Safety Profile of Opicapone in the Management of Parkinson's Disease

BACKGROUND: Opicapone is a catechol O-methyltransferase (COMT) inhibitor indicated for use as adjunct to levodopa therapy in patients with Parkinson's disease (PD) and motor fluctuations. OBJECTIVE: To characterize the safety and tolerability of adjunct opicapone (25 and 50 mg) in a pooled population of levodopa-treated PD patients who participated in the opicapone Phase-3 clinical program. METHODS: Patient-level data (placebo, opicapone 25 mg and 50 mg) from the BIPARK-1 and BIPARK-2 double-blind and open-label studies were combined. RESULTS: Pooled analyses included 766 patients from the double-blind studies and 848 patients from the open-label studies. In the double-blind studies, 63.3% of opicapone-treated patients reported treatment-emergent adverse events (TEAEs) versus 57.2% in the placebo group. The most common TEAEs reported in the opicapone group compared to placebo were dyskinesia, constipation and insomnia. The incidence of serious TEAEs was similar across opicapone and placebo groups (3.5% versus 4.3%, respectively). Overall, 71.3% patients treated with open-label opicapone reported at least one TEAE; most occurred within the first 2 months of the open-label studies, and then decreased thereafter. Throughout the Phase-3 clinical program, there were no serious AEs suggestive of hepatic toxicity, and the incidence of gastrointestinal disorders such as nausea and diarrhea remained low (<2%). There were no relevant changes in laboratory parameters including liver enzymes, vital signs, physical or neurological examinations, or ECG readings. CONCLUSIONS: Long-term use of opicapone once-daily over 1-year at doses of 25 mg or 50 mg was generally safe and well tolerated, supporting its clinical usefulness in the management of PD motor fluctuations

A GBF1-Dependent Mechanism for Environmentally Responsive Regulation of ER-Golgi Transport

How can anterograde membrane trafficking be modulated by physiological cues? A screen of Golgi-associated proteins revealed that the ARF-GEF GBF1 can selectively modulate the ER-Golgi trafficking of prohaemostatic von Willebrand factor (VWF) and extracellular matrix (ECM) proteins in human endothelial cells and in mouse fibroblasts. The relationship between levels of GBF1 and the trafficking of VWF into forming secretory granules confirmed GBF1 is a limiting factor in this process. Further, GBF1 activation by AMPK couples its control of anterograde trafficking to physiological cues; levels of glucose control GBF1 activation in turn modulating VWF trafficking into secretory granules. GBF1 modulates both ER and TGN exit, the latter dramatically affecting the size of the VWF storage organelles, thereby influencing the hemostatic capacity of the endothelium. The role of AMPK as a central integrating element of cellular pathways with intra- and extra-cellular cues can now be extended to modulation of the anterograde secretory pathway

Weibel-Palade bodies at a glance

The vascular environment can rapidly alter, and the speed with which responses to both physiological and pathological changes are required necessitates the existence of a highly responsive system. The endothelium can quickly deliver bioactive molecules by regulated exocytosis of its secretory granules, the Weibel−Palade bodies (WPBs). WPBs include proteins that initiate both haemostasis and inflammation, as well those that modulate blood pressure and angiogenesis. WPB formation is driven by von Willebrand factor, their most abundant protein, which controls both shape and size of WPBs. WPB are generated in a range of sizes, with the largest granules over ten times the size of the smallest. In this Cell Science at a Glance and the accompanying poster, we discuss the emerging mechanisms by which WPB size is controlled and how this affects the ability of this organelle to modulate haemostasis. We will also outline the different modes of exocytosis and their polarity that are currently being explored, and illustrate that these large secretory organelles provide a model for how elements of secretory granule biogenesis and exocytosis cooperate to support a complex and diverse set of functions

The Nature of Surface Oxides on Corrosion-Resistant Nickel Alloy Covered by Alkaline Water

A nickel alloy with high chrome and molybdenum content was found to form a highly resistive and passive oxide layer. The donor density and mobility of ions in the oxide layer has been determined as a function of the electrical potential when alkaline water layers are on the alloy surface in order to account for the relative inertness of the nickel alloy in corrosive environments

Minor psychiatric disorders among Brazilian ragpickers: a cross-sectional study

BACKGROUND: Ragpickers are informal workers who collect recyclable materials to earn a small wage. Their life and working conditions are extremely difficult. We examined minor psychiatric disorders (MPD) among a cohort of ragpickers in Pelotas, a city in southern Brazil. METHODS: Ragpickers were matched by sex, age, and years of schooling with a sample of non-ragpickers from the same poor neighborhoods. The cross-sectional study gathered data by interview on 990 individuals in 2004. MPD were assessed using a standard self-reporting questionnaire, the SRQ-20. RESULTS: The prevalence of MPD among ragpickers was 44.7%, higher than reported by neighborhood controls (33.6%; p < 0.001). MPD were more common among females, those of lower economic level, smokers and alcoholics. Among occupational characteristics, MPD prevalence was associated with frequent static postures, low job satisfaction and recent work accidents. CONCLUSION: Ragpickers more frequently report MPD than other poor workers living in the same neighborhoods, with many of the same life conditions. Improving the work lives of these precarious workers should address not only the physical hazards of their jobs but their mental and emotional health as well

Free daily newspapers : too strong incentives to print?

A free daily newspaper distributes news to readers and sells ad-space to advertisers, having private information about its audience. For a given number of distributed copies, depending on the type of audience (favorable or unfavorable), the newspaper may either have a large readership or a small readership. A large readership provides a greater return to advertisers, because ads are visualized by more people. A favorable audience has also the advantage of requiring a lower distribution cost (for a given number of distributed copies), because readers are willing to exert more effort to obtain a copy of the free newspaper and are less likely to reject a copy that is handed to them. We find that when the audience is unfavorable, the number of distributed copies and the price of ad-space coincide with those of the perfect information scenario. In contrast, if the audience is favorable, the newspaper prints extra copies to send a credible signal to the advertisers that the audience is favorable. Overprinting is not necessarily welfare-detrimental since readers benefit from the existence of additional copies.info:eu-repo/semantics/publishedVersio

The Underestimation Of Egocentric Distance: Evidence From Frontal Matching Tasks

There is controversy over the existence, nature, and cause of error in egocentric distance judgments. One proposal is that the systematic biases often found in explicit judgments of egocentric distance along the ground may be related to recently observed biases in the perceived declination of gaze (Durgin & Li, Attention, Perception, & Psychophysics, in press), To measure perceived egocentric distance nonverbally, observers in a field were asked to position themselves so that their distance from one of two experimenters was equal to the frontal distance between the experimenters. Observers placed themselves too far away, consistent with egocentric distance underestimation. A similar experiment was conducted with vertical frontal extents. Both experiments were replicated in panoramic virtual reality. Perceived egocentric distance was quantitatively consistent with angular bias in perceived gaze declination (1.5 gain). Finally, an exocentric distance-matching task was contrasted with a variant of the egocentric matching task. The egocentric matching data approximate a constant compression of perceived egocentric distance with a power function exponent of nearly 1; exocentric matches had an exponent of about 0.67. The divergent pattern between egocentric and exocentric matches suggests that they depend on different visual cues

Tissue Localization and Extracellular Matrix Degradation by PI, PII and PIII Snake Venom Metalloproteinases: Clues on the Mechanisms of Venom-Induced Hemorrhage

20 páginas, 4 figuras, 3 tablas y 7 tablas en material suplementario.Snake venom hemorrhagic metalloproteinases (SVMPs) of the PI, PII and PIII classes were compared in terms of tissue localization and their ability to hydrolyze basement membrane components in vivo, as well as by a proteomics analysis of exudates collected in tissue injected with these enzymes. Immunohistochemical analyses of co-localization of these SVMPs with type IV collagen revealed that PII and PIII enzymes co-localized with type IV collagen in capillaries, arterioles and post-capillary venules to a higher extent than PI SVMP, which showed a more widespread distribution in the tissue. The patterns of hydrolysis by these three SVMPs of laminin, type VI collagen and nidogen in vivo greatly differ, whereas the three enzymes showed a similar pattern of degradation of type IV collagen, supporting the concept that hydrolysis of this component is critical for the destabilization of microvessel structure leading to hemorrhage. Proteomic analysis of wound exudate revealed similarities and differences between the action of the three SVMPs. Higher extent of proteolysis was observed for the PI enzyme regarding several extracellular matrix components and fibrinogen, whereas exudates from mice injected with PII and PIII SVMPs had higher amounts of some intracellular proteins. Our results provide novel clues for understanding the mechanisms by which SVMPs induce damage to the microvasculature and generate hemorrhage.This work was performed in partial fulfillment of the requirements for the PhD degree for Cristina Herrera at Universidad de Costa Rica.Peer reviewe