Percutaneous transluminal angioplasty in patients with peripheral arterial disease does not affect circulating monocyte subpopulations

Monocytes are mononuclear cells characterized by distinct morphology and expression of CD14 and CD16 surface receptors. Classical, quiescent monocytes are positive for CD14 (lipopolysaccharide receptor) but do not express Fc gamma receptor III (CD16). Intermediate monocytes coexpress CD16 and CD14. Nonclassical monocytes with low expression of CD14 represent mature macrophage-like monocytes. Monocyte behavior in peripheral arterial disease (PAD) and during vessel wall directed treatment is not well defined. This observation study aimed at monitoring of acute changes in monocyte subpopulations during percutaneous transluminal angioplasty (PTA) in PAD patients. Patients with Rutherford 3 and 4 PAD with no signs of inflammatory process underwent PTA of iliac, femoral, or popliteal segments. Flow cytometry for CD14, CD16, HLA-DR, CD11b, CD11c, and CD45RA antigens allowed characterization of monocyte subpopulations in blood sampled before and after PTA (direct angioplasty catheter sampling). Patients were clinically followed up for 12 months. All 61 enrolled patients completed 12-month follow-up. Target vessel failure occurred in 12 patients. While absolute counts of monocyte were significantly lower after PTA, only subtle monocyte activation after PTA (CD45RA and β-integrins) occurred. None of the monocyte parameters correlated with long-term adverse clinical outcome. Changes in absolute monocyte counts and subtle changes towards an activation phenotype after PTA may reflect local cell adhesion phenomenon in patients with Rutherford 3 or 4 peripheral arterial disease

Looking for novel, brain-derived, peripheral biomarkers of neurological disorders

The role of blood brain barrier (BBB) is to preserve a precisely regulated environment for proper neuronal signaling. In many of the central nervous system (CNS) pathologies, the function of BBB is altered. Thus, there is a necessity to evaluate a fast, noninvasive and reliable method for monitoring of BBB condition. It seems that revealing the peripheral diagnostic biomarker whose release pattern (concentration, dynamics) will be correlated with clinical symptoms of neurological disorders offers significant hope. It could help with faster diagnosis and efficient treatment monitoring. In this review we summarize the recent data concerning exploration of potential new serum biomarkers appearing in the peripheral circulation following BBB disintegration, with an emphasis on epilepsy, traumatic brain injury (TBI) and stroke. We consider the application of well-known proteins (S100β and GFAP) as serum indicators in the light of recently obtained results. Furthermore, the utility of molecules like MMP-9, UCHL-1, neurofilaments, BDNF, and miRNA, which are newly recognized as a potential serum biomarkers, will also be discussed

Immune System Involvement in the Degeneration, Neuroprotection, and Restoration after Stroke

Cerebrovascular diseases are currently among the three primary causes of death worldwide and are the first cause of disability in adults. Nevertheless, there are no neuroprotective or neurorestorative therapies that have shown considerable beneficial effects, except for the FDA-approved recombinant tissue plasminogen activator (rtPA), which has been used for decades for the treatment of stroke and its effectiveness is still controversial. This is why it is very important to develop effective therapeutic options. In order to achieve this objective, it is essential to recognize the secondary mechanisms involved in the pathological development. The immunological system is one of these mechanisms that participate during the acute and chronic phases of disease, both in deleterious and beneficial manners. It is known that the immune system’s duality contributes to the ischemic injury through proinflammatory cytokine (tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6)), and oxygen reactive species production, etc. Nevertheless, it also provides protection and even restoration through anti-inflammatory cytokine (interleukin-4 (IL-4), interleukin-10 (IL-10), transforming growth factor-β (TGF-β)), and growth factor (brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4)) production. This states that innovative therapeutic options must be proposed with the goal of protecting and restoring the tissue after the ischemic event. Such therapies are exposed in the present chapter

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Understanding the pathophysiology of TBI is crucial for the development of more effective therapeutic strategies. At the moment of the traumatic impact, transfer of kinetic forces causes neurologic damage; this primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes, called secondary neural injury. These areas of ongoing secondary injury, or areas of “traumatic penumbra,” represent crucial targets for therapeutic interventions. This chapter is focused on the interplay between progression of parenchymal injury and the neuroprotective and neurorestorative processes that are emerging and developing subsequently to traumatic impact. Thus, we emphasized the role of traumatic penumbra in TBI pathogenesis and suggested a crucial contribution of the neurovascular units (NVUs) and paracrine effects of exosomes and miRNAs in promoting neurological recovery

Dual role of matrix metalloproteinases in brain injury and neurorepair after cerebral ischemia

L'ictus isquèmic és una de les principals causes de mortalitat, discapacitat de llarg termini i de morbiditat al món. Actualment, els únics tractaments eficaços són el tractament trombolític intravenós amb activador del plasminogen tissular (tPA) i les novedoses trombectomies intra-arterials, que requereixen ser administrades en la fase hiperaguda de la malaltia ( 4,5 hores per al tractament amb tPA i 6 hores per les emergents la teràpies endovasculars). Per tant, és necessari investigar noves teràpies que podrien ser utilitzades per tractar un gran nombre de pacients en una fase posterior de la malaltia per reparar el teixit danyat. Alguns enfocaments terapèutics apunten que per assolir aquest objectiu és necessari potenciar la remodelació vascular i la neurogènesi en el cervell isquèmic. L'objectiu d'aquesta tesi és l'estudi de la modulació de la metaloproteinasa de matriu-13 (05P-13) en la neurorreparación i el d'investigar diverses 05Ps com a biomarcadors que serveixin per monitoritzar la millora de la funció motora durant la teràpia neuro-rehabilitadora. Utilitzant un model d'isquèmia cerebral per oclusió de l'arteria cerebral mitja en ratolins, es va trobar que expressió de la 05P-13 està implicada en el dany i en mecanismes de reparació post-isquèmia. Després de la isquèmia-reperfusió, la deficiència en 05P-13 redueix la mida de l'infart, millora l'estatus funcional en la fase més aguda i protegeix de l'aparició de transformacions hemorràgiques, però interfereix negativament en la recuperació del teixit cortical mitjançant la reducció en la migració neuroblast en proliferació, en el remodelat vascular i en un microambient amb factors tròfics reduïts. Al mateix temps les cèl·lules endotelials progenitores amb un silenciament transitori de l'expressió de 05P-13 presenten una funció aberrant en assajos de tubulogènesis, in vitro. Com que la deficiència de 05P-13 protegia del dany cerebral en el model animal d'isquèmia al temps que participava en la recuperació del teixit en fases de reparació, aquesta tesi també estudia el perfil temporal dels nivells plasmàtics de 05P-3, 05P-12 i 05P-13 durant la teràpia neuro-rehabilitadora per investigar el seu paper com a potencials biomarcadors del teixit en recuperació. Els nostres resultats mostren que alts nivells de plasma 05P-13, així com 05P-12, estan fortament associats amb la severitat i extensió de la isquèmia, però no els de 05P-3. Curiosament, els pacients amb un millor status en la funció motora durant la rehabilitació presenten els nivells més elevats de 05P-3 i reduïts de 05P-12 / -13. També, els valors de 05P-3 estan estretament associats amb la millor recuperació motora després de l'accident cerebrovascular, el que indica el seu potencial com a biomarcador de la millora en la funció motora. Aquests resultats són importants per imaginar el futur ús d'un biomarcador per tal de poder ajustar, personalitzar i modular teràpies de neuro-rehabilitació d'acord a les necessitats dels pacients. En conclusió aquesta tesi mostra el paper de les 05Ps en el dany i reparació de teixits després de l'ictus isquèmic i ressalta la importància de monitoritzar i modular aquestes proteases en favor de la recuperació dels pacients.Ischemic stroke is a leading cause of mortality, long-time disability and morbidity in the world. Currently, the only effective treatments are the intravenous thrombolytic therapy with tissue plasminogen activator (tPA) and the new emerging intra-arterial thrombectomies, which require to be administered in the hyperacute phase of stroke ( 4.5 hours for tPA treatment and 6 hours for endovascular therapy). Therefore, it is necessary to investigate new therapies that could be used to treat a large number of patients in a later phase to repair and rewire the damaged tissue. One approach to achieve these objectives is to enhance vascular remodeling and neurogenesis in the ischemic brain. The aim of this thesis is to study the modulation of extracellular matrix metalloproteinase-13 (MMP-13) in brain injury and neurorepair and to investigate several MMPs as serving biomarkers to monitor motor and functional improvement during neurorehabilitation therapy. Using a distal middle cerebral artery occlusion model of ischemia in mice, we found that the modulation of MMP-13 is involved in ischemic damage and repair mechanisms. After ischemia-reperfusion, MMP-13 deficiency reduces infarct size, improves functional outcome and protects from hemorrhagic transformation, but impairs cortical tissue recovery by reducing proliferating neuroblast migration and vessel remodelling in a microenvironment with reduced trophic factors. At the same time MMP-13-silenced endothelial progenitor cells present an aberrant in vitro tubulogenesis function. As MMP-13 deficiency protects brain injury acutely and participates in post-stroke tissue recovery, this thesis also studies the temporal profile of plasma MMP-3, MMP-12 and MMP-13 during rehabilitation therapy to investigate their potential role as biomarkers of tissue recovery. Our results show that high levels of plasma MMP-13, as well as MMP-12, are strongly associated with stroke severity acutely, but not MMP-3. Interestingly, those patients with a better motor outcome during rehabilitation present elevated MMP-3 and decreased MMP-12/-13 levels. MMP-3 is closely associated with the better post-stroke motor recovery, indicating the potential as a biomarker of final functional improvement. These are important results that envision the use of biomarkers that could help to adjust, personalize and modulate neurorehabilitation therapies according to patients' needs. In conclusion this thesis shows the role of MMPs in tissue injury and repair after stroke and the importance to monitor and modulate these proteases in favor of patients' recovery

European Stroke Science Workshop

The European Stroke Organisation held its first European Stroke Science Workshop in Garmisch-Partenkirchen, Germany (December 15-17, 2011). Stroke experts based in Europe were invited to present and discuss their current research. The scope of the workshop was to review the most recent findings of selected topics in stroke, to exchange ideas, to stimulate new research, and to enhance collaboration between European stroke research groups. Seven scientific sessions were held, each starting with a keynote lecture to review the state of the art of the given topic, followed by 4 or 5 short presentations by experts. They were asked to limit their presentations to 10 slides containing only recent information. The meeting was organized by the executive committee of the European Stroke Organisation (Heinrich Mattle, chairman, Michael Brainin, Angel Chamorro, Werner Hacke, Didier Leys) and supported by the European Stroke Conference (Michael Hennerici). The following sections summarize the content of the workshop. Copyright (c) 2012 S. Karger AG, Base

Advances in biomarker for stroke patients: from marker to regulator

Biomarkers refer to indicators found in the blood, other body fluids or tissues that predict physiologic or disease states, increased disease risk, or pharmacologic responses to a therapeutic intervention. Stroke is a heterogeneous condition, and stroke biomarkers could be used as a guiding tool for more effective personalized therapy. In this review, the recent advances in the biomarkers in stroke field are discussed. First, various types of biomarkers including genetic, extracellular vesicle, and metabolomics-associated biomarkers as well as protein biomarkers were recently introduced. The studies reviewed herein suggest that comprehensive analysis of different types of stroke biomarkers will improve the understanding of individual pathophysiologies and further promote the development of screening tool of high-risk patients, predicting model of stroke outcome and rational stroke therapy tailored to the characteristics of each case. Second, several biomarkers can be bio-‘makers’ that regulate compensatory or pathological process in the development of stroke etiology and recovery after stroke. Several protein (e.g.,chemokines, caveoli), genetic (e.g., microRNA), and extracellular vesicles (e.g., cancer cell, stem cells-derived) may be directly involved in these processes. These bio-makers may be molecular target of treatment and can be used for new drug development

Effect of protein-energy malnutrition on nuclear factor kappa B activation following global ischemia

Our laboratory previously found that protein-energy malnutrition (PEM) existing prior to brain ischemia impaired functional outcome measured in an open field test, and one-third of animals showed a marked increase in reactive gliosis. It was hypothesized that PEM worsened stroke outcome by increasing inflammation via increased activation of the transcription factor, nuclear factor kappa B (NFκB). Mongolian gerbils (11-12 wk old) were randomly assigned to a control diet (12.5% protein) or a protein-deficient diet (2%) for 28 days. The control group on average gained 4.9g and the PEM group lost 7.4g. PEM gerbils had significantly decreased food intake (