Regulation of monoaminergic functions by GPCRs with a special emphasis on mental and movement disorders

Dysfunction of the brain’s monoaminergic system has been implicated in many human neurological and psychiatric disorders, such as Parkinson’s disease (PD), major depressive disorder (MDD) and schizophrenia. The monoamines that are most dysregulated in these diseases, are dopamine and serotonin. Monoamines act as signalling molecules through their receptors, which belong predominately to the G-protein coupled receptor (GPCR) superfamily¹. Most of the clinically employed drugs that are used to tackle these diseases, target directly or indirectly the monoaminergic class of GPCRs. This thesis aims to identify the role of four understudied GPCR-signalling related molecules (GPR88, TAAR1, p11 and NURR1) in animal models of PD, MDD and schizophrenia. The main findings relate to the functions of GPR88, TAAR1, p11 and NURR1 in relationship to PD, MDD and schizophrenia. GPR88 has been suggested as crucial suppressor of striatal medium spiny neuron activity. We showed that loss of GPR88 facilitates L- dihydroxyphenylalanine treatment for PD by aiding its therapeutic efficacy without worsening its side effects. TAAR1 has been described as negative regulator of dopamine neurons firing rate. Herein, we report that TAAR1 deletion enhances the response of non-selective monoamine oxidase inhibitors but no other classes of antidepressants. Furthermore, we provide evidence that the antipsychotic action of the pioneering drug, SEP-856, depends in part on TAAR1 agonism. P11 is a small GPCR-adaptor protein that has been linked to MDD and antidepressant treatment response. In the current thesis, we demonstrate that loss of p11 causes an overt response to stress by triggering the activity of hypothalamic-pituitary-adrenal and sympathetic-adrenomedullary axes. Finally, NURR1 is a GPCR regulated transcription factor, which is linked to PD and schizophrenia as a consequence of its fundamental role in coordinating midbrain dopamine neuron development. In the present work, we describe the role of NURR1 in extra-dopaminergic brain structures such as striatum and claustrum. In detail, we show that induced striatal NURR1 is crucial for locomotor sensitization to L-DOPA. Moreover, we revealed that NURR1 is important factor for claustral neuron transcriptional identity without affecting the occurrence of hallucinogen states’ neural correlates. Overall, we explored new avenues in the fields of neurology and psychiatry related molecular neurobiology. These findings may support future drug discovery research on PD, MDD and schizophrenia though the identification of novel pharmaceutical agents to treat these detrimental disorders. Thus, this body of work contributes to the better understanding of both the pharmacology and pathophysiology of mental and movement disorders

Pericardial cyst: An unusual cause of chest pain

AbstractPericardial cysts are uncommon paracardiac lesions, usually located within the right cardiophrenic space. They usually do not cause symptoms and are detected by chance. Chest X-ray, echocardiography, and chest computed tomography or magnetic resonance imaging are useful diagnostic tools. We report a case of a man with symptomatic pericardial cysts of unusual location, review the literature, and discuss the diagnostic approach and treatment options.<Learning objective: Pericardial cysts are uncommon mediastinal lesions, diagnosed safely when suspected by echocardiography and computed tomography or magnetic resonance imaging. An invasive therapeutic approach should be preferred in symptomatic cases.

Certified Approximation Algorithms for the Fermat Point and n-Ellipses

Given a set A of n points in ?^d with weight function w: A??_{> 0}, the Fermat distance function is ?(x): = ?_{a?A}w(a)?x-a?. A classic problem in facility location dating back to 1643, is to find the Fermat point x*, the point that minimizes the function ?. We consider the problem of computing a point x?* that is an ?-approximation of x* in the sense that ?x?*-x*? ?(x*) and d = 2. Finally, all our planar (d = 2) algorithms are implemented in order to experimentally evaluate them, using both synthetic as well as real world datasets. These experiments show the practicality of our techniques

Delayed Intraventricular Hemorrhage following a Ventriculoperitoneal Shunt Placement: Exploring the Surgical Anatomy of a Rare Complication

Ventriculoperitoneal shunt (VPS) placement is one of the commoner neurosurgical procedures worldwide. The purpose of this article is to report a case of delayed intraventricular hemorrhage (IVH) following a VPS and to review the literature regarding anatomic factors that could potentially explain this rare complication. A 78-year-old man with normal pressure hydrocephalus, who underwent an uneventful right VPS placement, suffered from a catastrophic isolated IVH five days later. The reported cases of delayed intracerebral hemorrhage (ICH) following VPS are rare and those with IVH are even rarer. Potential factors of surgical anatomy that could cause delayed ICH/IVH following a VPS procedure include erosion of vasculature by catheter cannulation, multiple attempts at perforation, puncture of the choroid plexus, improper placement of the tubing within the brain parenchyma, VPS system revision, venous infarction, vascular malformations, head trauma, and brain tumors. Other causes include generalized convulsion, VPS system malfunction, increased intracranial or blood pressure, sudden intracranial hypotension, and bleeding disorders. According to the current literature, our case is the first reported delayed isolated IVH after a VPS placement so far. Neurosurgeons should be aware of the delayed ICH/IVH as a rare, potentially fatal complication of VPS, as well as of its risk factors

The Voronoi Diagram of Rotating Rays With applications to Floodlight Illumination

We introduce the Voronoi Diagram of Rotating Rays, a Voronoi structure where the input sites are rays, and the distance function is the counterclockwise angular distance between a point and a ray-site. This novel Voronoi diagram is motivated by illumination and coverage problems, where a domain has to be covered by floodlights (wedges) of uniform angle, and the goal is to find the minimum angle necessary to cover the domain. We study the diagram in the plane, and we present structural properties, combinatorial complexity bounds, and a construction algorithm. If the rays are induced by a convex polygon, we show how to construct the ray Voronoi diagram within this polygon in linear time. Using this information, we can find in optimal linear time the Brocard angle, the minimum angle required to illuminate a convex polygon with floodlights of uniform angle. This last algorithm improves upon previous results, settling an interesting open problem

Exploring the Effect of Ultrafiltration/Diafiltration Processing Conditions on the Lactoferrin and Immunoglobulin G Content of Feta Whey Protein Concentrates

In this paper, the production of powder enriched in lactoferrin (Lf) and immunoglobulin G (IgG) from untreated feta cheese whey is studied. More specifically, the influence of transmembrane pressure (Δp) and temperature on flux and separation ability during ultrafiltration combined with continuous diafiltration is investigated. Two different types of membranes were used, a spiral polyvinylidene fluoride (PVDF) (molecular weight cut-off [MWCO 75 kDa) and a set of 18 cylindrical PVDF membranes (MWCO 100 kDa). For the production of the whey powder, two drying methods were compared: spray and freeze drying. All combinations lead to powder with high total protein content and with a notable content in these two bioactive proteins. However, cylindrical membranes (at a temperature of 20C and a transmembrane pressure of 4 bar) in combination with freeze drying resulted in the highest yield from whey into Lf and IgG and excellent sensory characteristics. Practical Applications Whey powder enriched in the multifunctional proteins lactoferrin and immunoglobulin G have very large potential both as nutrition additives and for pharmaceutical purposes. The systematic study of the parameters affecting all unit operations involved leads to the most efficient and cheapest production. In order to achieve this, the methodology was kept as simple and low cost as possible. This way, a strong tool could be created for the utilization of the cheese-making by-product whey, which still causes large environmental problems

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies

Background: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. Methods: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London