Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Viscum album Exerts Anti-Inflammatory Effect by Selectively Inhibiting Cytokine-Induced Expression of Cyclooxygenase-2

Viscum album (VA) preparations are extensively used as complementary therapy in cancer and are shown to exert anti-tumor activities which involve the cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their application in cancer therapy, VA preparations have also been successfully utilized in the treatment of several inflammatory pathologies. Owing to the intricate association of inflammation and cancer and in view of the fact that several anti-tumor phytotherapeutics also exert a potent anti-inflammatory effect, we hypothesized that VA exerts an anti-inflammatory effect that is responsible for its therapeutic benefit. Since, inflammatory cytokine-induced cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) play a critical role in the pathogenesis of inflammatory diseases, we investigated the anti-inflammatory effect of VA on regulation of cyclo-oxygenase expression and PGE2 biosynthesis by using human lung adenocarcinoma cells (A549 cells) as a model. A549 cells were stimulated with IL-1β and treated with VA preparation (VA Qu Spez) for 18 hours. PGE2 was analysed in the culture supernatants by enzyme immunoassay. Expression of COX-2 and COX-1 proteins was analyzed by immunoblotting and the expression of COX-2 mRNA was assessed by semi-quantitative RT-PCR. We found that VA Qu Spez inhibit the secretion of IL-1β-induced PGE2 in a dose-dependent manner. Further, we also show that this inhibitory action was associated with a reduced expression of COX-2 without modulating the COX-1 expression. Together these results demonstrate a novel anti-inflammatory mechanism of action of VA preparations wherein VA exerts an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2

Disaster relief operations: past, present and future

The aim of the preface is to introduce the scope of this special issue (SI). We explain our editorial approach and summarise our findings based on articles included in this SI. Finally, we outline future research questions which stemmed out of the discussions of this SI

Dissecting the anti-inflammatory effects of Viscum album: inhibition of cytokine-induced expression of cyclooxygenase-2 and secretion of prostaglandin E2.

International audienceReports unraveling the beneficial effects of Viscum album (VA) preparations as complementary therapies for cancer have increasingly revealed the underlying molecular and cellular mechanisms, which encompass cytotoxic properties, induction of apoptosis, inhibition of angiogenesis and several other immunomodulatory mechanisms. In addition to their propitious relevance to cancer therapy, VA preparations are also relevant for the treatment of several inflammatory pathologies. In view of the intricate association of inflammation and cancer and the fact that several anti-tumor phytotherapeutics exert potent anti-inflammatory effects, we believe that an anti-inflammatory effect is responsible for the therapeutic benefits of VA preparations. One of the underlying molecular mechanisms of this inflammatory response is the selective down-regulation of the cyclo-oxygenase (COX)-2-mediated cytokine-induced secretion of prostaglandin E2 (PGE2). This inhibitory action has been associated with reduced expression of COX-2, without modulating COX-1 expression. This mechanism is associated with VA-induced destabilization of COX-2 mRNA, thereby depleting the functional COX-2 mRNA available for protein synthesis and for subsequent induction of secretion of PGE2. Together, these results demonstrate a novel anti-inflammatory mechanism of action of VA preparation, wherein VAQUSpez an anti-inflammatory effect by inhibiting cytokine-induced PGE2 via selective inhibition of COX-2 and destabilization of COX-2 mRNA

Education on, exposure to, and management of vascular anomalies during otolaryngology residency and pediatric otolaryngology fellowship

Copyright © 2016 American Medical Association. All rights reserved. IMPORTANCE The field of vascular anomalies presents diverse challenges in diagnosis and management. Although many lesions involve the head and neck, training in vascular anomalies is not universally included in otolaryngology residencies and pediatric otolaryngology (POTO) fellowships. OBJECTIVE To explore the education in, exposure to, and comfort level of otolaryngology trainees with vascular anomalies. DESIGN, SETTING, AND PARTICIPANTS A surveywas distributed to 39 POTO fellows and 44 residents in postgraduate year 5 who matched into POTO fellowships from April 22 through June 16, 2014. MAIN OUTCOMES AND MEASURES Survey responses from trainees on exposure to, education on, and comfort with vascular anomalies. RESULTS Forty-four residents in postgraduate year 5 who applied to POTO fellowships and 39 POTO fellows were emailed the survey. Fourteen respondents were unable to be contacted owing to lack of a current email address. Thirty-six of 69 residents and fellows (18 fellows and 18 residents [52%]) responded to the survey. Twenty-seven trainees (75%) reported no participation in a vascular anomalies clinic during residency; 6 of these 27 individuals (22%) trained at institutions with a vascular anomalies clinic but did not participate in the clinic, and 28 of the 36 respondents (78%) reported that they had less than adequate or no exposure to vascular anomalies in residency. Among POTO fellows, 11 of 17 (65%) did not participate in a vascular anomalies clinic during fellowship, even though 8 of the 11 had a vascular anomalies clinic at their fellowship program. During fellowship training, 12 of 18 fellows (67%) reported that they had adequate exposure to vascular anomalies. Only 20 respondents (56%) felt comfortable distinguishing among diagnoses of vascular anomalies, and only 4 residents (22%) and 9 fellows (50%) felt comfortable treating patients with vascular anomalies. All fellows believed that training in vascular anomalies was important in fellowship, and 100% of respondents indicated that increased exposure to diagnosis and management of vascular anomalies would have been beneficial to their ability to care for patients. CONCLUSIONS AND RELEVANCE These data indicate that most otolaryngology trainees do not receive formal training in vascular anomalies in residency and that such training is valued among graduating trainees. Conversely, most POTO fellows felt their exposure was adequate and 50% of fellows felt comfortable treating vascular anomalies. However, 65%of POTO fellows had no participation in a vascular anomalies clinic, where many patients are managed by a multidisciplinary team. This findingmay indicate that POTO fellows may have a false sense of confidence in managing patients with vascular anomalies and that residency and fellowship programs may consider changes in didactic and clinical programs