Euroopan unionin sijoituspalveluyrityksiä koskeva sääntely reguloivan hallinnon viitekehyksessä : Tilivelvollisuussuhteiden tarkastelu MiFID 2 -direktiivin sijoittajansuojaa koskevissa määräyksissä

Tutkimuksessa perehdytään Euroopan unionin rahoitusmarkkinoita koskevaan sääntelyyn ja sen muuttumiseen sekä millä tavoin tämän muutoksen voidaan nähdä ilmentävän hallintatapojen paradigman muutosta. Hallinnon paradigman muutoksella tarkoitetaan tässä tutkimuksessa siirtymää kansallisvaltiokeskeisestä vallasta ja hallinnasta kohti globaalia hajautettua hallintaa. Hallintatapojen muutosta tarkastellaan aineistossa ilmenevien tilivelvollisuussuhteiden kautta. Tutkimuksen johdannossa esitellään tutkimuksen yhteiskunnallinen ja ajallinen konteksti, joka nojaa vuoden 2008 finanssikriisiin ja erityisesti kriisin jälkeiseen rahoitusmarkkinoiden sääntelyyn Euroopan unionissa. Syy sille, miksi tutkimus on ajankohtainen juuri sen kirjoittamishetkellä, on se, että 1.3.2018 Euroopan unionissa astuu voimaan valtava rahoitusmarkkinoiden sääntelyhanke, jonka juuret ulottuvat vuoden 2008 kriisiin. Tämä sääntelyhanke, ja erityisesti siihen kuuluva MiFID 2 -direktiivi toimivat tämän tutkimuksen pääasiallisena aineistona. Luvussa kaksi esitellään tutkimuksen teoreettinen viitekehys joka nojaa jaotteluun positiivisen valtion ja reguloivan hallinnon välillä. Viitekehyksen sisällä tarkastellaan vallan ja hallinnan legitimiteettiä sekä siihen vaikuttavaa käsitettä tilivelvollisuudesta ja miten nämä käsitteet ja ilmiöt ovat muuttuneet siirryttäessä positiivisesta valtiosta kohti reguloivaa hallintaa. Positiivisen valtion legitimiteetin perustana pidetään suoraa poliittista tilivelvollisuutta, jota voidaan tarkastella esimerkiksi äänestyskäyttäytymisen kautta, kun taas reguloivaa hallintoa tarkasteltaessa tilivelvollisuussuhteiden nähdään olevan jakautuneita useammalla toimijalle vallan ja hallinnan jakautumisen myötä, mikä koetan haasteellisena toiminnan legitimiteetin kannalta. Luku kolme keskittyy käsittelemään sääntelyä ilmiönä, sekä millainen on rahamarkkinoiden sääntelyn lähihistoria Euroopan unionissa. Luvussa esitellään mitä sääntelyllä terminä ja prosessina tarkoitetaan sekä miten eri jäsenvaltiot ovat suhtautuneet Euroopan unionin rahamarkkinoiden sääntelypolitiikkaan. Luvussa neljä esitellään tutkimuksessa käytettävä aineisto, eli MiFID 2 -direktiivi ja siihen liittyvät viranomaismateriaalit koskien sijoittajansuojan sääntelyä sekä tutkimuksessa tehtävä analyysi. Analyysi toteutetaan luvussa viisi sisällönanalyysin keinoin. Tutkimuksen aineisto on luokiteltu viiteen kategoriaan jotka kuvaavat sijoittajansuojan eri osa-alueita. Aineistosta pyritään analyysissa identifioimaan tilivelvollisuussuhteita kysymysten kenelle, kuka, miksi, miten ja mistä- avulla. Analyysin perusteella tutkimuksessa todetaan, että valittu aineisto ja sijoittajansuojan sääntely edustavat enemmän kansallisvaltiolle tyypillisiä piirteitä kuin reguloivan hallinnon piirteitä. Analyysissä esitetyt tilivelvollisuussuhteet nojaavat pääasiassa hierarkioihin ja suoraan tilivelvollisuuteen, minkä voidaan nähdä ilmentävän kansallisvaltiokeskeistä hallintatapaa. Tutkimuksen johtopäätöksissä kuitenkin todetaan, ettei toteutetun analyysin perusteella voida vetää liian kauaskantoisia johtopäätöksiä siitä, miten Euroopan unioni kokonaisuudessaan käsitteellistetään reguloivan hallinnon viitekehyksessä

Cerebral Blood Flow Measurement Using fMRI and PET: A Cross-Validation Study

An important aspect of functional magnetic resonance imaging (fMRI) is the study of brain hemodynamics, and MR arterial spin labeling (ASL) perfusion imaging has gained wide acceptance as a robust and noninvasive technique. However, the cerebral blood flow (CBF) measurements obtained with ASL fMRI have not been fully validated, particularly during global CBF modulations. We present a comparison of cerebral blood flow changes (ΔCBF) measured using a flow-sensitive alternating inversion recovery (FAIR) ASL perfusion method to those obtained using H215O PET, which is the current gold standard for in vivo imaging of CBF. To study regional and global CBF changes, a group of 10 healthy volunteers were imaged under identical experimental conditions during presentation of 5 levels of visual stimulation and one level of hypercapnia. The CBF changes were compared using 3 types of region-of-interest (ROI) masks. FAIR measurements of CBF changes were found to be slightly lower than those measured with PET (average ΔCBF of 21.5 ± 8.2% for FAIR versus 28.2 ± 12.8% for PET at maximum stimulation intensity). Nonetheless, there was a strong correlation between measurements of the two modalities. Finally, a t-test comparison of the slopes of the linear fits of PET versus ASL ΔCBF for all 3 ROI types indicated no significant difference from unity (P > .05)

Effects of short-term energy restriction on liver lipid content and inflammatory status in severely obese adults: results of a randomised controlled trial (RCT) using two dietary approaches

Short-term very low energy diets (VLED) are used in clinical practice prior to bariatric surgery, however, regimens vary and outcomes for a short intervention are unclear. We examined the effect of two VLEDs; a food-based diet (FD) and meal replacement plan (MRP) (LighterLife) over two weeks in a randomised controlled trial (RCT). We collected clinical and anthropometric data, fasting blood samples, and dietary evaluation questionnaires. Surgeons took liver biopsies and made a visual assessment of the liver. We enrolled 60 participants and 54 completed (FD n=26, MRP n=28). Baseline demographic features, reported energy intake, dietary evaluation and liver histology were comparable between groups. Both diets induced significant weight loss. Perceived difficulty of surgery correlated significantly with the degree of steatosis on histology. Circulating inflammatory mediators: CRP, Fetuin-A and IL6 reduced pre to post diet. Diets achieved comparable weight loss and reduction in inflammatory biomarkers, perceived operative difficulty, and patient evaluation. NAFLD histology assessments post-diet were also not significantly different between diets. Results indicate effectiveness of short term very low energy diets and energy restriction irrespective of macronutrient composition although small sample size precluded detection of subtle differences between interventions

Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Background: Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease in Western countries. The development of non-alcoholic steatohepatitis (NASH) and fibrosis identifies an at-risk group with increased risk of cardiovascular and liver-related deaths. The identification and management of this at-risk group remains a clinical challenge. \ud \ud Aim: To perform a systematic review of the established and emerging strategies for the diagnosis and staging of NAFLD. \ud \ud Methods: Relevant research and review articles were identified by searching PubMed, MEDLINE and EMBASE. \ud Results: There has been a substantial development of non-invasive risk scores, biomarker panels and radiological modalities to identify at-risk patients with NAFLD without recourse to liver biopsy on a routine basis. These modalities and algorithms have improved significantly in their diagnosis and staging of fibrosis and NASH in patients with NAFLD, and will likely impact on the number of patients undergoing liver biopsy. \ud \ud Conclusions: Staging for NAFLD can now be performed by a combination of radiological and laboratory techniques, greatly reducing the requirement for invasive liver biopsy

RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca2+ channel genes that may explain disrupted Ca2+ homeostasis in SMA and activation of Cdk5

Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques

We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a common disease in Western society and ranges from steatosis to steatohepatitis to end-stage liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanisms that are involved in the progression of steatosis to more severe liver damage in patients are not fully understood. A deeper investigation of NAFLD pathogenesis is possible due to the many different animal models developed recently. In this review, we present a comparative overview of the most common dietary NAFLD rodent models with respect to their metabolic phenotype and morphological manifestation. Moreover, we describe similarities and controversies concerning the effect of NAFLD-inducing diets on mitochondria as well as mitochondria-derived oxidative stress in the progression of NAFLD

A phase 2, randomized, double‐blind, placebo‐controlled study of GS‐9450 in subjects with nonalcoholic steatohepatitis

In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS‐9450 has a potential for altering the course of the liver disease. In this phase 2, double‐blind study, 124 subjects with biopsy‐proven NASH were randomized to once‐daily placebo or 1, 5, 10, or 40 mg GS‐9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase‐3–cleaved cytokeratin (CK)‐18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40‐mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 ( P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40‐mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK‐18 fragment levels had decreased to 393 (723) U/L in the GS‐9450 10‐mg group and 125 (212) U/L in the 40‐mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment‐emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS‐9450 treatment groups versus 35% in the placebo group. Conclusion : GS‐9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK‐18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH. (H epatology 2012)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90118/1/24747_ftp.pd

A New Composite Model including metabolic syndrome, Alanine aminotransferase and Cytokeratin-18 for the Diagnosis of Non-Alcoholic Steatohepatitis in Morbidly Obese Patients

International audienceBackground and aims: Non invasive approaches are useful to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH) in obese and morbidly obese patients. The aim of this study was to develop a new scoring system to diagnose definitive NASH. Methods: Preoperative clinical and biological data including serum caspase 3-generated cytokeratin-18 fragments (CK18) and peroperative liver biopsies were obtained from 464 morbidly obese patients who had undergone bariatric surgery. The cohort was divided into two groups: training group (n=310) and validation group (n=154). Definitive NASH was defined according to Kleiner's classification with a NAFLD Activity Score (NAS) ≥5. Results: Alanine aminotransferase (ALT), CK18 fragments and the presence of metabolic syndrome (MS) were independent predictors for discriminating patients with NAS ≥5 in the training group. These three parameters were used to carry out a scoring system for the prediction of NAS ≥5. Whereas serum CK18 fragment alone had an Area under the Receiver Operating Characteristic (AUROC) curve = 0.74, AUROC curves of the scoring system were 0.88 and 0.83 in the training and in the validation group respectively. Conclusion: A simple and non invasive composite model including MS, ALT and CK18 fragments was able to accurately predict NAS ≥5 in morbidly obese subjects

Breath Biopsy Assessment of Liver Disease Using an Exogenous Volatile Organic Compound-Toward Improved Detection of Liver Impairment.

INTRODUCTION: Liver cirrhosis and its complication - hepatocellular carcinoma (HCC) - have been associated with increased exhaled limonene. It is currently unclear whether this increase is more strongly associated with the presence of HCC or with the severity of liver dysfunction. METHODS: We compared the exhaled breath of 40 controls, 32 cirrhotic patients, and 12 cirrhotic patients with HCC using the Breath Biopsy platform. Breath samples were analyzed by thermal desorption-gas chromatography-mass spectrometry. Limonene levels were compared between the groups and correlated to bilirubin, albumin, prothrombin time international normalized ratio, and alanine aminotransferase. RESULTS: Breath limonene concentration was significantly elevated in subjects with cirrhosis-induced HCC (M: 82.1 ng/L, interquartile range [IQR]: 16.33-199.32 ng/L) and cirrhosis (M: 32.6 ng/L, IQR: 6.55-123.07 ng/L) compared with controls (M: 6.2 ng/L, IQR: 2.62-9.57 ng/L) (P value = 0.0005 and 0.0001, respectively) with no significant difference between 2 diseased groups (P value = 0.37). Levels of exhaled limonene correlated with serum bilirubin (R = 0.25, P value = 0.0016, r = 0.51), albumin (R = 0.58, P value = 5.3e-8, r = -0.76), and international normalized ratio (R = 0.29, P value = 0.0003, r = 0.51), but not with alanine aminotransferase (R = 0.01, P value = 0.36, r = 0.19). DISCUSSION: Exhaled limonene levels are primarily affected by the presence of cirrhosis through reduced liver functional capacity, as indicated by limonene correlation with blood metrics of impaired hepatic clearance and protein synthesis capacity, without further alterations observed in subjects with HCC. This suggests that exhaled limonene is a potential non-invasive marker of liver metabolic capacity (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/CTG/A388).Owlstone Medical Lt