23 research outputs found
Einfluà von Plasmatryptophan und Verhaltensmerkmalen auf das Akustisch Evozierte Potential : ist die IntensitÀtsabhÀngigkeit der N1/P2-Komponente des AEPs ein Spiegel der serotoninergen Neurotransmission?
PrimĂ€res Ziel dieser Arbeit war es, einen direkten Beweis fĂŒr die Annahme zuerbringen, dass eine starke IntensitĂ€tsabhĂ€ngigkeit der N1/P2- Komponente des AEPs und im besonderen des tangentialen Dipols durch eine erniedrigte serotoninerge Neurotransmission verursacht wird. Gleichzeitig konnte als klinisch relevanter Effekt die mögliche Verwendbarkeit der IntensitĂ€tsabhĂ€ngigkeit als biologischer Marker fĂŒr das AktivitĂ€tsniveau des serotoninergen Systems getestet werden. Durch das Studiendesign wurde zusĂ€tzlich die ĂberprĂŒfung des allgemein postulierten Zusammenhanges zwischen einer impulsiv-aggressiven Persönlichkeitsstruktur und einer hohen IntensitĂ€tsabhĂ€ngigkeit evozierter Potentiale als Nebenziel ermöglicht. Mit Hilfe in ihrer Zusammensetzung verschiedener AminosĂ€ure-Mischungen, die eineperiphere Tryptophandepletion herbeifĂŒhren, sollte eine verminderte zentrale serotoninerge Neurotransmission erzielt werden.Die IntensitĂ€tsabhĂ€ngigkeit des AEPs an den Tagen mit verminderter VerfĂŒgbarkeit des einzigen PrĂ€kursors von Serotonin, der essentiellen AminosĂ€ure Tryptophan, wurde im Vergleich zu einem Kontrolltag ĂŒberprĂŒft, an dem nur ein Placebo verabreicht worden war.Dazu wurden 13 gesunde Probanden (7w, 6m) im Alter von 24-32 Jahren nach ausfĂŒhrlicher psychologischer Erfassung ihrer Persönlichkeitsstruktur einemdoppelblinden, placebokontrolliertem Cross-over Studiendesign unterworfen, in dem jede Versuchsperson die AminosĂ€ure-Mischung Young 50 bzw. 100 und Moja als Tryptophandepletionstest (TDT) neben einem Placebo erhielt. Die IntensitĂ€tsabhĂ€ngigkeit des AEPs am Kontrolltag wurde mit den bei der Voruntersuchung erhobenen Persönlichkeitsmerkmalen in Zusammenhang gesetzt. Das Hauptergebnis dieser Arbeit war eine positive Korrelation der Plasmatryptophanspiegels mit der IntensitĂ€tsabhĂ€ngigkeit des tangentialen Dipols des N1/P2-Komplexes (r=0,46; p<0,05).Dies steht im Widerspruch zu den bisher veröffentlichten Arbeiten zu diesem Thema. Ein Grund fĂŒr dieses kontrĂ€re Resultat mag eine durch den TDT nicht herbeigefĂŒhrte Erniedrigung der zentralen serotoninergen transmissiven AktivitĂ€t sein. Zudem wurden die meisten anderen Untersuchungen an Patienten, bei denen eine Störung im serotoninergen System von vornherein angenommen worden war, vorgenommen, was einen Hauptunterschied zu dieser Studie, die mit gesunden Probanden durchgefĂŒhrt worden war, darstellt. Und ob bei normalen Probanden eine Tryptophandepletion es vermag, eine Erniedrigung serotoninerger Neurotransmission zuverursachen, bleibt fraglich. Auch ist die IntensitĂ€tsabhĂ€ngigkeit des AEPs wohl nicht ein rein spezifischer, sondernhöchstens ein relativ spezifischer Parameter fĂŒr die zentrale AktivitĂ€t serotoninerger Neurone. Sie kann also auch von anderen Transmittersystemen mit beeinflusst sein. Mit der unterschiedlichen AusprĂ€gung der IntensitĂ€tsabhĂ€ngigkeit des AEPs in den HemisphĂ€ren liess sich allerdings ein weiteres Indiz fĂŒr eine funktionelle Seitenasymmetrie in der Reizverarbeitung und wohl auch im serotoninergen Stoffwechsel finden. Aber auch das Ergebnis, dass die IntensitĂ€tsabha"ngigkeit des radialen und tangentialen Dipols teilweise hochsignifikant negativ mit als eher aggressiv und impulsiv zu beurteilenden Eigenschaften korrelierte, widerspricht den bisherigen Studienergebnissen, nach der eine hohe serotoninerge Neurotransmission generell inhibierend auf das Verhalten wirke, und somit AggressivitĂ€"t und ImpulsivitĂ€t beiPersonen mit hoher IntensitĂ€tsabhĂ€ngigkeit evozierter Potentiale auftreten mĂŒsste. Zweifel, ob die IntensitĂ€tsabhĂ€ngigkeit wirklich den geeigneten Parameter zur Beurteilung des AktivitĂ€tsniveaus im serotoninerge System darstellt, lassen das Ergebnis weniger widersprĂŒchlich erscheinen. Ebenso erfordert die KomplexitĂ€t des Zusammenspiels vieler verschiedener Modulatoren wohl eine enger gefasste Fragestellung, die auch andere Transmittersysteme, wie etwa das noradrenerge und dopaminerge, und Hormone, wie Testosteron oder Cortisol, mit einschliesst. Eine Beteiligung des serotoninergen Transmittersystems bei der Beeinflussungaggressiven und impulsiven Verhaltens lĂ€sst sich jedoch aus der Beobachtung vermuten, dass die VerĂ€nderung der IntensitĂ€tsabhĂ€ngigkeit durch den Tryptophandepletionstestsich bei verschieden Persönlichkeitstypen anders verhielten. Neugierverhalten und ImpulsivitĂ€t zeigten eine signifikant negative Korrelation, mit der depletionsabhĂ€ngigen SteigungsĂ€nderung (DSA"), Schadensvermeidung dagegen eine signifikant positive. Die Auswirkungen des TDT auf die Befindlichkeit und das Verhalten derteilnehmenden Probanden waren Themen einer anderen Arbeit (Sadigorsky, in Vorbereitung), ebenso wie die neuropharmakologischen Aspekte der Tryptophandepletion (Kewitz, in Vorbereitung). Durch die hier vorgestellten Ergebnisse erfĂ€hrt die Hoffnung, einen biologischen Marker fĂŒr einen fĂŒr die Genese vieler psychiatrischer Störungen wichtigen Neurotransmitter gefunden zu haben, der nicht invasiv ist und schnell Einzug in dieklinische Routinediagnostik halten könnte, leider keinen RĂŒckhalt. Zu viele Zweifel bestehen an der Aussagekraft und SpezifitĂ€t dieses Funktionsparameters
Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe
The evolving role of targeted biological agents in the management of indolent B-cell lymphomas
Improved understanding of the mechanisms of lymphomagenesis has resulted in a surge of development for new targeted agents. An impressive number of biological agents targeting different steps in the pathways of tumor proliferation, survival and apoptosis have become available. The management of patients with indolent non-Hodgkin lymphomas (iNHLs) is rapidly transforming with incorporation of those targeted biological agents into the front-line and relapsed/refractory setting. This review highlights several categories of novel biological agents and will discuss their potential role in the contemporary management of patients with iNHLs
Comparing Two Intestinal Porcine Epithelial Cell Lines (IPECs): Morphological Differentiation, Function and Metabolism
The pig shows genetical and physiological resemblance to human, which predestines it as an experimental animal model especially for mucosal physiology. Therefore, the intestinal epithelial cell lines 1 and J2 (IPEC-1, IPEC-J2) - spontaneously immortalised cell lines from the porcine intestine - are important tools for studying intestinal function. A microarray (GeneChip Porcine Genome Array) was performed to compare the genome wide gene expression of IPECs. Different significantly up-regulated pathways were identified, like âlysosomeâ, âpathways in cancerâ, âregulation of actin cytoskeletonâ and âoxidative phosphorylationâ in IPEC-J2 in comparison to IPEC-1. On the other hand, âspliceosomeâ, âribosomeâ, âRNA-degradationâ and âtight junctionâ are significantly down-regulated pathways in IPEC-J2 in comparison to IPEC-1. Examined pathways were followed up by functional analyses. ATP-, oxygen, glucose and lactate-measurement provide evidence for up-regulation of oxidative phosphorylation in IPEC-J2. These cells seem to be more active in their metabolism than IPEC-1 cells due to a significant higher ATP-content as well as a higher O2- and glucose-consumption. The down-regulated pathway âribosomeâ was followed up by measurement of RNA- and protein content. In summary, IPEC-J2 is a morphologically and functionally more differentiated cell line in comparison to IPEC-1. In addition, IPEC-J2 cells are a preferential tool for in vitro studies with the focus on metabolism
An Evaluation of Mobilization Efficiency, Efficacy and Toxicity among 3 Different Approaches: Chemomobilization, Chemomobilization with Preemptive Plerixafor Use and Plerixafor with G-CSF as Stem Cell Mobilization (SCM) Strategies in Lymphoid Malignancies
Stimulation of Adrenergic Activity By Desipramine Enhances Hematopoietic Stem and Progenitor Cell Mobilization Along with G-CSF in Multiple Myeloma - a Pilot Study of Safety and Efficacy
CMV and BK Virus Reactivation in Post Transplant Cyclophosphamide (PTCY) after Allogeneic MUD, MRD and Haploidentical Transplant
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Retrospective Analysis of Lymphomas in the Setting of Autoimmune Disease and the Impact of Immunosuppression
Abstract
Introduction: Post-transplant lymphoproliferative disease (PTLD) encompasses a heterogeneous array of cases of lymphoma/lymphoma-like conditions arising in the setting of immunosuppression (IS) for prior organ or marrow transplant. Such pts face heightened risk of toxicity from exposure to cytotoxic chemotherapy, and may be best treated in the frontline with reduction of IS (RI) and anti-CD20 monoclonal antibody treatment (Trappe, 2012). Autoimmune (AI) disease has been associated with an increased risk of developing lymphoma; however, the relative impact of baseline clinical features, including prior IS, is unknown.
Methods: We conducted a multicenter, retrospective analysis of adult pts with pre-existing AI conditions who were diagnosed with lymphoma since 1997. Baseline clinical features at diagnosis of lymphoid malignancy, including International Prognostic Index (IPI) risk factors; underlying AI disease; duration and type of IS; EBV status (by EBER in-situ hybridization); and primary therapy received (RI, rituximab [R] monotherapy, chemotherapy [+/- R]); were collected. Survival analyses were performed using Kaplan-Meier method. We then focused on those who had A) received IS other than corticosteroids (CS) alone; and B) those diagnosed with DLBCL. Those variables found to have significant correlation with OS by univariate analyses (UVA) were used to construct Cox proportional hazards model (multivariate analysis [MVA]) in order to determine which might have the strongest association with OS. Lastly, we sought to evaluate a potential role for RI and/or R as frontline therapy for those with DLBCL.
Results: A total of 130 pts were included (Table 1). The most frequent AI disease was rheumatoid arthritis and for all cases, 76% had documented exposure to IS, for a median duration of 4.5 years (range 0.17-57 years) prior to diagnosis of lymphoma. The most common histologic subtype was DLBCL (52%). EBV status was reported for only 34% of pts, but was positive in 68% (25/37), all of whom had received prior exposure to IS beyond CS, and 80% of whom (20/25) were diagnosed with DLBCL. EBV status was infrequently tested in pts not previously exposed to IS (3/31). At a median follow-up of 61 months for the entire cohort, 2-year PFS and OS were 79% and 91%, respectively (Figure 1, Panel A). By UVA, age>60; PS>1; LDH> upper limit of normal (ULN); DLBCL (vs all other histologies); underlying rheumatoid arthritis (RA; vs all other AI diseases); and prior exposure to IS, each correlated with inferior OS (Table 1). By MVA, PS>1 and prior IS maintained significance (p1 (p 0.002) and prior IS (p 0.010) maintain significance (data not shown).
Among 67 pts with DLBCL, median age was 61 (range 26-90), 60% had advanced stage disease, and 32% had IPI of 4 or 5. At a median follow-up of 32 months, the 2-year PFS and OS were 82% and 84%, respectively. There were no differences in frequency of any IPI factors between patients exposed to prior IS (n=53) and those who were naĂŻve to prior IS (n=14). For those not exposed to prior IS, the 2-year OS was 100%, compared to 80% in those who received prior IS (p 0.24); corresponding 2-year PFS were 92% and 79%, respectively (p 0.41). Age>60 and PS>1 were associated with an inferior OS but use of IS was not associated with outcome (Table 2). The 2 year OS for those treated with R plus CHOP(like) chemotherapy, CHOP(like) chemotherapy (without R), R alone (+/- RI), and with RI alone were 92%, 75%, 90%, and 67%, respectively (Figure 1, Panel B; log-rank p value 0.55). Patients who received CHOP-like therapy +/- R, as compared to R and/or RI were more likely to be naĂŻve to IS therapy (15/46 vs 0/22, p = 0.003) and have 2 or more EN sites of disease (15/46 vs 2/22, =0.041). These differences notwithstanding, the 2-year PFS for the two groups were 86% and 74% (p 0.16), and 2-year OS for the two groups were 88% and 82%, respectively (Figure 1, Panel C; p 0.91).
Conclusions: Pts with immunosuppression-related lymphoma have high rates of 2-year OS and in DLBCL, IS does not appear to be associated with an inferior outcome. Similar to evolving treatment paradigms in PTLD, rituximab monotherapy and other cytotoxic chemotherapy-free regimens as well as risk-adapted approaches may warrant further evaluation in IS-related DLBCL.
Disclosures
Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Barta:Seattle Genetics: Research Funding. Feldman:Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding