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Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.
Natural killer (NK) cells play an important role following allogeneic hematopoietic stem cell transplantation (HSCT) exerting graft-versus-leukemia/tumor effect and mediating pathogen-specific immunity. Although NK cells are the first donor-derived lymphocytes reconstituting post-HSCT, their distribution of CD56++CD16− (CD56bright), CD56++CD16+ (CD56intermediate=int), and CD56+CD16++ (CD56dim) NK cells is explicitly divergent from healthy adults, but to some extent comparable to the NK cell development in early childhood. The proportion of CD56bright/CD56int/CD56dim changed from 15/8/78% in early childhood to 6/4/90% in adults, respectively. Within this study, we first compared the NK cell reconstitution post-HSCT to reference values of NK cell subpopulations of healthy children. Afterward, we investigated the reconstitution of NK cell subpopulations post-HSCT in correlation to acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) as well as to viral infections. Interestingly, after a HSCT follow-up phase of 12 months, the distribution of NK cell subpopulations largely matched the 50th percentile of the reference range for healthy individuals. Patients suffering from aGvHD and cGvHD showed a delayed reconstitution of NK cells. Remarkably, within the first 2 months post-HSCT, patients suffering from aGvHD had significantly lower levels of CD56bright NK cells compared to patients without viral infection or without graft versus host disease (GvHD). Therefore, the amount of CD56bright NK cells might serve as an early prognostic factor for GvHD development. Furthermore, a prolonged and elevated peak in CD56int NK cells seemed to be characteristic for the chronification of GvHD. In context of viral infection, a slightly lower CD56 and CD16 receptor expression followed by a considerable reduction in the absolute CD56dim NK cell numbers combined with reoccurrence of CD56int NK cells was observed. Our results suggest that a precise analysis of the reconstitution of NK cell subpopulations post-HSCT might indicate the occurrence of undesired events post-HSCT such as severe aGvHD.values
BACKGROUND: Time-limited, early-life exposures to institutional deprivation are associated with disorders in childhood, but it is unknown whether effects persist into adulthood. We used data from the English and Romanian Adoptees study to assess whether deprivation-associated adverse neurodevelopmental and mental health outcomes persist into young adulthood.
METHODS: The English and Romanian Adoptees study is a longitudinal, natural experiment investigation into the long-term outcomes of individuals who spent from soon after birth to up to 43 months in severe deprivation in Romanian institutions before being adopted into the UK. We used developmentally appropriate standard questionnaires, interviews completed by parents and adoptees, and direct measures of IQ to measure symptoms of autism spectrum disorder, inattention and overactivity, disinhibited social engagement, conduct or emotional problems, and cognitive impairment (IQ score <80) during childhood (ages 6, 11, and 15 years) and in young adulthood (22-25 years). For analysis, Romanian adoptees were split into those who spent less than 6 months in an institution and those who spent more than 6 months in an institution. We used a comparison group of UK adoptees who did not experience deprivation. We used mixed-effects regression models for ordered-categorical outcome variables to compare symptom levels and trends between groups.
FINDINGS: Romanian adoptees who experienced less than 6 months in an institution (n=67 at ages 6 years; n=50 at young adulthood) and UK controls (n=52 at age 6 years; n=39 at young adulthood) had similarly low levels of symptoms across most ages and outcomes. By contrast, Romanian adoptees exposed to more than 6 months in an institution (n=98 at ages 6 years; n=72 at young adulthood) had persistently higher rates than UK controls of symptoms of autism spectrum disorder, disinhibited social engagement, and inattention and overactivity through to young adulthood (pooled p<0·0001 for all). Cognitive impairment in the group who spent more than 6 months in an institution remitted from markedly higher rates at ages 6 years (p=0·0001) and 11 years (p=0·0016) compared with UK controls, to normal rates at young adulthood (p=0·76). By contrast, self-rated emotional symptoms showed a late-onset pattern with minimal differences versus UK controls at ages 11 years (p=0·0449) and 15 years (p=0·17), and then marked increases by young adulthood (p=0·0005), with similar effects seen for parent ratings. The high deprivation group also had a higher proportion of people with low educational achievement (p=0·0195), unemployment (p=0·0124), and mental health service use (p=0·0120, p=0·0032, and p=0·0003 for use when aged <11 years, 11-14 years, and 15-23 years, respectively) than the UK control group. A fifth (n=15) of individuals who spent more than 6 months in an institution were problem-free at all assessments.
INTERPRETATION: Notwithstanding the resilience shown by some adoptees and the adult remission of cognitive impairment, extended early deprivation was associated with long-term deleterious effects on wellbeing that seem insusceptible to years of nurturance and support in adoptive families.
FUNDING: Economic and Social Research Council, Medical Research Council, Department of Health, Jacobs Foundation, Nuffield Foundation.
Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8+ T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningitis virus (LCMV), a finding showing that the spleen was not necessary in generating autoimmunity. By contrast, the absence of LNs prevented the priming of LCMV-specific CD8+ T cells, and diabetes did not develop in these mice. Additionally, we found that dendritic cells are responsible for the distribution of virus in secondary lymphoid organs, when LCMV was administered intravenously. Preventing this distribution with the sphingosine-1-phosphate receptor antagonist FTY720 inhibits the transport of antigen to peripheral LNs and consequently prevented the onset of diabetes. However, in case of subcutaneous infection, administration of FTY720 could not inhibit the onset of diabetes because the viral antigen is already presented in the peripheral LNs. These findings demonstrate the importance of preventing the presence of antigen in LNs for maintaining tolerance.
Background. Colorectal cancers (CRC) shed DNA into blood circulation. There is growing evidence that the analysis of circulating tumor DNA can be effectively used for monitoring of disease, to track tumor heterogeneity and to evaluate response to treatment. Case Presentation. Here, we describe two cases of patients with advanced CRC. The first case is about a patient with no available tissue for analysis of RAS mutation status. Liquid biopsy revealed RAS-wild-type and the therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibody cetuximab could be initiated. In the second case, the mutational profile of a patient with initial wild-type RAS-status was continually tracked during the course of treatment. An acquired KRAS exon 3 mutation was detected. The number of KRAS mutated fragments decreased continuously after the discontinuation of the therapy with EGFR-specific antibodies. Conclusion. Liquid biopsy provides a rapid genotype result, which accurately reproduces the current mutation status of tumor tissue. Furthermore, liquid biopsy enables close monitoring of the onset of secondary resistance to anti-EGFR therapy.
This introductory analysis on the subject of werewolves in the Greek and Roman worlds in its legendary, mythical, scientific and medical dimension emphasizes an intrinsic combination of negative and positive aspects, human and non-human factors, and ancient and modern components, laying the groundwork for the study of the gendered duplicity of the werewolf's Self in the modern and contemporary literature of southern and northern Italy. In this presentation of the werewolf motif on the Italian literary panorama from the 19th to the 21st century through an overview of short stories and novels, we will examine the writers who have combined ancient rural legends with metropolitan reveries to underscore the complexity and obscure double life of the werewolf.
Bei der Schlussszene in 'Nathan der Weise', in der auf Lessings Regieanweisung hin "Unter stummer Wiederholung allseitiger Umarmungen" der Vorhang fällt, wird das Toleranzpostulat der Ringparabel als wirksam besiegelt, obwohl die Erwartung an eine konventionelle Auflösung im Liebesglück enttäuscht wird. Die allseitige Umarmung erscheint manchem_r irritierend oder gar befremdend. Es stellt sich leicht ein Unbehagen ein. Doch unterliegt dem so tolerant gelösten Religionsstreit ein ethnographisches Tableau, auf dessen Basis die Differenz durch Transkulturalität bewältigt wird. Lessing klärt die in der Aufklärung aufkommende ethnografische Konstruktion von Differenz auf, indem er die religiöse und kulturelle Grenzziehung durch die Erzählung zweier Vorgeschichten ihrer essentiellen Grundlage beraubt. Zwar enden diese beide tragisch, denn Nathans Familie wird von antisemitischen Kreuzzugshorden ermordet und die Eltern des Geschwisterpaares sterben im Kreuzzug, doch die Kinder der transkulturellen Familiengründung, Recha/Blanda und der Tempelherr, überleben. Recha, die als Pfand der Tugend von Hand zu Hand geht, wird nicht nur aus den Flammen, sondern auch aus dem Zwiespalt der Loyalitäten gerettet. In Recha wird Transkulturalität zur Gestalt. Nicht nur auf ihrem Körper sondern auch in ihrem Geist oszilliert die Kommunikation und wird die Blockade zwischen den Kulturen überwunden. Dabei bleibt sie jedoch als machtlose weibliche Figur das zirkulierende Objekt der Begierde. Der Tempelherr - wie Recha ein Waise - durchläuft einen Bildungsprozess, in dem er seine Position ständig neu finden muss und Fragen der Transkulturalität ausgehandelt werden. Das happy-end, in dem sich Recha und der Tempelherr als Geschwister und verwaiste Kinder einer Deutschritterin und eines Bruders des Sultans in den Armen Nathans, des Sultans und dessen Schwester wiederfinden, entspricht weder dem romantischem Muster noch der Erwartung eines tragischen Verlusts. Nein, 'Nathan der Weise' ist nicht als Trauerspiel, auch nicht als Lustspiel angelegt. Das dramatische Gedicht in fünf Aufzügen setzt dagegen zwei Erzählungen ins Verhältnis - die über Toleranz und die über Transkulturalität. Während Toleranz als Gebot in der Ringparabel ausgegeben wird, wird Transkulturalität in Lessings multikulturellem Jerusalem des 11. Jahrhunderts, wenn auch unter klaren Machtverhältnissen, gelebt. Glücklich ausgehen kann das Drama nur, weil Lessing so der Transkulturalität durch Blutsbande eine tragfähige Basis schafft. Meine These ist, dass Lessing einen solchen Schluss schreiben musste, wenn er das in der Ringparabel entwickelte Gebot der Toleranz als reale Chance verwirklicht sehen wollte. Aus postkolonialer Sicht stellt sich für die heutige Rezeption die Frage, wie notwendig das Konzept der Kreolisierung für die Entwicklung einer toleranten Gesellschaft ist.
Nolan brings a fairly recognizable style to all his movies, often described as "dark" or "gritty." The tone is relentlessly serious, and the narratives are infused with the ambiguity and pessimism of film noir. His protagonists are, without exception, tortured, obsessed men, struggling with the loss of loved ones or past mistakes. Not only do these men face an uncaring world with murky morality, their sense of self is also unstable. To go along with the faulty memories and self-deceptions of his characters, Nolan also has a knack for misleading his audience with convoluted narratives. As Fisher puts it, he specializes in puzzles that can't be solved. 'Inception', to my mind, makes an excellent showcase for all these themes. Therefore, through an examination of its use of space and architecture as metaphors for the mind, I aim to determine the concept of the malleable self that underlies all of Nolan's movies.
Der vorliegende Artikel beschäftigt sich mit dem im Westen noch weitgehend unbekannten Genre des chinesischen Kriminalromans "gongàn xiaoshuo", sowie dessen produktiver Rezeption durch den niederländischen Diplomaten und Schriftsteller Robert H. van Gulik (*09.08.1910, †24.09.1967). Als Verständnisgrundlage sollen dabei zunächst einige grundsätzliche Ausführungen und Erläuterungen zu besagtem Genre getätigt werden. Danach wird sich der Text van Guliks "Richter Di" zuwenden, jener Romanreihe, der der Sinologe seine bis heute anhaltende Bekanntheit, auch über wissenschaftliche Kreise hinaus, verdankt. Um den Rahmen dieser Aufsatzes nicht zu sprengen, soll sich jedoch vorwiegend auf die durch van Gulik angefertigte und veröffentlichte Übersetzung des ursprünglichen chinesischen Originals, 'Wǔ Zétian sì dà qí àn' ( 武則天四大奇案 , "Vier außerordentlich seltsame Fälle in der Regierungszeit der Kaiserin Wu") (auch: 'Dee Goong An' ( 狄公案, "Richter Dis Fälle")), sowie den dritten Roman der Reihe, 'Geisterspuk in Peng-lai', konzentriert werden, da in diesem der Beginn der Karriere Richter Dis beschrieben wird. Auf diese Weise kann sowohl die besondere Form des chinesischen Kriminalromans - die van Gulik in seinen übrigen "Richter Di"- Romanen übernimmt -, wie auch das tradierte China-Bild und die Anklänge konfuzianischer Philosophie in angemessenem Umfang bearbeitet werden. Die in den Romanen dargestellten Formen des Alltagslebens, die Regierungsstrukturen, die politischen Verschwörungen und die Angriffe von außen, sind historisch korrekt beschrieben und gewähren somit einen faszinierenden Einblick in die Welt des historischen Chinas.