Iron Chelation Therapy in Thalassemia Syndromes

Transfusional hemosiderosis is a frequent complication in patients with transfusion dependent chronic diseases such as thalassemias and severe type of sickle cell diseases. As there are no physiological mechanisms to excrete the iron contained in transfused red cells (1 unit of blood contains approximately 200 mg of iron) the excess of iron is stored in various organs. Cardiomyopathy is the most severe complication covering more than 70% of the causes of death of thalassemic patients. Although the current reference standard iron chelator deferoxamine (DFO) has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Despite poor compliance, because of the inconvenience of subcutaneous infusion, DFO improved considerably the survival and quality of life of patients with thalassemia. Deferiprone since 1998 and Deferasirox since 2005 were licensed for clinical use. The oral chelators have a better compliance because of oral use, a comparable efficacy to DFO in iron excretion and probably a better penetration to myocardial cells. Considerable increase in iron excretion was documented with combination therapy of DFO and Deferiprone. The proper use of the three chelators will improve the prevention and treatment of iron overload, it will reduce complications, and improve survival and quality of life of transfused patients

Actinic Papillary Fibroelastoma of the Left Ventricle

We present the case of a 69-year-old woman with a history of endometrial carcinoma in 1996, who underwent a total hysterectomy and bilateral adnexectomy. The patient also received chemotherapy (doxorubicin and cisplatinum) and local radiotherapy (50 Gy) because of a single lung metastasis, with total remission during later follow-up. During follow-up, 10 years later following radiotherapy, a transthoracic echocardiogram (TTE) revealed an image consistent with a primary cardiac tumor (papillary fibroelastoma) or metastatic cardiac tumor on the posteromedial papillary muscle. Cardiac magnetic resonance imaging (MRI) revealed a solid mass on the posteromedial papillary muscle with late enhancement, consistent with a primary cardiac tumor. During surgery, the tumor located in the posteromedial papillary muscle was resected. A pathological examination revealed the presence of a tumor mass with a core of dense connective tissue surrounded by a layer of hyperplastic endocardial cells characteristic of a papillary fibroelastoma. After 8 years of follow-up, the patient remains asymptomatic

beacon based context aware architecture for crowd sensing public transportation scheduling and user habits

Abstract: Crowd sourcing and sensing are relatively recent paradigms that, enabled by the pervasiveness of mobile devices, allow users to transparently contribute in complex problem solving. Their effectiveness depends on people voluntarism, and this could limit their adoption. Recent technologies for automating context-awareness could give a significant impulse to spread crowdsourcing paradigms. In this paper, we propose a distributed software system that exploits mobile devices to improve public transportation efficiency. It takes advantage of the large number of deployed personal mobile devices and uses them as both mule sensors, in cooperation with beacon technology for geofecing, and clients for getting information about bus positions and estimated arrival times. The paper discusses the prototype architecture, its basic application for getting dynamic bus information, and the long-term scope in supporting transportation companies and municipalities, reducing costs, improving bus lines, urban mobility and planning

The regulatory role of IL-10 in neurodegenerative diseases

IL-10, an immunosuppressive cytokine, is considered an important anti-inflammatory modulator of glial activation, preventing inflammation-mediated neuronal degeneration under pathological conditions. In this narrative review, we summarize recent insights about the role of IL-10 in the neurodegeneration associated with neuroinflammation, in diseases such as Multiple Sclerosis, Traumatic Brain Injury, Amyotrophic lateral sclerosis, Alzheimer’s Disease, and Parkinson’s Disease, focusing on the contribution of this cytokine not only in terms of protective action, but also as possibly responsible for clinical worsening. The knowledge of this double face of the same coin, regarding the biological role of the IL-10, could aid the development of targeted therapies useful for limiting neurodegenerative processes

Design, synthesis and biological evaluation of new small-molecule modulators of Protein Methyltransferases (PMTs)

2014 - 2015A large amount of evidences indicate that dysregulation of protein methylation is linked to the genesis and progression of several human diseases, including cancer. Therefore over the past years small-molecule modulators targeting Protein Methyltransferases (PMTs) have been actively developed as anticancer drugs as well as chemical tools to better understand the biological and physiological roles of protein methylation. In this thesis the design, synthesis and biological evaluation of three different classes of compounds, designed as isozyme-selective PRMT inhibitors, are reported. (1) Inspired by the structure-activity relationships (SAR) of pyrazole and indole compounds, the most potent PRMT4 inhibitors, we developed a series of pyrrole-based compounds, designed as inhibitors of PRMT4. A potent inhibition was observed when testing pyrrole derivatives against PRMT4 (i.e. EML 438, IC50 = 2.42 μM), nevertheless they didn’t prove a significant cellular activity, due to their poor transcellular permeability. Therefore, in order to increase the activity and the lipophilicity of these compounds and supported by computational studies, we started a process of structural optimization of this class of compounds. Novel derivatives have been designed and selected. (2) Furthermore, in collaboration with Professor Nathaniel Martin from the University of Utrecht, we have successfully synthesized a set of novel PRMT4 bisubstrate inhibitors. Preliminary screening of their biological activity revealed a nanomolar inhibition of PRMT4 (P2-C3-unsat, IC50 = 43 nM) with about 900-fold selectivity for CARM1 over PRMT1. This data confirm our hypothesis that a potent and selective enzymatic inhibition is achieved by compounds characterized by structural features able to bind both the enzymatic substrate binding sites, thereby mimicking the transition state. (3) We also started a program aiming at developing inhibitors of PRMT3. Three series of indole-based compounds were prepared and their activity against a panel of PRMTs was assessed. EML598 and EML599 showed a selective inhibition of PRMT3 at fixed dose (70% at 100 μM). Further biophysical assays are still ongoing in order to better evaluate their biological activity. [edited by author]XIV n.s

Inflammaging and Brain: Curcumin and Its Beneficial Potential as Regulator of Microglia Activation

Inflammaging is a term used to describe the tight relationship between low-grade chronic inflammation and aging that occurs during physiological aging in the absence of evident infection. This condition has been linked to a broad spectrum of age-related disorders in various organs including the brain. Inflammaging represents a highly significant risk factor for the development and progression of age-related conditions, including neurodegenerative diseases which are characterized by the progressive dysfunction and degeneration of neurons in the brain and peripheral nervous system. Curcumin is a widely studied polyphenol isolated from Curcuma longa with a variety of pharmacologic properties. It is well-known for its healing properties and has been extensively used in Asian medicine to treat a variety of illness conditions. The number of studies that suggest beneficial effects of curcumin on brain pathologies and age-related diseases is increasing. Curcumin is able to inhibit the formation of reactive-oxygen species and other pro-inflammatory mediators that are believed to play a pivotal role in many age-related diseases. Curcumin has been recently proposed as a potential useful remedy against neurodegenerative disorders and brain ageing. In light of this, our current review aims to discuss the potential positive effects of Curcumin on the possibility to control inflammaging emphasizing the possible modulation of inflammaging processes in neurodegenerative diseases

Beneficial Effects of Spirulina Consumption on Brain Health

Spirulina is a microscopic, filamentous cyanobacterium that grows in alkaline water bodies. It is extensively utilized as a nutraceutical food supplement all over the world due to its high levels of functional compounds, such as phycocyanins, phenols and polysaccharides, with anti-inflammatory, antioxidant, immunomodulating properties both in vivo and in vitro. Several scientific publications have suggested its positive effects in various pathologies such as cardiovascular diseases, hypercholesterolemia, hyperglycemia, obesity, hypertension, tumors and inflammatory diseases. Lately, different studies have demonstrated the neuroprotective role of Spirulina on the development of the neural system, senility and a number of pathological conditions, including neurological and neurodegenerative diseases. This review focuses on the role of Spirulina in the brain, highlighting how it exerts its beneficial anti-inflammatory and antioxidant effects, acting on glial cell activation, and in the prevention and/or progression of neurodegenerative diseases, in particular Parkinson's disease, Alzheimer's disease and Multiple Sclerosis; due to these properties, Spirulina could be considered a potential natural drug

Fibroblast involvement in soft connective tissue calcification

Soft connective tissue calcification is not a passive process, but the consequence of metabolic changes of local mesenchymal cells that, depending on both genetic and environmental factors, alter the balance between pro- and anti-calcifying pathways. While the role of smooth muscle cells and pericytes in ectopic calcifications has been widely investigated, the involvement of fibroblasts is still elusive. Fibroblasts isolated from the dermis of pseudoxanthoma elasticum (PXE) patients and of patients exhibiting PXE-like clinical and histopathological findings offer an attractive model to investigate the mechanisms leading to the precipitation of mineral deposits within elastic fibers and to explore the influence of the genetic background and of the extracellular environment on fibroblast-associated calcifications, thus improving the knowledge on the role of mesenchymal cells on pathologic mineralizatio

Qualification concepts and quality aspects for protein analysis with capillary electrophoresis

Die pharmazeutische Industrie, Forschungseinrichtungen und Behörden fordern von Verfahren, die Einsatz in der Analytik von Arzneistoffen und Arzneimitteln finden, die Produktion von hochwertigen und zuverlässigen Daten. Zur Zeit ist die HPLC die Standardmethode für Gehalts- und Reinheitsprüfungen nach den Arzneibüchern Europas und der USA, allerdings hat sich seit der Einführung der automatisierten Kapillarelektrophorese Anfang der 1990er Jahre die Technik weiterentwickelt. Mit der steigenden Anzahl an Zulassungen für gentechnisch hergestellte Wirkstoffe werden Techniken wie die Kapillarelektrophorese benötigt, die komplexe Mischungen und Proteine analysieren können. In dieser Arbeit werden Konzepte und Methoden vorgestellt, die zeigen, dass die Kapillarelektrophorese die Anforderungen von Laboren der pharmazeutischen Industrie und der Lebenswissenschaften erfüllen kann. Der erste Teil beschäftigt sich mit dem Einsatz eines berührungsfreien IR-Thermometers, um die bei Analysen entstehende Temperatur an der Oberfläche der Kapillaren zu erfassen. Eine konstante Temperatur ist eine Voraussetzung für die Reproduzierbarkeit von Analyseergebnissen. Deswegen wurden die Daten für eine Bewertung von verschiedenen Kapillarelektrophorese-Systemen genutzt. Im zweiten Teil wird ein durchgängiges Konzept für die Qualifizierung von Kapillarelektrophoresen nach den Anforderungen des US-amerikanischen Arzneibuches vorgestellt. Dafür werden Parameter definiert, Methoden entwickelt und Akzeptanzkriterien festgelegt. Der dritte Teil zeigt am Beispiel der Proteomforschung, wie die in der Kapillarelektrophorese genutzte isoelektrische Fokussierung für die Analytik von komplexen Mischungen optimiert werden kann und welche Faktoren berücksichtigt werden müssen. Im letzten Teil wird erläutert, wie die Reinheitsprüfung von Proteinen und monoklonalen Antikörpern mit der Kapillarelektrophorese durchgeführt werden kann. Hieraus ergibt sich eine alternative Methode zur Gelelektrophorese, die zusätzlich nach Optimierung auch die Quantifizierung von Proteinen ermöglicht.Pharmaceutical industry, research facilities and authorities require the production of high-quality, reliable data from techniques applied in the analysis of active pharmaceutical ingredients and pharmaceutical products. HPLC is still the standard method for testing assay and impurities according to the pharmacopoeia of Europe and USA. Since the introduction of automated capillary electrophoresis in the early 1990s the technique was advanced. The increasing number of marketing authorisations for recombinant drugs requires techniques such as capillary electrophoresis which can analyse complex mixtures and proteins. In this work concepts and methods are presented which demonstrate that capillary electrophoresis can fulfil the demands placed by the laboratory of the pharmaceutical industry and the life sciences. The first part addresses the application of a contactless infrared thermometer measuring the temperature arising during analyses at the surface of the capillary. A constant temperature is important for reproducibility of results. On that account the data was used to assess different capillary electrophoresis systems. In the second part an integrated concept is presented for the qualification of capillary electrophoresis according to the requirements of the US pharmacopoeia. It includes definitions of parameters, development of methods and determination of acceptance criteria. On basis of an example from proteome research the third part demonstrates, how to optimise the isoelectric focussing used with a capillary electrophoresis and which factors have to be considered. The last part illustrates, how to perform the impurities testing for proteins and monoclonal antibodies with capillary electrophoresis instead of gel electrophoresis. After method optimising a quantification of proteins is possible as well