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Search Results: 1 - 10 of 1429 matches for " Jerzy Krupinski "
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Emerging Molecular Targets for Brain Repair after Stroke
Jerzy Krupinski,Mark Slevin
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/473416
Abstract:
Emerging Molecular Targets for Brain Repair after Stroke
Jerzy Krupinski,Mark Slevin
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/473416
Abstract: The field of neuroprotection generated consistent preclinical findings of mechanisms of cell death but these failed to be translated into clinics. The approaches that combine the modulation of the inhibitory environment together with the promotion of intrinsic axonal outgrowth needs further work before combined therapeutic strategies will be transferable to clinic trials. It is likely that only when some answers have been found to these issues will our therapeutic efforts meet our expectations. Stroke is a clinically heterogeneous disease and combinatorial treatments require much greater work in pharmacological and toxicological testing. Advances in genetics and results of the Whole Human Genome Project (HGP) provided new unknown information in relation to stroke. Genetic factors are not the only determinants of responses to some diseases. It was recognized early on that “epigenetic” factors were major players in the aetiology and progression of many diseases like stroke. The major players are microRNAs that represent the best-characterized subclass of noncoding RNAs. Epigenetic mechanisms convert environmental conditions and physiological stresses into long-term changes in gene expression and translation. Epigenetics in stroke are in their infancy but offer great promise for better understanding of stroke pathology and the potential viability of new strategies for its treatment. 1. Where Are We? The classical molecular targets for stroke include those involved in oedema/inflammation control, axonal regeneration/plasticity, neurogenesis/angiogenesis, and events that support recovery. For decades, old targets for stroke were based on observations of molecular and cellular changes after stroke. Numerous inflammatory markers, growth-associated proteins, cell cycle proteins, NMDA receptors, molecules involved in synaptic plasticity, dendritic branching, neural sprouting or extracellular matrix remodelling were key targets. The field of neuroprotection generated consistent preclinical findings of mechanisms of cell death but these failed to be translated into clinical therapies. Many clinical trials were carried out using doses that were already known to be ineffective in preclinical trials, or employing time delays outside the established therapeutic window. Some trials were based on preclinical data showing relatively weak effects or those that were only established in one limited model. Similar problems may occur in the field of neural repair without careful work on the key points associated with clinical translation [1]. The effective delivery of neural
Antithrombotic Medication for Cardioembolic Stroke Prevention
M. àngels Font,Jerzy Krupinski,Adrià Arboix
Stroke Research and Treatment , 2011, DOI: 10.4061/2011/607852
Abstract: Embolism of cardiac origin accounts for about 20% of ischemic strokes. Nonvalvular atrial fibrillation is the most frequent cause of cardioembolic stroke. Approximately 1% of population is affected by atrial fibrillation, and its prevalence is growing with ageing in the modern world. Strokes due to cardioembolism are in general severe and prone to early recurrence and have a higher long-term risk of recurrence and mortality. Despite its enormous preventive potential, continuous oral anticoagulation is prescribed for less than half of patients with atrial fibrillation who have risk factors for cardioembolism and no contraindications for anticoagulation. Available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke. Anticoagulation therapy's associated risk of hemorrhage and monitoring requirements have encouraged the investigation of alternative therapies for individuals with atrial fibrillation. New anticoagulants being tested for prevention of stroke are low-molecular-weight heparins (LMWH), unfractionated heparin, factor Xa inhibitors, or direct thrombin inhibitors like dabigatran etexilate and rivaroxaban. The later exhibit stable pharmacokinetics obviating the need for coagulation monitoring or dose titration, and they lack clinically significant food or drug interaction. Moreover, they offer another potential that includes fixed dosing, oral administration, and rapid onset of action. There are several concerns regarding potential harm, including an increased risk for hepatotoxicity, clinically significant bleeding, and acute coronary events. Therefore, additional trials and postmarketing surveillance will be needed. 1. Introduction Embolism of cardiac origin accounts for about 20% of ischemic strokes. Several heart conditions enhance stroke risk. Atrial fibrillation is the most common condition of cardioembolic stroke, and anticoagulation is the treatment generally indicated for secondary prevention and in some cases for primary prevention. In this review, we analyse cardiac conditions prone to cardioembolic infarct and its management. We review atrial fibrillation, acute myocardial infarct, congestive heart failure and dilated cardiomyopathies, cardiac procedures, pacemakers, valve diseases, and endocarditis. We provide a table with AHA recommendations for patients with cardioembolic stroke types (Table 1) [1]. Transesophageal echocardiography has also provided evidence that the aortic arch is a common source of embolic material, but the risk of cerebral embolism appears to be directly related to the size of
Controlling the angiogenic switch in developing atherosclerotic plaques: Possible targets for therapeutic intervention
Mark Slevin, Jerzy Krupinski, Lina Badimon
Vascular Cell , 2009, DOI: 10.1186/2040-2384-1-4
Abstract: In recent years, an increasing number of angiogenic therapeutic targets have been proposed in order to facilitate modulation of neovascularization and its consequences in diseases such as cancer and macular degeneration. A complete knowledge of the mechanisms responsible for initiation of adventitial vessel proliferation, their extension into the intimal regions and possible de-novo synthesis of neovessels following differentiation of bone-marrow-derived stem cells is required in order to contemplate potential single or combinational anti-angiogenic therapies. In this review, we will examine the importance of angiogenesis in complicated plaque development, describe the current knowledge of molecular mechanisms of its initiation and maintenance, and discuss possible future anti-angiogenic therapies to control plaque stability.According to a World Health Organization Fact Sheet (EURO/03/06) cardiovascular disease (CVD) is the number one killer in Europe, with heart disease and stroke being the major cause of death in all 53 Member States. Figures show that 34,421 (23% of all non-communicable diseases) of Europeans died from CVD in 2005. The report also highlighted the fact that there is approximately a 10-fold difference in premature CVD mortality between Western Europe and countries in Central and Eastern Europe with a higher occurrence of CVD amongst the poor and vulnerable. Although improvements in understanding have helped to reduce the number of Western European dying from CVD and related diseases further advances will require a clearer understanding of the pathobiological mechanisms responsible for the development of stroke, atherosclerosis and myocardial infarction. Approximately 75% of acute coronary events and 60% of symptomatic carotid artery disease are associated with disruption of atherosclerotic plaques [1]. In 1971, Folkman [2]introduced the concept of angiogenesis as a necessity for tumour growth. Its importance in other pathological conditions, includ
Nanotechnology for the treatment of coronary in stent restenosis: a clinical perspective
Garry McDowell, Mark Slevin, Jerzy Krupinski
Vascular Cell , 2011, DOI: 10.1186/2045-824x-3-8
Abstract: The first human safety trial of systemic nanoparticle paclitaxel (nab-paclitaxel) for in stent restenosis (SNAPIST-I) is discussed. The results showed no significant adverse advents attributable to the nab-paclitaxel at 10 or 30 mg/m2, although moderate neutropenia, sensory neuropathy and mild to moderate reversible alopecia occurred at higher doses. No major adverse cardiac events were recorded at 2 months, whilst at 6 months, 4 target lesions required revascularisation. The investigators concluded therefore that systemic nab-paclitaxel was well tolerated at a dose of <70 mg/m2. To date however, no formal clinical evaluation has been reported as to the clinical utility of nab-paclitaxel, or any of the nano preparations discussed, for the suppression of coronary in stent restenosis.Cardiovascular disease, including acute coronary syndromes and cerebrovascular events continue to be a major source of mortality and morbidity. Current medical screening and diagnosis is limited and many of the symptoms and signs of cardiovascular and cerebrovascular disease are non-specific.Nanomedicine provides a unique opportunity to explore at a cellular or organ level the various pathophysiologies of the cardiovascular system. Nanomolecules have been used in:? Assessing and treating atherosclerosis in asymptomatic patients? Coronary revasculariation? Thrombolytic therapy? Treatment of coronary in stent restenosis.There is still a significant requirement for a novel drug delivery mechanism for the treatment of coronary in stent restenosis, due to the limitations of the current modalities including late stent thrombosis.A nanoparticle based approach is ideal for the treatment of restenosis since targeted delivery of nanoparticles is feasible and much lower concentrations of the active drug can be used hence reducing systemic toxicity.The size of particle however is critical in the distribution of nanoparticles in the blood vessel wall. Westedt et al [1], in experiments conducted using
CD105 positive neovessels are prevalent in early stage carotid lesions, and correlate with the grade in more advanced carotid and coronary plaques
Ana Luque, Mark Slevin, Marta M Turu, Oriol Juan-Babot, Lina Badimon, Jerzy Krupinski
Vascular Cell , 2009, DOI: 10.1186/2040-2384-1-6
Abstract: We have used immunohistochemical analysis to investigate the expression of CD105-positive vessels in both large (carotid) and medium calibre (coronary and middle cerebral artery, MCAs) diseased vessels in an attempt to identify any correlation with plaque growth, stage and complication/type.Here we show, that carotid arteries expressed intimal neovascularization associated with CD105-positive endothelial cells, concomitant with increased inflammation in early stage lesions, preatheroma (I-III) whilst they were not present in coronary plaques of the same grade. Some of these CD105-positive neovessels were immature, thin walled and without smooth muscle cell coverage making them more prone to haemorrhage and rupture. In high-grade lesions, neovessel proliferation was similar in both arterial types and significantly higher numbers of CD105-positive vasa vasorum were associated with plaque regions in coronary arteries. In contrast, although the MCAs exhibited expanded intimas and established plaques, there were very few CD105 positive neovessels.Our results show that CD105 is a useful marker of angiogenesis within adventitial and intimal vessels and suggest the existence of significant differences in the pathological development of atherosclerosis in separate vascular beds which may have important consequences when considering management and treatment of this disease.Atherosclerosis is strongly associated with symptomatic cardiovascular disease and ischemic stroke, which are the leading causes of death and disability in the Western world. Atherosclerosis is considered to be a multifactorial disease with numerous risk factors including smoking, alcohol abuse, hypertension, diabetes mellitus, dyslipidemia and infection with microorganisms including Chlamydia pneumoniae [1]. All these factors involve complex interactions between pathways associated with inflammation, lipid metabolism, coagulation, hypoxia, apoptosis and the immune response. Atherosclerotic plaque instabili
Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1
Krupinski Jerzy,Abudawood Manal,Matou-Nasri Sabine,Al-Baradie Raid
Vascular Cell , 2012, DOI: 10.1186/2045-824x-4-20
Abstract: Background Citicoline is one of the neuroprotective agents that have been used as a therapy in stroke patients. There is limited published data describing the mechanisms through which it acts. Methods We used in vitro angiogenesis assays: migration, proliferation, differentiation into tube-like structures in Matrigel and spheroid development assays in human brain microvessel endothelial cells (hCMEC/D3). Western blotting was performed on protein extraction from hCMEC/D3 stimulated with citicoline. An analysis of citicoline signalling pathways was previously studied using a Kinexus phospho-protein screening array. A staurosporin/calcium ionophore-induced apoptosis assay was performed by seeding hCMEC/D3 on to glass coverslips in serum poor medium. In a pilot in vivo study, transient MCAO in rats was carried out with and without citicoline treatment (1000 mg/Kg) applied at the time of occlusion and subsequently every 3 days until euthanasia (21 days). Vascularity of the stroke-affected regions was examined by immunohistochemistry. Results Citicoline presented no mitogenic and chemotactic effects on hCMEC/D3; however, it significantly increased wound recovery, the formation of tube-like structures in Matrigel and enhanced spheroid development and sprouting. Citicoline induced the expression of phospho-extracellular-signal regulated kinase (ERK)-1/2. Kinexus assays showed an over-expression of insulin receptor substrate-1 (IRS-1). Knock-down of IRS-1 with targeted siRNA in our hCMEC/D3 inhibited the pro-angiogenic effects of citicoline. The percentage of surviving cells was higher in the presence of citicoline. Citicoline treatment significantly increased the numbers of new, active CD105-positive microvessels following MCAO. Conclusions The findings demonstrate both a pro-angiogenic and protective effect of citicoline on hCMEC/D3 in vitro and following middle cerebral artery occlusion (MCAO) in vivo.
Identification of pro-angiogenic markers in blood vessels from stroked-affected brain tissue using laser-capture microdissection
Mark Slevin, Jerzy Krupinski, Norma Rovira, Marta Turu, Ana Luque, Maribel Baldellou, Coral Sanfeliu, Nuria de Vera, Lina Badimon
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-113
Abstract: Here, we have isolated active (CD105/Flt-1 positive) and inactive (CD105/Flt-1 minus (n=5) micro-vessel rich-regions from stroke-affected and contralateral tissue of patients using laser-capture micro-dissection. Areas were compared for pro- and anti-angiogenic gene expression using targeted TaqMan microfluidity cards containing 46 genes and real-time PCR. Further analysis of key gene de-regulation was performed by immunohistochemistry to define localization and expression patterns of identified markers and de novo synthesis by human brain microvessel endothelial cells (HBMEC) was examined following oxygen-glucose deprivation (OGD). Our data revealed that seven pro-angiogenic genes were notably up-regulated in CD105 positive microvessel rich regions. These were, beta-catenin, neural cell adhesion molecule (NRCAM), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hepatocyte growth factor-alpha (HGF-alpha), monocyte chemottractant protein-1 (MCP-1) and and Tie-2 as well as c-kit. Immunohistochemistry demonstrated strong staining of MMP-2, HGF-alpha, MCP-1 and Tie-2 in stroke-associated regions of active remodeling in association with CD105 positive staining. In vitro, OGD stimulated production of Tie-2, MCP-1 and MMP-2 in HBMEC, demonstrated a de novo response to hypoxia.In this work we have identified concurrent activation of key angiogenic molecules associated with endothelial cell migration, differentiation and tube-formation, vessel stabilization and stem cell homing mechanisms in areas of revascularization. Therapeutic stimulation of these processes in all areas of damaged tissue might improve morbidity and mortality from stroke.Stroke is a leading cause of death and disability in the Western world. Neuronal survival in peri-infarcted regions determines the extent of patient recovery [1]. Patients with a higher density of blood vessels have reduced morbidity and mortality [2]. Restoration of cerebral microvascular circu
On $ω$-categorical groups and rings with NIP
Krzysztof Krupinski
Mathematics , 2010,
Abstract: We show that $\omega$-categorical rings with NIP are nilpotent-by-finite. We prove that an $\omega$-categorical group with NIP and fsg is nilpotent-by-finite. We also notice that an $\omega$-categorical group with at least one strongly regular type is abelian. Moreover, we get that each $\omega$-categorical, characteristically simple $p$-group with NIP has an infinite, definable abelian subgroup. Assuming additionally the existence of a non-algebraic, generically stable over $\emptyset$ type, such a group is abelian.
On relationships between algebraic properties of groups and rings in some model-theoretic contexts
Krzysztof Krupinski
Mathematics , 2010,
Abstract: We study relationships between certain algebraic properties of groups and rings definable in a first order structure or $*$-closed in a compact $G$-space. As a consequence, we obtain a few structural results about $\omega$-categorical rings as well as about small, $nm$-stable compact $G$-rings, and we also obtain surprising relationships between some conjectures concerning small profinite groups.
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