizures. Moreover, these expert recommendations discuss criteria which determine the validity and informative value of a therapeutic trial in an individual patient and also suggest the application of individual outcome criteria. Agreement on common guidelines does not only render a basis for future optimization of individual patient management, but is also a presupposition for the design and implementation of clinical studies with highly standardized inclusion and exclusion criteria. Respective standardization will improve the comparability of findings from different studies and renders an improved basis for multicenter studies. Therefore, this proposal provides an in-depth discussion of the implications of outcome criteria for clinical studies. In particular ethical aspects and the different options for study design and application of individual patient-centered outcome criteria are considered

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

Restricted Expression of Epstein-Barr Virus Latent Genes in Murine B Cells Derived from Embryonic Stem Cells

Background: Several human malignancies are associated with Epstein-Barr virus (EBV) and more than 95 % of the adult human population carries this virus lifelong. EBV efficiently infects human B cells and persists in this cellular compartment latently. EBV-infected B cells become activated and growth transformed, express a characteristic set of viral latent genes, and acquire the status of proliferating lymphoblastoid cell lines in vitro. Because EBV infects only primate cells, it has not been possible to establish a model of infection in immunocompetent rodents. Such a model would be most desirable in order to study EBV’s pathogenesis and latency in a suitable and amenable host. Methodology/Principal Findings: We stably introduced recombinant EBV genomes into mouse embryonic stem cells and induced their differentiation to B cells in vitro to develop the desired model. In vitro differentiated murine B cells maintained the EBV genomes but expression of viral genes was restricted to the latent membrane proteins (LMPs). In contrast to human B cells, EBV’s nuclear antigens (EBNAs) were not expressed detectably and growth transformed murine B cells did not arise in vitro. Aberrant splicing and premature termination of EBNA mRNAs most likely prevented the expression of EBNA genes required for B-cell transformation. Conclusions/Significance: Our findings indicate that fundamental differences in gene regulation between mouse and ma

The differentiation status of primary gonadal germ cell tumors correlates inversely with telomerase activity and the expression level of the gene encoding the catalytic subunit of telomerase

BACKGROUND: The activity of the ribonucleoprotein enzyme telomerase is detectable in germ, stem and tumor cells. One major component of telomerase is human telomerase reverse transcriptase (hTERT), which encodes the catalytic subunit of telomerase. Here we investigate the correlation of telomerase activity and hTERT gene expression and the differentiation status of primary testicular germ cell tumors (TGCT). METHODS: Telomerase activity (TA) was detected by a quantitative telomerase PCR ELISA, and hTERT mRNA expression was quantified by online RT-PCR in 42 primary testicular germ cell tumors. The control group consisted of benign testicular biopsies from infertile patients. RESULTS: High levels of telomerase activity and hTERT expression were detected in all examined undifferentiated TGCTs and in the benign testicular tissue specimens with germ cell content. In contrast, differentiated teratomas and testicular control tissue without germ cells (Sertoli-cell-only syndrome) showed no telomerase activity and only minimal hTERT expression. CONCLUSIONS: These findings demonstrate an inverse relationship between the level of telomerase activity and hTERT mRNA expression and the differentiation state of germ cell tumors. Quantification of telomerase activity and hTERT mRNA expression enables a new molecular-diagnostic subclassification of germ cell tumors that describes their proliferation potential and differentiation status