TG6 auto-antibodies in dermatitis herpetiformis

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of gluten sensitivity. The interplay between B cell responses to these 3 transglutaminases in developing the clinical spectrum of disease manifestations is not completely understood. Also, the individual or combined diagnostic and predictive value of the respective autoantibodies is not fully explored. We examined the prevalence of TG6 antibodies in a cohort of patients with DH. TG6 positivity was found in 13/33 (39%), with IgA detected in 11 patients, IgG in 3, and both in 1. This was significantly higher compared to what is seen in the classic CD cases (14%) in a Finnish population. TG6 positive baseline samples constituted 60% of DH patients with no enteropathy (n = 10), as opposed to 17% positivity in those with overt enteropathy (n = 12; Marsh IIIB). Repeat testing after adherence to a gluten-free diet for 1 year showed reduced titers for TG6 antibodies in 11/13 (85%), whereby 7 patients were now TG6 antibody-negative. Four patients seroconverted and tested positive for TG6 antibodies at one year, due to the ongoing exposure to gluten. We report another patient who presented with neurological manifestations (encephalopathy) leading to the diagnosis of CD, who was intermittently adhering to a gluten-free diet. Serological testing at baseline showed him to be positive for antibodies to all 3 transglutaminases. Eleven years later, he developed DH. He also subsequently developed ataxia and peripheral neuropathy. Although TG3 and TG6 autoantibodies are linked to certain disease manifestations, TG2, TG3, and TG6 autoantibodies can be present across the spectrum of GRD patients and might develop years before onset of symptoms of extraintestinal manifestations. This is consistent with gluten-dependent adaptive immunity being a necessary but not sufficient pretext to organ-specific damage. TG6 antibodies appear to develop more frequently in patients where tolerance to gluten was broken but, either there was no development of the molecular state driving the tissue destruction at the level of the gut, or perhaps more likely, there was more resistance to developing this phenotype

The bank lending channel: an empirical assessment of measures to stimulate bank lending in the European Union

This thesis first examines the role of banks in the transmission mechanism of monetary policy by focusing on the eight European new member States of Central and Eastern Europe over the 2004-2013 period. We specifically investigate the influence of monetary policy changes on bank lending activity and if this potential influence is contingent on bank characteristics, such as banks’ size, capital, liquidity, risk factor and market power. Moreover, we focus on the prospective role of banks in the monetary policy transmission mechanism in order to reveal any clear trends in banks’ lending behaviour during the 2008-2011 financial crisis. Secondly, we investigate the impact of a protracted period of low monetary policy rates on loosening of banks’ credit standards regarding enterprises, households and consumer loans through concentrating on the nine Eurozone countries involved since the initiation of the Euro area Bank Lending Survey in the three distinct time frames of pre- (2002Q4-2008Q3), mid- (2008Q4-2010Q4) and post- (2011Q1-2014:Q4) financial crisis. Furthermore, we test the fundamental concept of the risk taking channel by examining excessive risk-taking behaviour by banks in stressed vs. non-stressed countries of the Eurozone. In an additional analysis, the efficacy of the European Central Bank’s 3 year Long-Term Refinancing Operations is evaluated in great depth in order to determine whether banks’ credit standards have been softened and the degree to which demand for loans has increased. Thirdly, we explore the financing structure of bank lending constrained Small and Medium Sized Enterprises in the eleven Eurozone countries by utilising firm-level data over the period of 2009 to 2014. We estimate if bank lending constrained firms demonstrate relatively more usage or requests for alternative financing. Additionally, a comprehensive investigation is presented by unveiling the impact and determinants of various financing constraints including credit lines, bank loans, trade credit and other lending on Eurozone firms. Furthermore, the notion of discouraged borrowers originally formulated by Kon and Storey (2003) is empirically evaluated. Finally, we present the conclusion of our research by further outlining its limitations and prospective scope for future studie

In Vivo Methods to Study Uptake of Nanoparticles into the Brain

Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods

The clinical impact of using complex molecular profiling strategies in routine oncology practice

Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients’ treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10–50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice