Affinitätsanalyse von Autoantikörpern bei Anti-NMDA-Rezeptor-Enzephalitis

Bei der Anti-NMDA-Rezeptor Enzephalitis handelt es sich um eine häufige Autoimmunenzephalitis, die mit Psychosen, Dyskinesien, autonomen Dysfunktionen und epileptischen Anfällen einhergeht. Pathogenetisch liegen diesem Krankheitsbild gegen die NR1-Untereinheit gerichtete Autoantikörper zugrunde, die die Funktion des NMDA Rezeptors beeinträchtigen. Da die jeweiligen Antikörpertiter nur partiell mit dem klinischen Verlauf korrelieren, wird vermutet, dass weitere Faktoren ausschlaggebend für die Schwere der Klinik sein können. Dafür wurden die Bindungskurven von monoklonalen Autoantikörpern und von Patientenliquor gegen NR1-exprimierende HEK293 Zellen mittels Durchflusszytometrie bestimmt. Hierbei zeigten sich für die monoklonalen Antikörper deutliche Unterschiede hinsichtlich ihrer Affinität zur NR1-Untereinheit mit Bindungskonstanten (halbmaximale Konzentration, c50) von 1 bis 74 μg/ml. Der Vergleich zwischen den Bindungskurven individueller monoklonaler Antikörper und von Patientenliquor legt die Vermutung nahe, dass das Liquorsignal hauptsächlich durch höher affine Antikörper generiert wird. Hierfür werden Konzentrationen zwischen 0,1 und 5 μg/ml angenommen, was ca. 1-10% des Gesamtliquor-IgG in der NMDAR Enzephalitis entsprechen würde. Darüber hinaus variierte das Bindungsverhalten der Antikörper je nach Liquorzusammensetzung, was darauf hindeutet, dass biophysikalische Eigenschaften der Antikörper Einfluss auf den Krankheitsverlauf ausüben können. Dies sollte vor allem bei der Interpretation etablierter klinischer Routineassays berücksichtigt werden. Mittels Normierung der Daten können NR1 Antikörpertiter in Patientenliquor zwischen unterschiedlichen Laboren verglichen und quantifiziert werden und eine Grundlage geschaffen werden, um die Antikörperaffinität in weiteren klinischen Studien als Surrogatmarker zu nutzen. Ausgehend von den vorliegenden Berechnungen könnten niedrig affine Antikörper in Routine-Zellassays undetektiert bleiben. Ihre Auswirkungen auf den klinischen Verlauf sollten in zukünftigen Studien weiter untersucht werden.Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a common immune-mediated encephalitis associated with psychosis, dyskinesia, autonomic dysfunction and seizures. The disease is characterized by autoantibodies directed against the NR1 subunit, which impair the function of the NMDA receptor. Since no clear correlation between the respective antibody titres and the clinical course could be found, it is believed that other factors may be decisive for the severity of the clinical course. Therefore, we measured the affinity of human monoclonal autoantibodies by analysing their binding curves as well as the binding behaviour of patients’ cerebrospinal fluid (CSF) by using flow cytometry-based assays with NR1-expressing HEK293 cells. Monoclonal antibodies showed significant differences in their affinity to the NR1 subunit with binding constants (half-maximal concentration, c50) of 1 to 74 μg/ml. Binding parameters of monoclonal antibodies and patient CSF indicate that high-affinity antibodies mainly account for the CSF signal, possibly in concentrations between 0.1 and 5 μg/ml, which constitute approximately 1-10% of total CSF IgG in NMDAR encephalitis. Furthermore, binding behaviour of antibodies varied depending on CSF composition, suggesting that the biophysical properties of the antibodies may influence the course of the disease. This should be taken into account especially when established routine clinical assays are performed and interpreted. By normalizing binding parameters, measurements proved to be highly reproducible allowing inter-laboratory comparison and quantification of antibody affinity in autoimmune encephalitis. This makes it a suitable surrogate marker for future clinical trials. According to these measurements, routine cell-based assays might not detect low-affinity antibodies. Future studies should analyse their relation to the clinical course in NMDAR encephalitis

Systematic review recommends the European Organization for Research and Treatment of Cancer colorectal cancer–specific module for measuring quality of life in colorectal cancer patients

Objectives: To critically appraise the measurement properties of standardized health-related quality of life (HRQOL) instruments for colorectal cancer (CRC) patients and to provide recommendations on the choice of HRQOL instruments. Study Design and Setting: Systematic review of English language literature published between January 1985 and May 2014 identified through a database search of PubMed, Web of Science, Embase, and Ovid MEDLINE. HRQOL instruments were rated on methodological quality and overall levels of evidence using a Consensus-based Standards for the selection of health Measurement Instrument checklist. Results: Internal consistency and hypothesis testing were evaluated most frequently in 63 studies identified. The Functional Assessment of Cancer Therapy-Colorectal (FACT-C) was the most extensively evaluated. The highest number of positive ratings in the overall level of evidence was found in the CRC-specific quality of life questionnaire module (QLQ-CR38) in European Organization for Research and Treatment of Cancer (EORTC) module, followed by the Memorial Sloan Kettering Cancer Center Bowel instrument, FACT-C, and Quick-FLIC. The EORTC QLQ-CR38 had the most positive ratings on measurement property and was recommended. Conclusion: The EORTC QLQ-CR38 was recommended to assess HRQOL in patients with CRC, regardless of disease stage and primary tumor site.postprin

New simplified analytical method for the Prediction of global stability of steel and composite sway frames

peer reviewedEurocode 4 is the European design code for composite construction; in its so-called EN 1994-1-1 version, the design of “non-sway buildings” is mainly covered. As a result, EC4 focuses on the check of structural elements like beams, columns, slabs and joints. However, in the last years, the construction of taller buildings and larger industrial halls without wind bracing systems tends to make global instability a relevant failure mode, which is not well covered by Eurocode 4. Recently, intensive experimental, numerical and theoretical investigations have been carried out at Liège University. The latter aimed at improving the knowledge in the field of sway composite building frames and at developing appropriate design rules. The rotational behavior of the beam-to-column composite joints is one of the key aspects of the problem to which a special attention has been paid. This paper reflects investigations carried out at Liege University on this topic. In particular, an innovative simplified analytical method to predict the ultimate loading factor and the associated collapse mode of both steel and composite frames subjected to static loadings is presented

E-Cigarette Awareness, Perceptions and Use among Community-Recruited Smokers in Hong Kong

Abstract Background Electronic cigarettes (e-cigarettes) are being increasingly used. We examined the correlates associated with e-cigarette awareness, use and perceived effectiveness in smoking cessation among Chinese daily smokers in Hong Kong. Methods Daily smokers (N = 1,307) were recruited to a community-based randomised controlled trial (‘Quit to Win’) in 2014. Socio-demographic characteristics, conventional cigarette smoking status, nicotine addiction level, quit attempts, quit intention, e-cigarette awareness, use and perceived effectiveness on quitting were reported at baseline and 1-week follow-up. Multivariate logistic regression was used to identify factors associated with e-cigarette awareness, use and perceived effectiveness in quitting. Results Most smokers (82.6%, 95% CI 80.2%-84.9%) had heard about e-cigarettes, and 13.3% (11.3%-15.5%) ever used e-cigarettes. Most users (74.1%) and non-users (91.2%) did not perceive e-cigarettes as effective in quitting. Being younger and having a larger family income were associated with e-cigarette awareness. Being younger, a tertiary education and a stronger addiction to nicotine were associated with e-cigarette use, which was itself associated with lower levels of intention to quit and had no association with attempts to quit (P for trend 0.45). E-cigarette use, the last quit attempt being a month earlier, having made a quit attempt lasting 24 hours or longer and perceiving quitting as important were all associated with the perceived effectiveness of e-cigarettes in quitting (all P <0.05). Conclusions Among community-recruited smokers who intended to quit, awareness of e-cigarettes was high, but most did not perceive e-cigarettes as effective in quitting. Correlates concerning ecigarette perceptions and use will help to inform prospective studies, public education and policy on controlling e-cigarettes.published_or_final_versio

Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons.

Disrupting particular mitochondrial fission and fusion proteins leads to the death of specific neuronal populations; however, the normal functions of mitochondrial fission in neurons are poorly understood, especially in vivo, which limits the understanding of mitochondrial changes in disease. Altered activity of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) may contribute to the pathophysiology of several neurologic diseases. To study Drp1 in a neuronal population affected by Alzheimer's disease (AD), stroke, and seizure disorders, we postnatally deleted Drp1 from CA1 and other forebrain neurons in mice (CamKII-Cre, Drp1lox/lox (Drp1cKO)). Although most CA1 neurons survived for more than 1 year, their synaptic transmission was impaired, and Drp1cKO mice had impaired memory. In Drp1cKO cell bodies, we observed marked mitochondrial swelling but no change in the number of mitochondria in individual synaptic terminals. Using ATP FRET sensors, we found that cultured neurons lacking Drp1 (Drp1KO) could not maintain normal levels of mitochondrial-derived ATP when energy consumption was increased by neural activity. These deficits occurred specifically at the nerve terminal, but not the cell body, and were sufficient to impair synaptic vesicle cycling. Although Drp1KO increased the distance between axonal mitochondria, mitochondrial-derived ATP still decreased similarly in Drp1KO boutons with and without mitochondria. This indicates that mitochondrial-derived ATP is rapidly dispersed in Drp1KO axons, and that the deficits in axonal bioenergetics and function are not caused by regional energy gradients. Instead, loss of Drp1 compromises the intrinsic bioenergetic function of axonal mitochondria, thus revealing a mechanism by which disrupting mitochondrial dynamics can cause dysfunction of axons

Development of a Health Empowerment Programme to improve the health of working poor families: protocol for a prospective cohort study in Hong Kong

Introduction: People from working poor families are at high risk of poor health partly due to limited healthcare access. Health empowerment, a process by which people can gain greater control over the decisions affecting their lives and health through education and motivation, can be an effective way to enhance health, health-related quality of life (HRQOL), health awareness and health-seeking behaviours of these people. A new cohort study will be launched to explore the potential for a Health Empowerment Programme to enable these families by enhancing their health status and modifying their attitudes towards health-related issues. If proven effective, similar empowerment programme models could be tested and further disseminated in collaborations with healthcare providers and policymakers. Method and analysis: A prospective cohort study with 200 intervention families will be launched and followed up for 5 years. The following inclusion criteria will be used at the time of recruitment: (1) Having at least one working family member; (2) Having at least one child studying in grades 1–3; and (3) Having a monthly household income that is less than 75% of the median monthly household income of Hong Kong families. The Health Empowerment Programme that will be offered to intervention families will comprise four components: health assessment, health literacy, self-care enablement and health ambassador. Their health status, HRQOL, lifestyle and health service utilisation will be assessed and compared with 200 control families with matching characteristics but will not receive the health empowerment intervention. Ethics and dissemination: This project was approved by the University of Hong Kong—the Hospital Authority Hong Kong West Cluster IRB, Reference number: UW 12-517. The study findings will be disseminated through a series of peer-reviewed publications and conference presentations, as well as a yearly report to the philanthropic funding body–Kerry Group Kuok Foundation (Hong Kong) Limited.published_or_final_versio

Continuous entecavir for treatment-naïve Chinese chronic hepatitis B in the real world setting: the six-year results

This journal suppl. entitled: 2014 DDW AbstractBACKGROUND: There is a paucity of data on uninterrupted entecavir for treatment-naive chronic hepatitis B (CHB) beyond 5 years. METHODS: Treatment-naive Chinese CHB patients were treated continuously with entecavir 0.5mg daily in the real world setting for up to 6 years. The cumulative rates of hepatitis B e antigen (HBeAg) seroconversion, alanine aminotransferase (ALT) normalization, DNA undetectability, virologic breakthrough (>1 log HBV DNA increase from the nadir) and genotypic resistance to entecavir were determined. HBV DNA levels were measured by Roche Taqman real time PCR assay (lower limit of detection: 20 IU/mL). Resistance profile was determined by line probe assay (LiPA, Innogenetics NV, Gent, Belgium) for patients ...postprin

Widened pulse pressure is a potential risk factor for significant cognitive impairment among community-dwelling Chinese younger old people

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