The importance of reporting unexpected drug failure

Unexpected drug failure is a lack of therapeutic effect, which is not expected based on the characteristics of the drug and patient. Essentially, it may occur either for interactions (with other drugs or foods) or for biopharmaceutical issues. The risk arising from interactions is generally well characterised and physicians are well aware of it, and the importance of reporting cases of failure due to interactions is obvious. Less is known about the mechanisms and potential risk deriving from biopharmaceutical problems, and we will therefore focus on this issue. Biopharmaceutics describes the influence of the physical/chemical properties of the drug and drug product on the rate and extent of systemic drug absorption. Because after oral administration of solid pharmaceutical forms drugs must dissolve in gastrointestinal fluids before being absorbed through the intestinal epithelium, biopharmaceutical problems essentially arise from an insufficient dissolution performance. A typical situation where an insufficient dissolution may cause unexpected drug failure is when a patient is switched from one drug product to a different product. Different drug products with the same active substance may differ in manufacture and excipient composition

Ciò che non torna mai a casa: Marionette, automi, spettri

Weird is what never comes home, even though it haunts the “home”, every “home”. It’s what never leaves the homeand cannot be thrown out of the home. It’s not at all disorienting because it is too familiar, like Freud's Unheimliche;but it’s the disconcerting presence of the non-human in the human, of death in life, of being in appearing and appearingin being. It’s the spectral. It’s what resists irony. The more you try to distance yourself from it the more you getentangled, like your / my sensations or like my / your garbage.This essay reflects - with extensive reference to the writings of Timothy Morton - on the concept-field of "weird",understood through the notion of the "included third" and paying attention to some "weird objects" such as puppets,automata, specters

Delle necessarie trasduzioni: Sull'ontologia delle interfacce

The essay addresses the question of interfaces from the perspective of object-oriented ontology. If the knowledge ofobjects always implies continuous transductions, thanks to which the object reality is translated into a sensibleappearance, the function of the interfaces shows itself in its structural necessity. All object knowledge is transductive.But this implies that the real being of each object withdraws from direct access. The essay, however, argues that thebeing of objects, due to its futurality (Morton), even partially escapes indirect access; and this explains why interfacesare always ambiguously clear and obscure

Lifelong nutritional omega-3 deficiency evokes depressive-like state through soluble beta amyloid

Recent evidence pointed out that the prevalence of depression has reached epidemic proportions in last decades. This increase has been linked to many environmental factors, among these the influence of dietary factors has gained great attention. In particular, it has been reported that low n-3 polyunsaturated fatty acid (n-3 PUFA) intake in diet is correlated to the development of depressive and anxiety-like symptoms. Furthermore, maternal malnutrition is a widely accepted risk factor for developing mental illness in later adulthood; among others, depression has been strongly associated to this event. On the other hand, we have previously found that acute intracerebral injection of the soluble beta amyloid 1-42 (Aβ1-42) peptide induces a depressive-like behavior in rats, associated to altered hypothalamic-pituitary-adrenal (HPA) axis activation and reduced cortical serotonin and neurotrophin levels. The aim of the present work was to study the effect of pre- and post-natal (5 weeks post-weaning) exposure to diets differently enriched in n-3, n-6, as well as n-6/n-3 PUFA balanced, on immobility time displayed on the forced swimming test (FST), along with neuroendocrine quantification in offspring rats. Results showed that n-6 PUFA-enriched diet increased depressive- and anxiety-like behaviors, as shown by the elevation in the immobility time in the FST test and self-grooming in the open field test. Those effects were accompanied by reduced cortical serotonin, high plasmatic corticosterone and hypothalamic corticotropin-releasing factor levels. Finally, enhanced plasmatic Aβ1-42 levels after n-6 PUFA diet and reduced plasmatic Aβ1-42 levels after n-3 PUFA were found. Taken together, our data indicate that Aβ1-42 might be crucially involved in behavioral alterations found after n-6 rich PUFA diet and strongly endorse the protective role of n-3 and the detrimental effect of improper n-6 PUFA diet consumption

A self-sufficient approach for GERB cloudy radiance detection.

Geostationary Earth Radiation Budget (GERB) is the broadband radiometer onboard the Meteosat Second Generation (MSG) platform, launched at the end of August 2002 and still in commissioning phase. GERB data is planned to be used in many applications concerning Earth Radiation Budget (ERB) calculation. In order to evaluate the impact of clouds on ERB, a cloud detection is required and, at present, a cloud mask based on higher spatial and spectral resolution data acquired by Spinning Enhanced Visible and Infrared Imager (SEVIRI), the imager onboard the same MSG platform, is planned to be used in order to identify cloudy GERB soundings. As an alternative, a self-sufficient (only based on GERB data) method (OCA, the One-channel Cloudy-radiance-detection Approach) is proposed, as a time-saving and, probably, more suitable solution than the planned co-location approach. In this paper, preliminary results obtained by using several years of Meteosat data as well as GERB synthetic radiances (produced from Meteosat-7 observations) are presented. It is shown how results obtained by using GERB data alone can be comparable (and better in terms of number and spatial distribution of clear-sky GERB soundings identified) to the ones achieved if the co-location of a higher resolution cloud mask is use

Sirtuin functions and modulation: from chemistry to the clinic

Sirtuins are NAD+ -dependent histone deacetylases regulating important metabolic pathways in prokaryotes and eukaryotes and are involved in many biological processes such as cell survival, senescence, proliferation, apoptosis, DNA repair, cell metabolism, and caloric restriction. The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer. Furthermore, recent interest focusing on sirtuin modulators as epigenetic players in the regulation of fundamental biological pathways has prompted increased efforts to discover new small molecules able to modify sirtuin activity. Here, we review the role, mechanism of action, and biological function of the seven sirtuins, as well as their inhibitors and activators

Analysis of Catania Flash Flood Case Study by Using Combined Microwave and Infrared Technique

Abstract In this paper, the analysis of an extreme convective event atypical for the winter season, which occurred on 21 February 2013 on the east coast of Sicily and caused a flash flood over Catania, is presented. In just 1 h, more than 50 mm of precipitation was recorded, but it was not forecast by numerical weather prediction (NWP) models and, consequently, no severe weather warnings were sent to the population. The case study proposed is first examined with respect to the synoptic situation and then analyzed by means of two algorithms based on satellite observations: the Cloud Mask Coupling of Statistical and Physical Methods (MACSP) and the Precipitation Evolving Technique (PET), developed at the National Research Council of Italy. Both of the algorithms show their ability in the near-real-time monitoring of convective cell formation and their rapid evolution. As quantitative precipitation forecasts by NWP could fail, especially for atypical convective events like in Catania, tools like MACSP and PET shall be adopted by civil protection centers to monitor the real-time evolution of deep convection events in aid to the severe weather warning service

Early loss of blood-brain barrier integrity precedes NOX2 elevation in the prefrontal cortex of an animal model of psychosis

The social isolation rearing of young adult rats is a model of psychosocial stress and provides a nonpharmacological tool to study alterations reminiscent of symptoms seen in psychosis. We have previously demonstrated that social isolation in rats leads to increased oxidative stress and to cerebral NOX2 elevations. Here, we investigated early alterations in mRNA expression leading to increased NOX2 in the brain. Rats were exposed to a short period of social isolation (1 week) and real-time polymerase chain reaction (PCR) for mRNA expression of genes involved in blood-brain barrier (BBB) formation and integrity (ORLs, Vof 21 and Vof 16, Leng8, Vnr1, and Trank 1 genes) was performed. Real-time PCR experiments, immunohistochemistry, and Western blotting analysis showed an increased expression of these genes and related proteins in isolated rats with respect to control animals. The expression of specific markers of BBB integrity, such as matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), occludin 1, and plasmalemmal vesicle associated protein-1 (PV-1), was also significantly altered after 1 week of social isolation. BBB permeability, evaluated by quantification of Evans blue dye extravasation, as well as interstitial fluid, was significantly increased in rats isolated for 1 week with respect to controls. Isolation-induced BBB disruption was also accompanied by a significant increase of Interleukin 6 (IL-6) expression. Conversely, no differences in NOX2 levels were detected at this time point. Our study demonstrates that BBB disruption precedes NOX2 elevations in the brain. These results provide new insights in the interplay of mechanisms linking psychosocial stress to early oxidative stress in the brain, disruption of the BBB, and the development of mental disorders