FARMACI DOPAMINERGICI E ATTIVAZIONE DELLE CHINASI ERK1 E ERK2

La dopamina attraverso i suoi recettori dopaminergici modula numerose funzioni soprattutto a livello del sistema nervoso centrale quali l’attività psichica, cognitiva e motoria. Dal punto di vista patologico, il sistema dopaminergico ha un ruolo di primaria importanza in alcune malattie, come per esempio il morbo di Parkinson e la schizofrenia. Nella malattia di Parkinson vengono utilizzati farmaci che mimano gli effetti della dopamina ridotta nel tratto nigro-striatale (dopamino-agonisti), mentre nella schizofrenia e nelle psicosi vengono somministrati farmaci con azione di antagonismo rispetto ad una eccessiva produzione di dopamina nel tratto mesolimbico (dopamino-antagonisti). Tuttavia, il meccanismo di azione di tali farmaci non è stato ancora completamente chiarito ed altri neurotrasmettitori o altre proteine sono state studiate per comprendere meglio queste patologie. In particolare, nelle malattie del sistema nervoso centrale, un ruolo importante è svolto dalle chinasi ERK1 e ERK2 (dall’inglese Extracellular-signal regulated kinases) le quali sono coinvolte in meccanismi neuronali come la sopravvivenza cellulare, la sinaptogenesi e neurogenesi, fenomeni che risultano rilevanti nella malattia di Parkinson e nella schizofrenia. L’azione di farmaci dopaminergici sull’attivazione di ERK1 e ERK2, seppur riportata nella letteratura, non è stata ancora studiata in modo sistematico e completo. Questa tesi ha analizzato in dettaglio l’effetto di farmaci dopaminergici agonisti ed antagonisti, di prima e di seconda (nuova) generazione, sull’attivazione di ERK1 e ERK2. I dati sperimentali in vitro su colture cellulari che esprimevano i vari recettori presi in esame hanno evidenziato che farmaci anti-Parkinson di nuova generazione, come Ropinirolo, sono potenti attivatori delle chinasi ERK1 e ERK2, mentre i farmaci di prima generazione, come Bromocriptina, non inducono tale fenomeno. Per quanto riguarda invece i farmaci antipsicotici-antischizofrenici, quelli cosiddetti “atipici” di nuova generazione, come Clozapina, sono in grado ugualmente di attivare ERK1 e ERK2, mentre quelli “tipici” di prima generazione, come Aloperidolo, sono inattivi su tale meccanismo. Inoltre, mentre per i farmaci antiParkinson tale effetto è mediato dal recettore dopaminergico D2, per i farmaci antipsicotici “atipici” il meccanismo è differente e non coinvolge recettori dopaminergici, serotoninergici o adrenergici. L’attivazione delle chinasi ERK1 e ERK2 potrebbe avere un ruolo importante nei meccanismi di neuroprotezione indotta dai farmaci utilizzati nella malattia di Parkinson e/o nel miglioramento dei sintomi cognitivi e negativi presenti nella schizofrenia a seguito dell’utilizzo di antipsicotici come la Clozapina

Development of a visual navigation system for multirotor vehicles

In this thesis has been proposed a visual navigation system for multirotor vhicles, equipped with a stereo camera, and an onboard IMU sensor

Full Scale Validation Of A High Pressure Ratio Centrifugal Compressor

LectureThe present paper describes the test activities which have validated a new compressor architecture, developed by the OEM, which is able to deliver a higher pressure ratio in a single casing with respect to traditional configurations. The major differences with respect to the typical technologies used for high pressure machines are in the rotor design: Rotor stacked configuration with impellers connected through high precision toothed joint and a pre-stretched tie-rod; Shrouded and unshrouded impellers on a multistage between-bearings compressor; High peripheral speed journal and thrust bearings. The combination of unshrouded and shrouded impellers allows achieving same pressure ratio in a shorter bearing span, giving the possibility to increase the number of sections for each unit, making possible to reduce the number of casings. A full scale prototype has been built and tested to validate the new machine architecture. The prototype has been designed to fulfill a compression service made of three compression sections with a single unit; the same service could only be performed with at least two units if a standard compressor design was applied. The service requires serial compression of natural gas, characterized as follows: Design inlet volumetric flow close to10800m3/h; Design pressure ratio close to 30; Absorbed power~14MW; Design speed of 17619 RPM (MCS = 18500RPM, mos = 14095 RPM); First section comprises 2 open impellers; second section comprises 3 closed impellers and third section has 2 closed impellers. Impellers for first and second sections are in stacked configuration; third section’s impellers are mounted through shrink fitting. Considering the increased speed requirement, the prototype has been tested in conjunction with an epicyclic gear, which allows for improved efficiency for high gear ratio (12.34 in this case) with respect to standard parallel axes gears

Atypical antipsychotics and metabolic syndrome : from molecular mechanisms to clinical differences

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophre-nia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their ac-tions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′ AMP-activated protein kinase (AMPK) activity, thus producing a supra-physiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olan-zapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasi-done and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.Publisher PDFPeer reviewe

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part VII, nerves of the lower limb.

Funder: Università degli Studi di MilanoOBJECTIVES: To perform a Delphi-based consensus on published evidence on image-guided interventional procedures for peripheral nerves of the lower limb (excluding Morton's neuroma) and provide clinical indications. METHODS: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around peripheral nerves in the lower limb (excluding Morton's neuroma) to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper. RESULTS: Nine statements on image-guided interventional procedures for peripheral nerves of the lower limb have been drafted. All of them received strong consensus. Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. CONCLUSION: Despite the promising results reported by published papers on image-guided interventional procedures for peripheral nerves of the lower limb, there is still a lack of evidence on the efficacy of most procedures. KEY POINTS: • Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. • US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. • US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. The volume of local anesthetic affects the size of the blocked sensory area

Human-Machine Interface for Multi-Agent Systems Management using the Descriptor Function Framework

Human-machine interfaces for command and control of teams of autonomous agents is an enabling technology for the development of reliable multi-agent systems. Tools for proper modelling of these systems are sought in order to ease the creation of efficient interface that allow a single operator to control several agents, as well as monitor the execution state of the tasks the team is demanded to accomplish. If humans are present in the environment, the agents must sense their presence and collaborate with them toward the mission accomplishment. In this context, the descriptor function framework is a versatile tool that allows the human integration at two levels: the development of human-machine interfaces and the achievement of human-machine teaming. In this paper, we show how such results can be obtained and we propose a possible architecture for the framework implementation

A Visual-Haptic Display for Human and Autonomous Systems Integration

This paper introduces a novel concept of visual-haptic display for situational awareness improvement for crowded and low altitude airspace situations. The visual augmentation display that constitutes of Virtual Fences delimiting no-fly zones, and a specific tri-dimensional highlight graphics that enhances visibility of other remotely piloted or autonomous agents, as well as conventional manned aircraft operating in the area is presented first. Then the Shared Control paradigm and the Haptic Force generation mechanism, based on a Proportional-Derivative-like controller applied to repulsive forces generated by the Virtual Fences and other UAVs are introduced and discussed. Simulations with 26 pilots were performed in a photo-realistic synthetic environment showing that the combined use of Visual-haptic feedback outperforms the Visual Display only in helping the pilot keeping a safe distance from no-fly zones and other vehicles

Dopamine D2 receptors dimers: how can we pharmacologically target them?

Dopamine D2 and D3 receptors are important pharmacological targets in Schizophrenia and Parkinson’s disease. Intriguingly, many studies have shown that they form homo- and heterodimers, and they can be targeted in specific tissues with new drugs. In this direction, many efforts have been made to develop new molecules that are able to interact with these receptor dimeric complexes. Among various strategies for targeting dopamine receptors dimers, two distinct classes of compounds, such as bivalent and bitopic ligands, have gained particular attention and their use in pharmacology looks promising. Bivalent ligands target the orthosteric sites of the two monomers in the dimeric complex. Some studies have however questioned the bivalent properties of these ligands, which might interact with a receptor dimer or simply with a monomer and additionally, their high molecular weight makes them unfavorable for clinical use. The bitopic ligands target both the orthosteric and the allosteric sites in one monomeric receptor, thereby increasing selectivity over receptor subtypes. For dopamine D2 and D3 receptors, the bitopic ligand SB269,652 has been specifically demonstrated for dual action (dualsteric). This compound switches its antagonistic properties in favor of negative allosterism in the presence of dopamine receptor dimers and may offer therapeutic advantages and better tolerability in comparison with pure antagonists at D2 receptors. Recent studies have further complicated this picture by pointing out that dimer formation is a dynamic process where dimers dissociate and re-associate quickly, and this equilibrium is influenced by the pharmacological characteristics of the ligand where some compounds are able to increase dimer formation

Is adult hippocampal neurogenesis really relevant for the treatment of psychiatric disorders?

Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through the adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed as well