Kognitive Funktion bei bipolaren PatientInnen: neue Aspekte und Therapieansätze - über Impulsivität, autobiographisches Gedächtnis und Metakognitives Training

Hintergrund: Die Bipolare Störung geht über alle Krankheitsphasen hinweg mit Einschränkungen im Sozial- und Berufsleben einher; so zeigen bipolar Erkrankte auch in euthymer Affektlage ein eingeschränktes psychosoziales Funktionsniveau. Dimensionale Faktoren, wie beispielsweise Impulsivität oder neurokognitive Fähigkeiten stellen krankheitsbeeinflussende Variablen dar. Sie bedürfen zusätzlicher Forschung, um dem niedrigen psychosozialen Funktionsniveau zu Grunde liegende Mechanismen ausfindig zu machen und neue Therapieansätze zu entwickeln. Methoden: 40 bipolare PatientInnen und 30 gesunde KontrollprobandInnen nahmen an einer umfassenden neuropsychologischen Testung teil. Alle ProbandInnen bearbeiteten die Barratt Impulsivitäts-Skala (BIS) als Maß für selbsteingeschätzte Impulsivität. Im Stroop-Test wurde Inhibitionskontrolle als eine zentrale Komponente von Exekutivfunktionen erfasst (Studie 1). Um einen möglichen Zusammenhang zwischen neurokognitiven Funktionen und dem autobiographischen Gedächtnis zu explorieren, durchliefen 20 bipolar erkrankte und 22 gesunde Kontrollen zusätzlich einen Test zum autobiographischen Gedächtnis (autobiographical memory test, AMT) (Studie 2). 30 bipolar Erkrankte mit relativ niedrigem psychosozialen Funktionsniveau nahmen über acht Wochen an einem Metakognitiven Training (MKT) teil. Vor und nach der Intervention wurden psychosoziales Funktionsniveau und Lebensqualität erhoben (Studie 3). Ergebnisse: Impulsivität, gemessen im Selbsteinschätzungs-Fragebogen sowie im Verhaltenstest (als Einschränkung der Exekutivfunktion) zeigte sich bei PatientInnen im Vergleich zu KontrollprobandInnen erhöht, jedoch korrelierten die beiden Maße untereinander nicht (Studie 1). Über beide Gruppen hinweg korrelierten Exekutivfunktion, Verbales Gedächtnis und Aufmerksamkeit signifikant mit der Spezifität der autobiographischen Erinnerungen. Angesichts der Spezifität autobiographischer Erinnerungen fanden sich keine Unterschiede zwischen PatientInnen und Kontrollpersonen (Studie 2). Die TeilnehmerInnen am MKT verbesserten sich hinsichtlich des Funktionsniveaus mit großer Effektstärke, nicht jedoch hinsichtlich der Lebensqualität. Die Trainings-Adhärenz betrug 80% (Studie 3). Schlussfolgerung: Impulsivität in der Selbsteinschätzung und im Verhaltenstest (als Einschränkung der Exekutivfunktion) ist jeweils bei bipolar Erkrankten erhöht, jedoch stellen die beiden Maße voneinander unabhängige dimensionale Faktoren für die bipolare Störung dar. Die Spezifität autobiographischer Erinnerungen scheint in Zusammenhang mit neuropsychologischen Funktionen, wie beispielsweise der Exekutivfunktion, zu stehen, unterscheidet sich jedoch wider Erwarten nicht zwischen Erkrankten und Gesunden. In der Pilotstudie zeigten sich Durchführbarkeit, Akzeptanz sowie Hinweise auf Effektivität des MKTs für PatientInnen mit besonders niedrigem psychosozialen Funktionsniveau, die durch nachfolgende Studien mit größeren Stichproben sowie einer Kontrollbedingung bestätigt werden sollte.Background: In all phases of illness, bipolar disorder affects social and professional activities of its patients. Thus, even in an euthymic state, bipolar patients show a limited level of psychosocial functioning. Dimensional factors such as impulsivity or cognitive function constitute variables influencing the course of illness. There is a need to further investigate those factors to find underlying mechanisms of low psychosocial function and develop new therapeutic strategies. Methods: 40 bipolar patients and 30 healthy controls were recruited for comprehensive neuropsychological assessment. Both groups fulfilled the Barratt Impulsiveness Scale as a self-report of impulsivity. To assess inhibition control as a core feature of executive function, the Stroop Color and Word test was used (study 1). To explore a possible relationship between executive functions and autobiographical memory, in a second study 20 bipolar patients and 22 healthy controls additionally ran through the autobiographical memory test (AMT) (study 2). 30 bipolar patients with a particularly low level of psychosocial function took part in a metacognitive training (MCT) for eight weeks. At the beginning of and following the intervention, the level of psychosocial function and quality of life were assessed (Study 3). Results: Self-reported and behavioral impulsivity (measured as a lack of executive function) were increased amongst patients in comparison to the control group. The two measures, however, were not associated in the patient group. In study 2, across both groups, specificity in the AMT was positively correlated to several neuropsychological measures such as executive function, verbal memory and attention. The number of specific memories in the AMT did not differ between patients and controls. Regarding study 3, patients improved significantly in global psychosocial function, but not in quality of life. Treatment adherence was 80%. Conclusion: Self-reported and behavioral impulsivity (measured as a lack of executive functions) is increased in bipolar patients, but the two measures seem to constitute two independent dimensional factors of bipolar disorder. Better neuropsychological functioning, for example when measured as executive function, seems to be associated with more specific autobiographical memories. Contrary to previous results, there are no group differences in specificity of autobiographical memory. The pilot study shows feasibility of MCT in bipolar patients with a particularly low level of psychosocial functioning, and indicates acceptance and efficacy of MCT, which should be confirmed by larger studies with a control condition

Structured immune work-up in healthy children with a first episode of severe bacterial infection: a 7-year single-center study

Background: Severe bacterial infections (SBI) in otherwise healthy children are rare and may represent an underlying impairment of the immune system including primary immunodeficiency (PID). However, it is unclear if and how children should be assessed. Methods: We retrospectively analyzed data from hospital records of previously healthy children aged 3 days to 18 years with SBI including pleuropneumonia, meningitis, and/or sepsis. Patients were diagnosed or immunologically followed-up between 2013/01/01 and 2020/03/31. Results: Out of 432 children with SBI, 360 children could be analyzed. Follow-up data were available for 265 (74%) children, of whom 244 children (92%) had immunological testing. Laboratory abnormalities were found in 51 of 244 patients (21%), with 3 deaths (1%). There were 14 (6%) children with immunodeficiency considered clinically relevant (3 complement deficiencies, 1 autoimmune neutropenia, 10 humoral immunodeficiencies) and 27 (11%) with milder humoral abnormalities or findings suggestive of delayed adaptive immune maturation. Conclusions: A substantial proportion of children with SBI may benefit from routine immunological testing, revealing (potentially) clinically relevant impaired immune function in 6-17% of children. The identification of immune abnormalities allows for specific counselling of families and optimization of preventive measures such as booster vaccinations to avoid future SBI episodes

Safety and feasibility of intranasal heroin-assisted treatment: 4-week preliminary findings from a Swiss multicentre observational study

Background: Heroin-assisted treatment (HAT) is effective for individuals with severe opioid use disorder (OUD) who do not respond sufficiently to other opioid agonist treatments. It is mostly offered with injectable diacetylmorphine (DAM) or DAM tablets creating a barrier for individuals who need the rapid onset of action but are either unable or unwilling to inject, or primarily snort opioids. To explore another route of administration, we evaluated the safety and feasibility of intranasal (IN) DAM. Methods: This is a multicentre observational cohort study among patients in Swiss HAT. All patients planning to receive IN DAM within the treatment centres were eligible to participate. Participants were either completely switched to IN DAM or received IN DAM in addition to other DAM formulations or opioid agonists. Patients were followed up for four weeks. Sociodemographic characteristics, current HAT regimen, reasons for starting IN DAM, IN DAM doses, number of injection events in the sample, IN DAM continuation rate, and appearance of adverse events and nose-related problems were evaluated. Results: Participants (n = 52) reported vein damage, preference for nasal route of administration, and desire of a stronger effect or for a less harmful route of administration as primary reasons for switching to IN DAM. After four weeks, 90.4% of participants (n = 47) still received IN DAM. Weekly average realised injection events decreased by 44.4% from the month before IN DAM initiation to the month following. No severe adverse events were reported. Conclusions: After four weeks, IN DAM was a feasible and safe alternative to other routes of administration for patients with severe OUD in HAT. It addressed the needs of individuals with OUD and reduced injection behaviour. More long-term research efforts are needed to systematically assess efficacy of and patient satisfaction with IN DAM

Development of the EORTC QLQ-CAX24, a questionnaire for cancer patients with cachexia

Context Cachexia is commonly found in cancer patients and has profound consequences; yet there is only one questionnaire that examines the patient's perspective. Objective To report a rigorously developed module for patient self-reported impact of cancer cachexia. Methods Module development followed published guidelines. Patients from across the cancer cachexia trajectory were included. In Phase 1, health-related quality of life (HRQOL) issues were generated from a literature review and interviews with patients in four countries. The issues were revised based on patient and health care professional (HCP) input. In Phase 2, questionnaire items were formulated and translated into the languages required for Phase 3, the pilot phase, in which patients from eight countries scored the relevance and importance of each item, and provided qualitative feedback. Results A total of 39 patients and 12 HCPs took part in Phase 1. The literature review produced 68 HRQOL issues, with 22 new issues arising from the patient interviews. After patient and HCP input, 44 issues were formulated into questionnaire items in Phase 2. One hundred ten patients took part in Phase 3. One item was reworded, and 20 items were deleted as a consequence of patient feedback. Conclusions The QLQ-CAX24 is a cancer cachexia-specific questionnaire, comprising 24 items, for HRQOL assessment in clinical trials and practice. It contains five multi-item scales (food aversion, eating and weight-loss worry, eating difficulties, loss of control, and physical decline) and four single items

Interaction between NOD2 and CARD9 involves the NOD2 NACHT and the linker region between the NOD2 CARDs and NACHT domain.

NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD-NACHT linker and one in the NACHT itself.This work was funded by a Wellcome Trust Career Development Fellowship (WT085090MA) to TPM and a Medical Research Council grant (U117565398) to KR. RP and JPB were supported by BBSRC Doctoral Training Grants.This is the final published version of the article, which can also be found on the publisher's website at: http://www.sciencedirect.com/science/article/pii/S0014579314004979

Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model—a study based on data from an international multicentre project (EPCRC-CSA)

A cancer cachexia classification into stages is warranted in order to guide treatment decisions and clinical trial inclusion. Weight loss and BMI clearly discriminate between non-cachectic and cachectic patients both with regards to all the domains (Intake, Catabolism and Function) and survival. The precachexia stage might be better defined by additional factors in order to be discriminativ

Hedgehog Inhibition Promotes a Switch from Type II to Type I Cell Death Receptor Signaling in Cancer Cells

TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, proapoptotic components of the mitochondrial pathway. Hedgehog signaling modulated expression of X-linked inhibitor of apoptosis (XIAP), which serves to repress the Type I death receptor pathway. siRNA targeted knockdown of XIAP mimics sensitization to mitochondria-independent TRAIL killing achieved by Hedgehog inhibition. Regulation of XIAP expression by Hedgehog signaling is mediated by the glioma-associated oncogene 2 (GLI2), a downstream transcription factor of Hedgehog. In conclusion, these data provide additional mechanisms modulating cell death by TRAIL and suggest Hedgehog inhibition as a therapeutic approach for TRAIL-resistant neoplasms

Life-Cycle and Genome of OtV5, a Large DNA Virus of the Pelagic Marine Unicellular Green Alga Ostreococcus tauri

Large DNA viruses are ubiquitous, infecting diverse organisms ranging from algae to man, and have probably evolved from an ancient common ancestor. In aquatic environments, such algal viruses control blooms and shape the evolution of biodiversity in phytoplankton, but little is known about their biological functions. We show that Ostreococcus tauri, the smallest known marine photosynthetic eukaryote, whose genome is completely characterized, is a host for large DNA viruses, and present an analysis of the life-cycle and 186,234 bp long linear genome of OtV5. OtV5 is a lytic phycodnavirus which unexpectedly does not degrade its host chromosomes before the host cell bursts. Analysis of its complete genome sequence confirmed that it lacks expected site-specific endonucleases, and revealed the presence of 16 genes whose predicted functions are novel to this group of viruses. OtV5 carries at least one predicted gene whose protein closely resembles its host counterpart and several other host-like sequences, suggesting that horizontal gene transfers between host and viral genomes may occur frequently on an evolutionary scale. Fifty seven percent of the 268 predicted proteins present no similarities with any known protein in Genbank, underlining the wealth of undiscovered biological diversity present in oceanic viruses, which are estimated to harbour 200Mt of carbon

The Naturally Processed CD95L Elicits a c-Yes/Calcium/PI3K-Driven Cell Migration Pathway

Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca2+/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points