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Archive for February 2008

Stress Relieve And Alcoholism

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A molecular brain structure that underlies feelings of stress and anxiety shows promise as a new therapeutic target for alcoholism, according to new studies by researchers at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health (NIH).

In preclinical and clinical studies currently reported online, NIAAA Clinical Director Markus Heilig, M.D., Ph.D., and colleagues from the NIH, Lilly Research Laboratories, and University College in London found that a brain molecule known as the neurokinin 1 receptor, or NK1R, appears to be a central actor in stress-related drinking.

The researchers first demonstrated that NK1R plays an integral role in alcohol consumption in animals. Mice that were genetically engineered to lack NK1 receptors consumed much less alcohol than did normal mice with fully functional NK1R. Subsequently, in a small clinical study, the researchers showed that an experimental compound designed to block NK1 receptors reduced alcohol craving and improved overall wellbeing among recently detoxified alcohol-dependent individuals who had high levels of anxiety.

Using functional brain imaging, the researchers also showed that the exaggerated sensitivity to negative stimuli seen in alcoholics was dampened with the medication, while the lack of responses to pleasurable stimuli was restored.

“These findings advance our understanding of the link between stress and alcohol dependence and raise the prospect of a new class of medications for treating alcoholism,” adds NIAAA Director Ting-Kai Li, M.D.

Relapse to uncontrolled drinking after periods of sobriety is a defining characteristic of alcoholism and is often triggered by stress.

“The driving force behind dependent individuals’ alcohol use transitions from what we call reward craving to relief craving,” explains Dr. Heilig. “By the time people seek treatment for alcoholism, the pleasurable or rewarding effects of the drug are gone for most patients. Instead, alcohol-dependent individuals often feel low, anxious and are sensitive to stress, and they use alcohol to relieve these bad feelings.”

Previous studies have shown that a brain chemical known as Substance P (SP) is released in response to stress, produces symptoms of anxiety, and binds preferentially to NK1R. SP and NK1R are highly expressed in brain areas involved in stress responses and drug reward. Studies have also shown that anxiety and stress responses can be reduced in both animals and humans by inactivating NK1R. Such studies suggest that interfering with NK1R function could possibly subvert any role it might play in stress-related alcohol consumption.

Dr. Heilig and his colleagues conclude that if further studies establish activation of the SP-NK1R system as a consistent feature of alcohol dependence, compounds that block NK1R may have considerable potential for treating alcoholism, and potentially other addictions.
Science. 2008 Feb 14 [Epub ahead of print]

Neurokinin 1 Receptor Antagonism as a Possible Therapy for Alcoholism.

George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M.

Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.

Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. Here, we investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall wellbeing, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment target in alcoholism.

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Written by huehueteotl

February 28, 2008 at 9:29 pm

Lebensplanung

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Brauchen wir einen Lebensplan?

Der rote Faden in unserem Leben

Dann und wann stellt sich die Frage, ob wir selber die Weichen für unseren Lebensplan stellen können. Denn es kann sein, dass wir trotz beruflichen Erfolgs und äußerem Wohlstand, von dem Gefühl beherrscht sind, letzten Endes doch nicht das erreicht zu haben, was ein Leben sinnvoll machen kann.

Die Zeit verfliegt, ein Termin folgt dem nächsten, die Wochen vergehen, Monate und Jahre huschen vorbei. Was ist geschehen, mit der unwiederbringlichen Zeit, was habe ich daraus gemacht?

Ist es mir geglückt, Wesentliches – das heißt für mich dem individuellen Wesen Entsprechendes zu erkennen, zu bewahren und weiterzuentwickeln? Oder bin ich im Strom täglicher Aktivitäten fast untergegangen, konnte ich nicht innehalten und Atem holen.

Habe ich mich wie in einem Boot treiben lassen, habe ich das Ruder in die Hand genommen und den Kurs selbst bestimmt – habe ich ein Ziel gehabt, hat sich dieses vielleicht verschoben, wurde es erreicht oder war es irgendwann gar nicht mehr so wichtig …. Lebensplan ist nicht das ständige Ausgebucht-Sein, nicht der überfrachtete Termin-Kalender. Im Gegenteil, rastlose Geschäftigkeit ist nicht selten ein Zeichen von Selbst-Flucht, ein Alibi dafür, dass ich beim besten Willen wichtige Dinge, die mich persönlich betreffen – jetzt nicht in Angriff nehmen kann.

Das Treiben Lassen bis zur inneren Lähmung und das Überaktiv-Sein haben eine gemeinsame Seite – wo das eigene Tun keine Befriedigung bringt, wo äußerer Erfolg fehlt bzw. keine innere Erfüllung entsteht schwindet unsere Lebendigkeit.

Eine wichtige Rolle spielen in diesem Zusammenhang die verschiedenen Lebensphasen. Anforderungen bzw. Themen in der entsprechenden Lebensphase ändern sich. Diese Veränderungen zu berücksichtigen, ist ein wichtiges Element im Lebensplan – zu merken, wann was dran ist. Die Lebensphasen können wir orientierend in Rhythmen von 7 Jahren etwa einteilen – denken wir an die Kindheit bis 7, die Schulzeit bis etwa 14 Jahren, die Jugend- und frühe Erwachsenenzeit bis ca. 21 und die Lebensabschnitte so weiter….

Aber formale Zeitabschnitte, Allgemeinplätze und vorübergehende Trends können uns da nicht wirklich weiterhelfen. Den eigenen Weg finden, heißt kreativ sein , schöpferisch – einen einfallsreichen Umgang mit sich selbst haben – kurz gesagt den Willen zur Gestaltung pflegen. Dabei ist bewusste Gestaltung des Lebens immer auch eine Frage von Erfolg und Misserfolg. Menschen, die die Weichen in ihrem Leben nicht bewusst gestellt haben und plötzlich erkennen, dass sie im Grunde an ihren Bedürfnissen vorbeigelebt haben, entwickeln ein Gefühl des Unbehagens, da in unsere Zeit nicht selten anzutreffen ist, man könnte es auch Versäumnisangst nennen, eine Art Torschlusspanik über einen langen Zeitraum. Dieses Unbehagen verursacht ein Gefühl der Sinn-Losikgeit, kann sein, dass man fremdbestimmten Sachzwängen ausgeliefert ist, dass man glaubt kostbare Lebenszeit zu opfern, ohne dabei selbst zum Zug zu kommen. Folgen davon sind vielfältig, z.B. kritiklose Anpassung, an vorhandene Lebens- und Arbeitsbedingungen, Machtstreben, statt sozialen Verhaltens und Solidarität, Konsumieren, statt kreativer Einfälle, innere Leere statt emotionaler Bereicherung, aber auch Flucht in Suchtverhalten.

Zur bewussten Einleitung neuer Lebensphasen und zu deren schöpferischer Gestaltung, die in den unterschiedlichen Lebensphasen auch unterschiedlich aussieht, führt kein Weg daran vorbei, von Zukunft zu sprechen:

1. der Zukunft, die vorgegeben ist und nach irdischen Gesetzen der Trägheit und Abnützung verläuft, sie ist uns gewiss und hat mit zeitlicher Begrenzung zu tun, von allem Anfang an – die passive Zukunft.

2. von der neu entstandenen Zukunft, eine unvorhersehbare, überraschende, die immer wieder von uns auch miterschaffen wird, durch unsere eigene Weise, mit einer gegenwärtigen Situation umzugehen – unsere aktive Zukunft. Sie kann werden durch unser Verlangen nach Leben, nach Sinn, nach Erkenntnis, nach Liebe , nach Echtheit und nach Wachstum.

Diese sog. “Aktive Zukunft” ist auch Gegenstand unserer Lebensplanung.

Also:

Schaffen Sie sich eine Stunde störungsfreier Zeit in einer angenehmen Umgebung und nehmen Sie sich Zeit für einen wichtigen Brief – einen Brief an sich selbst über Ihren Lebensplan…

Die Grafik

Der erste Schritt ist

Das Potenzial

  • Analyse der beruflichen und persönlichen Stärken, Talente und Begabungen, Fähigkeiten, Erfahrungen und künftigen Entwicklungsmöglichkeiten
  • Analyse des bisherigen beruflichen Werdegangs
  • Definition der Erfahrungen – auch Lebenserfahrungen – Werte und Ideale
  • die eigene Persönlichkeit klar erkennen und ausbauen
  • Definition der beruflichen Wünsche und Ideen – Chancen sehen und nutzen
  • Analyse und Definition des ureigenen Potenzials
  • Behalten Sie dabei den Blick auf das Wesentliche!

Dann folgt

Das Konzept

  • Definition der Lebensziele und der Lebensqualität
  • Ziel-Visualisierung und Ziel-Beschreibung
  • Gegenüberstellung des persönlichen und beruflichen Potentials mit den momentanen und zukünftigen “Marktanforderungen” (Stärken-Nutzen-Analyse)
  • Definition der beruflichen und persönlichen Ziele, lang-, mittel- und kurzfristig
  • Definition der beruflichen Aufgabe und eigenen Philosophie
  • Definition von Arbeitsumfeld/Unternehmen, als auch privater Umgebung
  • Klarheit über Gemeinsamkeiten mit dem größtmöglichen Synergieeffekt zwischen den eigenen Stärken und dem entsprechenden Umfeld
  • Ist der Lebensplan bezahlbar? “Wirtschaftlichkeitsprüfung”

Schließlich muss auch eine

Umsetzung

her:

  • Erstellung des Mittel- und Maßnahmenkataloges
  • Terminplanung, lang-, mittel- und kurzfristig
  • Planung der konkreten Detailschritte
  • Beratung und Betreuung bei der Umsetzung

Die Grafik

Schreiben Sie sich einen Brief. Gehen Sie auf alle notwendigen Details ein und lassen Sie sich so viel Zeit, wie Sie brauchen. Verschließen Sie den Brief und lesen ihn am Ende jedes Jahre, oder machen Sie ihn zu Ihrem Bildschirmschoner. Aber behalten Sie Ihren Plan im Blick.

Das Geheimnis des Glücks

Eines Tages schickte ein Geschäftsmann seinen Sohn zu dem größten Weisen weit und breit, um ihm das Geheimnis des Glücks beizubringen. Der Jüngling wanderte vierzig Tage durch die Wüste, bis er schließlich an ein prachtvolles Schloss kam, das oben auf einem Berg lag. Dort wohnte der Weise, den er aufsuchen sollte. Anstatt nun einen Heiligen vorzufinden, kam der Jüngling in einen Raum, in welchem große Betriebsamkeit herrschte; Händler kamen und gingen, Leute standen in den Ecken und unterhielten sich, eine kleine Musikkapelle spielte leichte Melodien, und es gab eine festliche Tafel mit allen Köstlichkeiten dieser Gegend. Der Weise unterhielt sich mit jedem einzelnen, und der Jüngling musste zwei volle Stunden warten, bis er an der Reihe war. Der Weise hörte sich aufmerksam seine Geschichte an, sagte jedoch, er habe im Moment keine Zeit, ihm das Geheimnis des Glücks zu erklären. Er empfahl ihm, sich im Palast umzusehen und in zwei Stunden wiederzukommen.“Aber ich möchte dich um einen Gefallen bitten”, fügte der Weise hinzu und überreichte dem Jüngling einen Teelöffel, auf den er zwei Öltropfen träufelte. “Während du dich hier umsiehst, halte den Löffel, ohne dabei das Öl auszuschütten.” Der Jüngling stieg treppauf und treppab, ohne den Blick von dem Löffel zu lösen. Nach zwei Stunden erschien er wieder vor dem Weisen. “Na”, frage dieser, “hast du die kostbaren Perserteppiche in meinem Esszimmer gesehen? Und den prachtvollen Park, den der Gärtnermeister innerhalb von zehn Jahren anlegte? Und die schönen Pergamentrollen in meiner Bibliothek?” Beschämt musste der junge Mann zugeben, dass er nichts von alledem gesehen hatte, weil seine ganze Aufmerksamkeit dem Teelöffel mit dem Öl gegolten hatte, das ihm anvertraut worden war. “Also, dann zieh noch einmal los und schau dir all die Herrlichkeiten meiner Welt genau an”, sagte der Weise. “Man kann einem Menschen nicht trauen, bevor man sein Haus nicht kennt.”Nun schon etwas ruhiger, nahm er wieder den Löffel und machte sich erneut auf den Weg, doch diesmal achtete er auf all die Prachtgegenstände, die an den Wänden und an der Decke hingen. Er sah den Park, die Berge ringsherum, die Vielfalt der Blumen, die Vollendung, mit der jeder Kunstgegenstand am richtigen Ort eingefügt war. Zurück beim Weisen schilderte er ausführlich, was er alles gesehen hatte. “Aber wo sind die beiden Öltropfen, die ich dir anvertraute?” bemerkte der Weise. Als er auf den Löffel blickte, musste der Jüngling entsetzt feststellen, dass er sie verschüttet hatte. “Also, dies ist der einzige Rat, den ich dir geben kann”, sagte der weiseste der Weisen. “Das Geheimnis des Glücks besteht darin, alle Herrlichkeiten dieser Welt zu schauen, ohne darüber die beiden Öltropfen auf dem Löffel zu vergessen.”

aus: Der Alchemist von Paulo Coelho

Written by huehueteotl

February 28, 2008 at 5:35 pm

Posted in Psychology

Tagged with ,

Meth Knocks Down Immune Defense

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It has recently become popular among gay and bisexual men to consume very high levels of Meth. At the same time there is a new population of HIV+ men who are developing AIDS over months instead of years as typical.

Unsafe sex together with Meth abuse have been incriminated as reasons for rapid disease progression. While studies show exacerbated AIDS symptoms and disease progression in HIV+ Meth abusers, the molecular mechanism is yet unknown. It was assumed, yet unproven, that the rapid disease progression might be due to a mutant “superstrain” of HIV that was extremely virulent. Unsafe sex has been the other issue hold as culprit for rapid progression, although this would not explain the more rapid time course of the disease.

Recent reseach now demonstrates demonstrates the first direct evidence that Meth is blocking immune response, and that the molecular mechanism of this immunosuppression is due to the collapse of acidic conditions in cells of the immune system, inhibiting the functions of antigen uptake and processing. These effects compromise the immune response to opportunistic infections and HIV.

These findings could have a major impact on public health, as there are over 35 million Meth abusers worldwide

Tallóczy Z, Martinez J, Joset D, Ray Y, Gácser A, et al. (2008)
Methamphetamine Inhibits Antigen Processing, Presentation, and Phagocytosis.
PLoS Pathog 4(2): e28 doi:10.1371/journal.ppat.0040028

Methamphetamine (Meth) is abused by over 35 million people worldwide. Chronic Meth abuse may be particularly devastating in individuals who engage in unprotected sex with multiple partners because it is associated with a 2-fold higher risk for obtaining HIV and associated secondary infections. We report the first specific evidence that Meth at pharmacological concentrations exerts a direct immunosuppressive effect on dendritic cells and macrophages. As a weak base, Meth collapses the pH gradient across acidic organelles, including lysosomes and associated autophagic organelles. This in turn inhibits receptor-mediated phagocytosis of antibody-coated particles, MHC class II antigen processing by the endosomal–lysosomal pathway, and antigen presentation to splenic T cells by dendritic cells. More importantly Meth facilitates intracellular replication and inhibits intracellular killing of Candida albicans and Cryptococcus neoformans, two major AIDS-related pathogens. Meth exerts previously unreported direct immunosuppressive effects that contribute to increased risk of infection and exacerbate AIDS pathology.

Written by huehueteotl

February 28, 2008 at 12:27 am

Posted in HIV

Dramatic Boost To Immune Response With Engineered Artificial ‘Cells’

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Using artificial cell-like particles, Yale biomedical engineers have devised a rapid and efficient way to produce a 45-fold enhancement of T cell activation and expansion, an immune response important for a patient’s ability to fight cancer and infectious diseases, according to an advance on line report in Molecular Therapy.

Stimulatory particles (red) bound to activated T-cells (blue) as seen by fluorescence microscopy. Scale bar = 10 µm (Credit: Fahmy-Steenblock/Yale)

The artificial cells, developed by Tarek Fahmy, assistant professor of biomedical engineering at Yale and his graduate student Erin Steenblock, are made of a material commonly used for biodegradable sutures. The authors say that the new method is the first “off-the-shelf” antigen-presenting artificial cell that can be tuned to target a specific disease or infection.

“This procedure is likely to make it to the clinic rapidly,” said senior author Fahmy. “All of the materials we use are natural, biodegradable already have FDA approval.”

Cancer, viral infections and autoimmune diseases have responded to immunotherapy that boosts a patient’s own antigen-specific T cells. In those previous procedures, a patient’s immune cells were harvested and then exposed to cells that stimulate the activation and proliferation of antigen-specific T-cells. The “boosted” immune cells were then infused back into the patient to attack the disease.

Limitations of these procedures include costly and tedious custom isolation of cells for individual patients and the risk of adverse reaction to foreign cells, according to the Yale researchers. They also pointed to difficulty in obtaining and maintaining sufficient numbers of activated T-cells for effective therapeutic response.

In the new system, the outer surface of each particle is covered in universal adaptor molecules that serve as attachment points for antigens — molecules that activate the patient’s T-cells to recognize and fight off the targeted disease — and for stimulatory molecules. Inside of each particle, there are slowly released cytokines that further stimulate the activated T-cells to proliferate to as much as 45 times their original number.

“Our process introduces several important improvements,” said lead author Steenblock. “First, the universal surface adaptors allow us to add a span of targeting antigen and co-stimulatory molecules. We can also create a sustained release of encapsulated cytokines. These enhancements mimic the natural binding and signaling events that lead to T-cell proliferation in the body. It also causes a fast and effective stimulation of the patient’s T-cells — particularly T-cells of the cytotoxic type important for eradicating cancer.”

“Safe and efficient T-cell stimulation and proliferation in response to specific antigens is a goal of immunotherapy against infectious disease and cancer,” said Fahmy. “Our ability to manipulate this response so rapidly and naturally with an “off the shelf” reproducible biomaterial is a big step forward.”

Fahmy was recently awarded a five-year National Science Foundation (NSF) Career Award for work on this process and ways of engineering biomaterials to manipulate immune responses to fight cancer and other diseases. His approach incorporates signals important for T-cell stimulation in biocompatible polymer particulates, and integrates all the signals needed for efficient T-cell stimulation.

According to the NSF, devices as such these offer ease and flexibility in targeting different types of T-cells, and is expected to lead to state of the art improvements in the preparation of a new generation of therapeutic systems.

 

Molecular Therapy (2008); doi:10.1038/mt.2008.8

Mechanisms of Immunization Against Cancer Using Chimeric Antigens

Manuel E Engelhorn1, José A Guevara-Patiño2, Taha Merghoub1, Cailian Liu1, Cristina R Ferrone3, Gabriele A Rizzuto1, Daniel H Cymerman1, David N Posnett1, Alan N Houghton1 and Jedd D Wolchok1

  1. 1The Swim Across America Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  2. 2Section of Surgery and Committee on Immunology, University of Chicago, Chicago, Illinois, USA
  3. 3Division of General Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Jedd D Wolchok, Melanoma-Sarcoma Service, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room Z-1462, New York, New York 10021, USA. E-mail: wolchokj@mskcc.org

Received 29 October 2007; Accepted 28 December 2007; Published online 26 February 2008.

Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy. Here we explore nine different chimeric vaccine designs, in which the antigen of interest is expressed as an in-frame fusion with polypeptides that impact antigen processing or presentation. In DNA immunization experiments in mice, three of nine fusions elevated relevant CD8+ T-cell responses and tumor protection relative to an unfused melanoma antigen. These fusions were: Escherichia coli outer membrane protein A (OmpA), Pseudomonas aeruginosa exotoxin A, and VP22 protein of herpes simplex virus-1. The gains of immunogenicity conferred by the latter two are independent of epitope presentation by major histocompatibility complex class II (MHC II). This finding has positive implications for immunotherapy in individuals with CD4+ T-cell deficiencies. We present evidence that antigen instability is not a sine qua non condition for immunogenicity. Experiments using two additional melanoma antigens identified different optimal fusion partners, thereby indicating that the benefits of fusion vectors remain antigen specific. Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines.

Written by huehueteotl

February 27, 2008 at 10:28 am

New Switch Of The Immune System Discovered

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At the Institut Curie, Inserm researchers, in collaboration with collegues from Dynavax(1), have discovered a new mechanism controlling the choice in humans between two lines of defense in the event of attack. In the presence of viruses or bacteria, the immune system can trigger a response that is rapid but devoid of memory – innate immunity – or a response that takes longer to put in place but is more specifically targeted – adaptive immunity.

PI3-kinase, a protein essential to the activation of the innate response immune in this image, immune cells responding to attack: IRF-7 (red) is in the nucleus and so can trigger the innate immune response. (Credit: Copyright Cristiana Guiducci/Institut Curie)

The essential prerequisite to the proper functioning of innate immunity is the “turning on” of the protein PI3-kinase. Once PI3-kinase is activated, the immune response is triggered, leading to the production of type I interferons, the spearhead of innate immunity, which destroy the body’s invaders. This discovery opens up new therapeutic prospects since it may suggest ways of restoring the function of innate immunity, which is overactivated in autoimmune diseases and inhibited in certain cancers.

The body is often faced with attacks from outside (viral or bacterial infection) and sometimes from inside, because of the dysfunction of its own cells (cancer), and defends itself by activating its immune system. There are two types of defence. The first is innate immunity: this has no memory, and is permanently on guard to detect and destroy abnormal cells, tumor cells, or virus-infected cells. The second, which takes longer to initiate, is adaptive immunity, which specifically targets an invader. This response requires a education phase during which the cells of the immune system learn to recognize their enemy.

Dendritic cells, the body’s “sentinels”, are the first line of defence against invading pathogens: they recognize viruses and bacteria and then trigger an immune response, which, depending on the case, may be innate or adaptive. In response to an intruder, the so-called plasmacytoid dendritic cells can either produce large amounts of interferons, molecules that trigger a rapid response against viral infections, or “specialize” and become cells able to teach the immune system to recognize the pathogens.

At the Institut Curie, Vassili Soumelis(2) and his team (“Immunity and Cancer”, Inserm/Institut Curie Unit 653) have discovered how the dendritic cells choose between the two types of immune response. First, whatever the response, the presence of an intruder stimulates the TLR receptor inside the dendritic cells. Only then is the choice made between the two types of response. The PI3-kinase signaling pathway is activated, and the innate response is triggered. Kinase PI3 is the switch that turns on a whole cascade of proteins inside the cell. Information on the presence of an intruder in the body is thus transmitted to its final destination, in the cell’s nucleus, where the protein IRF-7 (transcription factor) modifies the expression of specific genes and so alters the cell’s behavior. In this specific case, IRF-7 induces the production of type 1 interferons (interferon-alpha, for example), which will bring about the destruction of the viruses and strongly activate various cells of the immune system.

Vassili Soumelis MD, PhD at the Institut Curie explains: “Activation of the protein PI3-kinase is one of the very first steps needed for the production of large quantities of type 1 interferons, leading to the triggering or strengthening of the innate immune response.”

In certain autoimmune diseases this innate response overstimulated, leading to an abnormal defense reaction of the immune system, which attacks its own cells, tissues, or organs. In some cancers, on the other hand, the innate response is virtually absent. It may be that the cancer cells are able to block the PI3-kinase signaling pathway. Through this discovery, Vassili Soumelis and his collaborators hope, in time, to develop new treatments for use in autoimmune diseases and oncology. By acting on PI3-kinase, it may be possible to adapt the innate response, so as to inhibit it in the treatment of autoimmune diseases and boost it in cancer treatment.

J Exp Med. 2008 Feb 18;205(2):315-22. Epub 2008 Jan 28.
PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation.

Dynavax Technologies Corporation, Berkeley, CA 94710, USA.

Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor alpha and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K delta subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor kappaB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases.

Written by huehueteotl

February 26, 2008 at 10:44 am

Cocaine’s Effects On Brain Metabolism May Contribute To Abuse

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Many studies on cocaine addiction – and attempts to block its addictiveness – have focused on dopamine transporters, proteins that reabsorb the brain’s “reward” chemical once its signal is sent. Since cocaine blocks dopamine transporters from doing their recycling job, it leaves the feel-good chemical around to keep sending the pleasure signal. Now a new study conducted at the U.S. Department of Energy’s Brookhaven National Laboratory suggests that cocaine’s effects go beyond the dopamine system. In the study, cocaine had significant effects on brain metabolism, even in mice that lack the gene for dopamine transporters.

Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans showing the effect of cocaine on brain metabolism in mice with normal levels of dopamine transporter proteins (DAT +/+) and mice lacking dopamine transporters (DAT -/-). Cocaine was compared with saline treatment (vehicle). Cocaine use blunted whole brain metabolism in both groups of mice (indicated by a reduced amount of yellow visible on the cocaine images), and had a particularly significant effect on the thalamus (TH) in DAT -/- mice. These results indicate that cocaine affects the brain in ways not modulated by its blockade of dopamine transporter proteins. (Credit: Image courtesy of DOE/Brookhaven National Laboratory)

“In dopamine-transporter-deficient mice, these effects on metabolism are clearly independent of cocaine’s effects on dopamine,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, who led the research. “These metabolic factors may be a strong regulator of cocaine use and abuse, and may also suggest new avenues for addiction treatments.”

The scientists used positron emission tomography, or PET scanning, to measure brain metabolism in dopamine-transporter deficient mice (known as DAT knockouts) and in littermates that had normal dopamine transporter levels. In this technique, the scientists administer a radioactively labeled form of sugar (glucose) – the brain’s main “fuel” – and use the PET scanner to track its site-specific concentrations in various brain regions. They tested the mice before and after cocaine administration, and compared the results to mice treated with saline instead of the drug.

Before any treatment, mice lacking dopamine transporters had significantly higher metabolism in the thalamus and cerebellum compared with normal mice. This elevated metabolism may be linked to chronically high levels of dopamine in the DAT knockout mice. It also suggests that dopamine levels may play an important role in modulating glucose levels in these brain areas, which play important roles integrating sensory information, learning, and motor function.

Interestingly, DAT knockout mice have been suggested as an animal model for attention-deficit hyperactivity disorder (ADHD). Elevated metabolism due to persistent elevated dopamine levels may be a factor contributing to the symptoms of ADHD, Thanos said.

After the scientists administered cocaine, whole brain metabolism decreased in both groups of mice, but more significantly in normal mice than in DAT knockouts. The scientists were able to detect this reduction in metabolism in a wide range of brain regions in the normal mice, suggesting that these decreases in metabolism are somehow associated with the blockade of dopamine transporters by cocaine.

The scientists also observed a reduction in metabolism in the thalamus region in the DAT knockout mice. This effect may likely be due to the effect of cocaine on other neurotransmitter systems, for example, norepinepherine or serotonin.

In summary, cocaine exposure has an effect on regional brain activity, which is mostly driven by dopamine action and to a secondary degree norepinephrine or serotonin. These results also support the idea that the thalamus and the cerebellum play key roles in cocaine’s mechanism of effect on sensory input, learning, and motor function. This is particularly of interest in better understanding the mechanism of cocaine addiction as well as the neurobiology of ADHD.

https://i1.wp.com/collegeave.colostate.edu/archive/vol1issue2/images/cocaine2.jpg

Synapse. 2008 Feb 19;62(5):319-324 [Epub ahead of print]
The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice.

Behavioral Neuropharmacology Lab, Medical Department, Brookhaven National Laboratory, Upton, New York 11973‐5000.

Cocaine’s ability to block the dopamine transporter (DAT) is crucial for its reinforcing effects. However the brain functional consequences of DAT blockade by cocaine are less clear since they are confounded by its concomitant blockade of norepinephrineand serotonin transporters. To separate the dopaminergic from the non-dopaminergic effects of cocaine on brain function we compared the regional brain metabolic responses to cocaine between dopamine transporter deficient (DAT(-/-)) mice with that of their DAT(+/+) littermates. We measured regional brain metabolism (marker of brain function) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and microPET (muPET) before and after acute cocaine administration (i.p. 10 mg/kg). Scans were conducted 2 weeks apart. At baseline DAT(-/-) mice had significantly greater metabolism in thalamus and cerebellum than DAT(+/+). Acute cocaine decreased whole brain metabolismand this effect was greater in DAT(+/+) (15%) than in DAT(-/-) mice (5%). DAT(+/+) mice showed regional decreases in the olfactory bulb, motor cortex, striatum, hippocampus, thalamus and cerebellum whereas DAT(-/-) mice showed decreases only in thalamus. The differential pattern of regional responses to cocaine in DAT(-/-) and DAT(+/+) suggests that most of the brain metabolic changes from acute cocaine are due to DAT blockade. Cocaine-induced decreases in metabolism in thalamus (region with dense noradrenergic innervation) in DAT(-/-) suggest that these were mediated by cocaine’s blockade of norepinephrine transporters. The greater baseline metabolism in DAT(-/-) than DAT(+/+) mice in cerebellum (brain region mostly devoid of DAT) suggests that dopamine indirectly regulates activity of these brain regions. Synapse, 62:319-324, 2008. Published 2008 Wiley-Liss, Inc.

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