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Treatment specific competence predicts outcome in cognitive therapy for social anxiety disorder
(2012)
Several studies have demonstrated a positive relationship between competence and outcome in CBT for depression but studies of CBT for anxiety disorders are lacking. The present study explores the relationship between competence and outcome in cognitive therapy (CT) for social anxiety disorder, using hierarchical linear modeling analyses (HLM). Data were drawn from a multicenter randomized controlled trial. Five trained raters evaluated videotapes of two therapy sessions per patient using the Cognitive Therapy Competence Scale for Social Phobia (CTCS-SP). Overall adherence to the treatment manual and patient difficulty were also assessed. Patient outcome was rated by other assessors using the Clinical Global Impression Improvement Scale (CGI-I) and the Liebowitz Social Anxiety Scale (LSAS). Results indicated that competence significantly predicted patient outcome on the CGI-I (β = .79) and LSAS (β = .59). Patient difficulty and adherence did not further improve prediction. The findings support the view that competence influences outcome and should be a focus of training programs. Further research is needed to compare different ways of assessing competence and to understand the complex relationships between competence and other therapy factors that are likely to influence outcome.
Limb loss is a devastating disability and while current treatments provide aesthetic and functional restoration, they are associated with complications and risks. The optimal solution would be to harness the body's regenerative capabilities to regrow new limbs. Several methods have been tried to regrow limbs in mammals, but none have succeeded. One such attempt, in the early 1970s, used electrical stimulation and demonstrated partial limb regeneration. Several researchers reproduced these findings, applying low voltage DC electrical stimulation to the stumps of amputated rat forelimbs reporting "blastema, and new bone, bone marrow, cartilage, nerve, skin, muscle and epiphyseal plate formation". In spite of these encouraging results this research was discontinued. Recently there has been renewed interest in studying electrical stimulation, primarily at a cellular and subcellular level, and studies have demonstrated changes in stem cell behavior with increased proliferation, differentiation, matrix formation and migration, all important in tissue regeneration. We applied electrical stimulation, in vivo, to the stumps of amputated rat limbs and observed significant new bone, cartilage and vessel formation and prevention of neuroma formation. These findings demonstrate that electricity stimulates tissue regeneration and form the basis for further research leading to possible new treatments for regenerating limbs.
A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.
Estimates suggest that more than 25,000 to 125,000 people die annually from snakebite envenomation worldwide. In contrast to this major disease burden, thorough bibliometric studies do not exist so far that illustrate the overall research activity over a long time span. Therefore, the NewQIS-platform conducted an analysis on snakebite envenoming using the Thomson Reuters database Web of Science. To determine and assess changes regarding the scientific activities and to specifically address the more recent situation we analyzed two time intervals (t). During the first time interval from 1900 to 2007 (t1) 13,015 publications (p) were identified. In the following period (2008–2016 = t2) 4,982 publications were identified by the same search strategy. They originate from 114 (t1) respectively 121 countries (t2), with the USA (p = 3518), Brazil (p = 1100) and Japan (p = 961) being most productive in the first period, and the USA (p = 1087), Brazil (p = 991) and China (p = 378) in the second period, respectively. Setting the publication numbers in relation to GDP/capita, Brazil leads with 92 publications per 10,000 Int$GDP/capita, followed by India with 79 publications per 10000 Int$GDP/capita (t1). Comparing the country’s publication activity with the Human Development Index level indicates that the majority of the publications is published by highly developed countries. When calculating the average citation rates (citations per published item = CR) mainly European countries show the highest ranks: From 1900–2007 Sweden ranks first with a CR = 27, followed by the Netherlands (CR = 24.8), Switzerland (CR = 23), Spain, Austria and the USA (CR = 22). From 2008 to 2016 the highest rate achieves Switzerland with a value of 24.6, followed by Belgium (CR = 18.1), Spain (CR = 16.7), Costa Rica (CR = 14.9) and Netherlands (CR = 14). Compared with this, the USA was placed at rank 13 (CR = 9,5).
In summary, the present study represents the first density-equalizing map projection and in-depth scientometric analysis of the global research output on snakebites and its venoms. So it draws a sketch of the worldwide publication architecture and indicates that countries with a high incidence of snakebites and a low economical level still need to be empowered in carrying out research in this area.
BACKGROUND: Inflammatory events after kidney transplantation (Tx) may lead to activation of the tryptophane-catabolizing enzyme indoleamine 2,3-dioxygenase followed by the formation of kynurenine (KYN). Post-transplant KYN serum levels in kidney allograft recipients were analyzed for their diagnostic value.
MATERIAL AND METHODS: This was a retrospective analysis of KYN levels (normal value: 2.7±0.6 nmol/ml) measured in 4083 blood samples collected from 355 kidney graft recipients in connection with uncomplicated courses, acute rejections (ARs), infections, and type of immunosuppression. We performed descriptive data analysis and analysis of variance.
RESULTS: In 212 recipients with immediately functioning grafts, the KYN levels dropped from pre-Tx 13.3±5.9 nmol/ml to nearly normal values at day 5 (5.8±3.0 nmol/ml). In patients with delayed graft function, the KYN reduction started only after the last hemodialysis treatment. With respect to ARs in recipients with creatinine values <300 µmol/l pre-AR, the increase of KYN levels depended on the severity of ARs (steroid-sensitive ARs: from 4.5±1.4 to 6.0±6.1 nmol/ml; steroid-resistant ARs: from 6.1±3.1 to 12.9±7.1 nmol/ml; vascular rejections: from 5.8±3.0 to 16.9±9.1 nmol/ml). In patients with creatinine values ≥300 µmol/l pre-AR, a further increase of the KYN level (from 10.1 to 13.2 nmol/ml) was only observed in severe, steroid-resistant ARs. With respect to infections evaluated, the KYN levels before diagnosis/start of treatment were 5.7±3.4 nmol/ml in asymptomatic CMV infections, 7.5±4.4 nmol/ml in CMV diseases, 8.3±3.3 nmol/ml in pneumonia, and 10.4±6.5 nmol/ml in bacterial sepsis.
CONCLUSIONS: Serum KYN seems to be a reliable diagnostic tool for the assessment of post-transplant inflammatory complications, already in an early stage, and for monitoring the efficacy of therapeutic interventions. Prospective studies are recommended.
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.
Katamnese und Lebenszufriedenheit von Kindern und Jugendlichen mit Geschlechtsidentitätsstörungen
(2014)
Die Behandlung von Kindern und Jugendlichen mit Geschlechtsidentitätsstörungen (GIS) wird seit dem Beginn der pubertätshemmenden Hormontherapie in den neunziger Jahren international kontrovers diskutiert. Diese Störung scheint bei Kindern durch psychotherapeutische Intervention besser behandelbar als bei Jugendlichen. Erwartet wurden weniger psychopathologische Auffälligkeiten und eine höhere Lebenszufriedenheit bei umfassender psychotherapeutischer Begleitung. Des Weiteren wurden die Hypothesen geprüft, dass sich ein Geschlechtswechsel ebenfalls positiv auf Lebenszufriedenheit und Psychopathologie auswirkt.
Es nahmen insgesamt 37 Kinder, Jugendliche und Erwachsene an der schriftlichen Nachuntersuchung teil, die mindestens drei Jahre vor Studienbeginn aufgrund der Diagnose GIS des Kindes- und Jugendalters in der KJP Frankfurt vorgestellt wurden. Erfasst wurden Daten zur Geschlechtsidentität, zum Behandlungsverlauf und zur sexuellen Orientierung, zur Ausprägung der Psychopathologie laut altersangemessenem Screening-Inventar (CBCL, YSR, YASR) und zur Lebenszufriedenheit mithilfe des Inventars zur Erfassung der Lebensqualität bei Kindern und Jugendlichen (ILK). Außerdem wurden die Ausprägung der Psychopathologie (erfasst mit dem CBCL und oder YSR) bei der Erstvorstellung in der Klinik mit der jetzigen Einschätzung verglichen.
Die erhobenen Daten geben keinen Hinweis darauf, dass umfangreiche Psychotherapie oder ein Geschlechtswechsel zu einer höheren Lebenszufriedenheit und einer Verbesserung der Psychopathologie führen. Im Laufe der Zeit kam es zu einer signifikanten Reduktion der Werte der Syndromskalen soziale Probleme und aggressives Verhalten bei allen Studienteilnehmern. Allerdings wurde ein signifikanter Zusammenhang zwischen der Lebenszufriedenheit im Bereich seelische Gesundheit und der Zufriedenheit mit ihrer Psychotherapie gefunden. Die Drop-out-Analyse zeigte, dass Betroffene mit einer unbewältigten Problematik im Zusammenhang mit ihrer GIS eher nicht bereit waren, an dieser Studie teilzunehmen. Des Weiteren ergab sich, dass sich in der Gruppe der Studienteilnehmer signifikant mehr Personen für einen Geschlechtswechsel entschieden haben als in der Gruppe der Studienabbrecher.
Aus den Ergebnissen lässt sich ableiten, dass alle Teilnehmer der Nachuntersuchung mit ihrem Lebensweg gleichsam zufrieden sind, unabhängig vom Ausmaß der Psychotherapie und der Entscheidung für einen Geschlechtswechsel. Außerdem haben alle Personen der Stichprobe heute weniger Probleme mit aggressivem Verhalten und weniger soziale Probleme.
Da von einer Verzerrung der Stichprobe durch einen systematischen Ausfall von Teilnehmern auszugehen ist, sind weitere Nachuntersuchungen nötig, um die Hypothesen dieser Arbeit weiter zu überprüften. Darüber hinaus gilt es zu klären, ob bestimmte Psychotherapieformen bei einigen Patienten effektiver als andere sind.
as Locus coeruleus-noradrenerge System ist die primäre Quelle für zentrales corticales und subcorticales Noradrenalin. Die noradrenergen Projektionen des LC sind an der Modulation einer Vielzahl von funktionellen zentralen Abläufen beteiligt, u.a. an Aufmerksamkeitsprozessen, der Vermittlung von Stress und der Schlaf-Wach-Koordination, aber auch an der Koordination spezifischerer kognitiver Funktionen im Rahmen von Belohnungs-orientiertem Verhalten.
Die im Rahmen der vorliegenden Arbeit im anatomisch-topographischen Teil durchgeführten Experimente belegen eine dichte noradrenerge Innervation des präfrontalen Cortex, des dorsalen und ventralen Hippocampus, und des Kleinhirns durch Neurone des Locus coeruleus. Innerhalb des LC sind die nach präfrontal und hippocampal projizierenden Neurone vorwiegend im dorsalen Anschnitt über die gesamte rostro-caudale Achse zu finden. Der Anteil ipsilateral gelabelter Zellen überwiegt deutlich. Coeruleocerebelläre Neurone sind innerhalb des LC sowohl in den dorsalen als auch ventralen Abschnitten, ebenfalls über die gesamte rostro-caudale Achse, zu finden. Der Anteil kontralateral gelabelter Zellen ist relativ höher als bei den anderen Projektionen.
Die im ersten elektrophysiologischen Teil der Arbeit durchgeführten Experimente belegen ein in den Grundeigenschaften ähnliches Feuerungsmuster selektiv identifizierter coeruleo-präfrontaler und coeruleo-hippocampaler Nervenzellen. Einzelne Aktionspotential-Parameter waren signifikant unterschiedlich, hinweisend auf unterschiedliche hyperpolarisierende Ströme in beiden Populationen. Eine Überprüfung des a2-Autorezeptor-Status im zweiten elektrophysiologischen Teil der Arbeit ergab ein fehlendes Ansprechen der coeruleo-präfrontalen Neurone auf a2-Blockade (im Gegensatz zu den coeruleo-hippocampalen Neuronen); dieser Befund ist vereinbar am ehesten mit fehlenden oder funktionell down-regulierten a2-Rezeptoren selektiv in nach präfrontal projizierenden Neuronen des Locus coeruleus. Hierbei handelt es sich um einen in der Literatur nicht vorbeschriebenen Befund.
BACKGROUND: Platinum-based drugs are used as cancer chemotherapeutics for the last 40 years. However, drug resistance and nephrotoxicity are the major limitations of the use of platinum-based compounds in cancer therapy. Platinum (IV) complexes are believed to act as platinum prodrugs and are able to overcome some of platinum (II) limitations.
METHODS: A number of previously sensitized platinum (IV) complexes were evaluated for their anti-cancer activity by monitoring ability to affect proliferation, clonigenicity and apoptosis induction of Cisplatin sensitive and resistant cancer cells. In addition, the uptake of Cisplatin and the platinum (IV) derivatives to Cisplatin sensitive and resistant cancer cells was monitored.
RESULTS: The bis-octanoatoplatinum (IV) complex (RJY13), a Cisplatin derivative with octanoate as axial ligand, exhibited strong anti-proliferative effect on the Cisplatin resistant and sensitive ovarian cells, A2780cisR and A2780, respectively. Moreover, RJY13 exhibited good activity in inhibiting clonigenicity of both cells. Anti-proliferative activity of RJY13 was mediated by induction of apoptosis. Interestingly, a bis-lauratopaltinum (IV) complex (RJY6) was highly potent in inhibiting clonigenicity of both Cisplatin sensitive and Cisplatin resistant cells, however, exhibited reduced activity in assays that utilize cells growing in two dimensional (2D) conditions. The uptake of Cisplatin was reduced by 30% in A2780 in which the copper transporter-1 (Ctr1) was silenced. Moreover, uptake of RJY6 was marginally dependent on Ctr1, while uptake of RJY13 was Ctr1-independent.
CONCLUSIONS: Our data demonstrated the potential of platinum (IV) prodrugs in overcoming acquired and inherited drug resistance in cancer cell lines. Moreover, our data demonstrated that the uptake of Cisplatin is partially dependent on Ctr1 transporter, while uptake of RJY6 is marginally dependent on Ctr1 and RJY13 is Ctr1-independent. In addition, our data illustrated the therapeutic potential of platinum (IV) prodrugs in cancer therapy.
Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFα as mediators of IFNα/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNα to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNα/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNα/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFα signaling by the TNFα scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNα/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNα/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFα and TRAIL signaling, mRNA and protein expression is increased by IFNα/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFα even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFα while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFα determines the dependency on either death receptor ligand for IFNα/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNα/Smac mimetic combination treatment is an effective strategy to induce cell death in TNFα- or TRAIL-responsive cancers.