Adjuvant Lineage-Negative Cell Therapy as a Potential Silencer of the Complement-Mediated Immune System in ALS Patients.

ALS remains a fatal, neurodegenerative motor neuron disease. Numerous studies seem to confirm that innate immune system is involved in the pathophysiology of ALS. Hence, the assessment of the complement system and attempts to modify its activity remain the target of medical intervention in ALS. In the present study, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin-) cells were performed every 6 weeks in 20 sporadic ALS patients. The concentrations of various complement components in the cerebrospinal fluid and plasma at different time points after cell injection were quantified using a Luminex multiplex. The results of the complement system were correlated with the level of leukocytes, neutrophils, lymphocytes, fibrinogen and CRP in the peripheral blood and the functional status of ALS patients using Norris and ALS-FRSr scales. The study showed a statistically significant decrease in plasma C3b concentration in all 7th days after cell application. In parallel, a peak decrease in neutrophil count and CRP level was observed on days 5-7, with a simultaneous maximum clinical improvement on days 7-28 of each Lin- cell administration. Adjuvant Lin- cell therapy appears to have the silencing potential on the complement-mediated immune system and thus suppress pro-inflammatory reactions responsible for neurodegeneration. However, further in-depth studies are necessary to address this issue.

Free Fatty Acids Are Associated with the Cognitive Functions in Stroke Survivors.

Ischemic stroke is a leading cause of motor impairment and psychosocial disability. Although free fatty acids (FFA) have been proven to affect the risk of stroke and potentially dementia, the evidence of their impact on cognitive functions in stroke patients is lacking. We aimed to establish such potential relationships. Seventy-two ischemic stroke patients were prospectively analysed. Their cognitive functions were assessed seven days post-stroke and six months later as follow-up (n = 41). Seven days post-stroke analysis of serum FFAs levels showed direct correlations between Cognitive Verbal Learning Test (CVLT) and the following FFAs: C20:4n6 arachidonic acid and C20:5n3 eicosapentaenoic acid, while negative correlations were observed for C18:3n3 linolenic acid (ALA), C18:4 n3 stearidonic acid and C23:0 tricosanoic acid. Follow-up examination with CVLT revealed positive correlations with C15:0 pentadecanoid acid, C18:3n6 gamma linoleic acid, SDA, C23:0 tricosanoic acid and negative correlations with C14:0 myristic acid and C14:1 myristolenic acids. Several tests (Trail Making Test, Stroop Dots Trail, Digit Span Test and Verbal Fluency Test) were directly correlated mainly with C14:0 myristic acid and C14:1 myristolenic acid, while corresponding negatively with C18:1 vaccinic acid, C20:3n3 cis-11-eicosatrienoic acid, C22:1/C20:1 cis11- eicosanic acid and C20:2 cis-11-eicodienoic acid. No correlations between Montreal Cognitive Assessment (MOCA) test performed on seventh day, and FFAs levels were found. Saturated fatty acids play a negative role in long-term cognitive outcomes in stroke patients. The metabolic cascade of polyunsaturated fatty acids (n3 PUFA) and the synthesis of (AA) can be involved in pathogenesis of stroke-related cognitive impairment.

Atrial fibrillation risk factors in patients with ischemic stroke.

INTRODUCTION: Atrial fibrillation (AF) is the most common heart arrhythmia. The condition is known to increase the risk of ischemic stroke (IS). Classical risk factors for the development of AF include advanced age, hypertension, diabetes mellitus, coronary heart disease and lipid metabolism disorders. Importantly, these are also recognized risk factors for ischemic stroke. Therefore, the purpose of this study was to investigate AF risk factors in patients with IS. MATERIAL AND METHODS: This is single-centre retrospective study which included 696 patients with acute ischemic stroke and nonvalvular atrial fibrillation and 1678 patients with acute ischemic stroke without atrial fibrillation. RESULTS: In this study we found - based on a univariable and multivariable logistic regression model - that compared to the patients with IS without AF, the group of patients which suffered from IS with nonvalvular atrial fibrillation (NVAF) had a higher proportion of patients who smoked cigarettes (OR = 15.742, p < 0.01; OR = 41.1, p < 0.01), had hypertension (OR = 5.161, p < 0.01; OR = 5.666, p < 0.01), history of previous stroke (OR = 3.951, p < 0.01; OR = 4.792, p < 0.01), dyslipidemia (OR = 2.312, p < 0.01; OR = 1.592, p < 0.01), coronary heart disease (OR = 2.306, p < 0.01; OR = 1.988, p < 0.01), a greater proportion of female patients (OR = 1.717, p < 0.01; OR = 2.095, p < 0.01), higher incidence of diabetes mellitus (OR = 1.341, p < 0.01; OR = 1.261, p = 0.106) and more patients in old age (OR = 1.084, p < 0.01; OR = 1.101, p < 0.01). CONCLUSIONS: Our study demonstrates a need for thorough and systematic monitoring of post-ischemic stroke patients in whom AF has not been detected and who display other important risk factors. Regardless of the stroke, these factors may be responsible for development of AF.

Free Fatty Acids and Their Inflammatory Derivatives Affect BDNF in Stroke Patients.

OBJECTIVE: The neurotrophin brain-derived neurotrophic factor (BDNF) affects poststroke functional outcome, neurogenesis, neuroprotection, and neuroplasticity. Its level is related to the diet and nutritional status, and more specifically, it is free fatty acids (FFAs) and eicosanoids that can have an impact on the BDNF level. The aim of this study was to analyze the potential impact of FFAs and eicosanoids on the BDNF level in stroke patients. Material and Methods. Seventy-three ischemic stroke patients were prospectively enrolled in the study. Laboratory tests were performed in all subjects, including the levels of FFAs, eicosanoids, and BDNF. FFAs and inflammatory metabolites were determined by gas chromatography and liquid chromatography, while BDNF was evaluated by the immune-enzymatic method (ELISA). RESULTS: The plasma level of BDNF negatively correlated with C22:1n9 13 erucic acid, C18:3n3 linolenic acid (ALA), and lipoxin A4 15-epi-LxA4. A direct association was observed in relation to BDNF and C16:1 palmitoleic acid and C20:3n6 eicosatrienoic acid (dihomo-gamma-linolenic acid (DGLA)). CONCLUSIONS: Saturated fatty acids and omega-3 and omega-9 erucic acids can affect signaling in the BDNF synthesis resulting in the decrease in BDNF. There is a beneficial effect of DGLA on the BDNF level, while the effect of ALA on BDNF can be inhibitory. Specialized proresolving lipid mediators can play a role in the BDNF metabolism. BDNF can interact with inflammation as the risk factor in the cardiovascular disorders, including stroke.

Humoral Influence of Repeated Lineage-Negative Stem/Progenitor Cell Administration on Articulatory Functions in ALS Patients.

Amyotrophic lateral sclerosis (ALS) remains a fatal, neurodegenerative disease frequently leading to dysarthria and impaired swallowing. Better understanding of ALS pathophysiology is prompting the use of humoral cell therapies. Hence, a repeated cellular therapy was applied to ALS patients as an attempt to prevent speech deterioration. Autologous bone marrow-derived lineage-negative (Lin-) cells were intrathecally administered three times at six-week intervals to 42 sporadic ALS patients. Patients were examined for articulatory functions using subjective (VHI) and objective (FDA) scales. Selected trophic, proinflammatory factors and expression profiles of miRNA were measured in cerebrospinal fluid (CSF) and plasma by multiplex Luminex and q-PCR in different timepoints. Of the 42 patients who received the Lin- cells, 6 showed improvement in articulatory functions, 27 remained stable, and 9 deteriorated after 18 weeks of therapy according to FDA scale. Clinical improvement was particularly evident by the 7th day of each cell application and concerned better cough and swallow reflex, soft palate, laryngeal time, pitch, and volume. These results correlated with significant changes in the concentration of various trophic and proinflammatory factors and miRNA expression profiles. A multiple application of Lin- cells proved to be safe and feasible. The repeated procedure can potentate a humoral effect and prevent speech deterioration. A short-lasting trophic effect of each Lin- cells administration was observed on local and systemic level. However, further in-depth studies are necessary to sustain the beneficial effect.

Erratum to "Effects of Angiotensin-Converting Enzyme Inhibition on Circulating Endothelial Progenitor Cells in Patients with Acute Ischemic Stroke".

[This corrects the article DOI: 10.1155/2018/2827580.].

Repeated Application of Autologous Bone Marrow-Derived Lineage-Negative Stem/Progenitor Cells-Focus on Immunological Pathways in Patients with ALS.

Therapeutic interventions in amyotrophic lateral sclerosis (ALS) are still far from satisfying. Immune modulating procedures raise hopes for slowing the disease progression. Stem cell therapies are believed to possess the ability to regulate innate and adaptive immune response and inflammation processes. Hence, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin-) cells were performed every six weeks in 40 sporadic ALS patients. The concentrations of inflammatory-related proteins and expression profiles of selected miRNA in the cerebrospinal fluid (CSF) and plasma at different timepoints post-transplantation were quantified by multiplex Luminex and qRT-PCR. The global gene expression in nucleated blood cells was assessed using the gene microarray technique. According to the ALS Functional Rating Scale (FRSr), the study population was divided into responders (group I, n = 17) and non-responders (group II, n = 23). A thorough analysis of the pro-inflammatory expression profiles, regulated miRNA pathways, and global gene expression profiles at the RNA level revealed the local and systemic effects of Lin- cell therapy on the immune system of patients with ALS. The autologous application of Lin- cells in CSF modulates immune processes and might prevent the progression of neurodegeneration. However, further in-depth studies are necessary to confirm the findings, and prolonged intervention is needed to maintain therapeutic effects.

The Relationship between Selected Demographic Factors and Speech Organ Dysfunction in Sporadic ALS Patients.

Background and objectives: Speech disorders are observed in 30% of newly diagnosed sporadic amyotrophic lateral sclerosis (ALS) patients. Characterized by a dynamic course, dysfunction of articulation has not so far been well understood. The aim of this study was to analyze the influence of demographic factors (sex, age, duration of the disease) and concomitant diseases (degenerative spine disease, depression, hypertension, hypothyroidism, hyperthyroidism, and allergy) on the functioning of speech organs in ALS patients. Materials and Methods: The study group consisted of 65 patients with sporadic ALS. Patients were examined for articulatory functions by means of the Frenchay Dysarthria Assessment (FDA). Results: 68% of the study sample had spinal disorders. Logistic regression analysis showed that a decline in the functioning of lips, soft palate, length of phonation, and voice loudness was more common among men. Patients diagnosed with degenerative spine disease more often suffered from respiratory disorders, while younger patients (<60 years of age) significantly more often had the impairment of the sentence and spontaneous speech functions. Conclusions: The male gender in patients with ALS is associated with an increased risk of deterioration of the phonation length function. Patients under 60 years of age are associated with more often pronouncing sentences disorders and spontaneous speech disorders.

Articulation recovery in ALS patients after lineage-negative adjuvant cell therapy - preliminary report.

Background: Amyotrophic lateral sclerosis (ALS) is one of the most frequently occurring neurodegenerative diseases affecting speech and swallowing. This preliminary study aimed to investigate whether an autologous lineage-negative stem/progenitor cell therapy applied to ALS patients affects the level of selected trophic and proinflammatory factors, and subsequently improves the articulation. Methods: We enrolled 12 patients with sporadic ALS, who underwent autologous bone marrow-derived lineage negative (LIN-) cells administration into cerebrospinal fluid (CSF). We evaluated patients' articulation using the Frenchay Dysarthria Assessment on days 0 and 28 following the LIN- cells administration. Concentrations of various factors (BDNF, NGF, ANGP-2, VEGF, PDGF-AA, PEDF, COMP-FH, CRP, C3, C4) in CSF were quantified by multiplex fluorescent bead-based immunoassays in the samples collected on the day of LIN- cells administration and 28 days later. On top of this, we assessed levels of BDNF and NGF in the patients' plasma on the day of the injection, three, seven days and three months after the treatment. Results: Of the 12 patients who received the LIN- cell therapy 8 showed short-termed improvement in articulatory functions (group I), which was particularly noticeable in better phonation time, lips and soft palate performance, swallowing reflex and voice loudness. Four patients (group II) did not show substantial improvement. CSF concentrations of BDNF, ANGP-2 and PDGF-AA in group I decreased significantly 28 days after LIN- cells administration. The highest concentration levels of BDNF in group II and NGF in both groups in blood plasma were observed on day 3 following the injection. Conclusions: The outcomes of the LIN- cell application in ALS treatment of articulatory organs are promising. The procedure proved to be safe and feasible. A short-lasting trophic effect of autologous LIN- administration could encourage repeated cell's application in order to sustain their beneficial effects, however this approach needs further investigation.

Lipoxins, RevD1 and 9, 13 HODE as the most important derivatives after an early incident of ischemic stroke.

There is limited information available regarding the association of plasma free fatty acids (FFA) and inflammation mediators with ischemic stroke. At the same time, new treatment strategies are being pursued. The aim of this study was to carry out a thorough analysis of inflammation with multiple FFA-derivative mediators after and ischemic stroke and standard treatment. HPLC separations of 17 eicosanoids were performed using an Agilent Technologies 1,260 liquid chromatograph. The profiles of the esters of fatty acids were labelled by means of gas chromatography. FFA, and eicosanoid profiles in the group of patients after ischemic stroke significantly differed from the profile of the control group. Studies confirmed the involvement of derivative synthesis pathways responsible for the inflammation, especially palmitic acid (9 and 13 HODE), arachidonic acid, EPA and DHA. Arachidonic acid derivatives were synthesised on 5LOX, 15 LOX and COX pathways with the participation of prostaglandins while omega 3 derivatives strengthened the synthesis of resolvins, RevD1 in particular. The ability to accelerate the quenching of inflammation after ischemic stroke seems to be a promising strategy of stroke treatment in its early stage. In this context, our study points to lipoxins, RevD1, and 9, 13 HODE as the most important derivatives.

The Association of Free Fatty Acids and Eicosanoids with the Severity of Depressive Symptoms in Stroke Patients.

The study was designed to demonstrate the relationship of free fatty acids (FFAs) and eicosanoids levels with the severity of depressive symptoms in stroke. The ischemic stroke patients (n = 74) were included in the prospective study. The risk of depression was evaluated by the Beck Depression Inventory-II (BDI-II) 7 days and 6 months after the stroke onset. FFAs and inflammatory metabolites were determined by gas chromatography and liquid chromatography. In the acute phase of stroke, BDI-II and FFAs inversely correlated with C13:0 tridecanoic acid, C15:1 cis-10-pentadecanoid acid, C17:1 cis-10- heptadecanoid acid, C18:0 stearic acid, C20:3n6 eicosatrienoic acid, C22:1cis13 docosenoic acid and C22:6n3 docosahexaenoic acid (DHA). DHA level was significantly lower in patients with low vs. high BDI-II score. In the follow-up examination, BDI-II score directly correlated with C16:0 palmitic acid. The changes in BDI-II score during 6-month observation inversely correlated with lipoxin A4 and protectin D1, and directly correlated with 5-oxo-ETE. Importantly, the severity of depressive symptoms was associated with n3 PUFA level. Diet-derived FFAs were observed to potentially affect the inflammatory pathways in pathogenesis of depression in stroke and reduced DHA levels can attenuate depressive symptoms in stroke patients.

Risk factors for death by acute ischaemic stroke in patients from West-Pomerania, Poland.

AIM AND CLINICAL RATIONALE FOR STUDY: In Poland, it is widely believed that the outlook for ischaemic stroke patients is gradually improving due to the development of a network of stroke wards and other dedicated hospital units throughout the country. However, a study by Shah et al., reporting a significant increase in mortality from ischaemic stroke in several European countries including Poland, contradicts this belief. Therefore, the aim of this study was to determine the risk factors for death in patients with recent ischaemic stroke among a population of patients from Western Pomerania, a region in north-western Poland. MATERIALS AND METHODS: This retrospective study involved 2,374 patients with recent ischaemic stroke. Mortality was defined as death within 30 days of admission to hospital. Patients who died in hospital during this period were defined as deceased, while those who survived beyond this time were classified as alive. RESULTS: We found that compared to ischaemic stroke patients who survived, the group of ischaemic stroke patients who died included a higher number of patients who smoked cigarettes (OR = 6.08 in univariable model; OR = 6.22 in adjusted model), had hypertension (OR = 2.57; OR = 1.85), had a history of previous stroke (OR = 2.63; OR = 2.14), had coronary heart disease (OR = 1.78; OR=1.36), and were older (OR = 1.06; OR = 1.05). For all these factors, p-value was lower than 0.001. Females had a higher risk of death (OR = 1.48, p < 0.001; OR = 1.35, p = 0.01). For dyslipidemia, only univariable model was statistically significant (OR = 1.38, p < 0.001). CONCLUSION AND CLINICAL IMPLICATIONS: Older age, female sex, dyslipidemia, hypertension, coronary heart disease, and smoking are not only recognised risk factors for ischaemic stroke, but also risk factors associated with an unfavourable prognosis following stroke.

Local and Systemic Humoral Response to Autologous Lineage-Negative Cells Intrathecal Administration in ALS Patients.

Amyotrophic lateral sclerosis (ALS) remains a fatal disease with limited therapeutic options. Signaling via neurotrophins (NTs), neuroinflammation, and certain micro-RNAs are believed to play essential role in ALS pathogenesis. Lineage-negative stem/progenitor cells (Lin-) were obtained from bone marrow of 18 ALS patients and administered intrathecally. Clinical assessment was performed using ALS Functional Rating Scale (FRSr) and Norris scale. Protein concentrations were measured in plasma and cerebrospinal fluid (CSF) by multiplex fluorescent bead-based immunoassay. Gene expression in nucleated blood cells was assessed using gene microarray technique. Finally, miRNA expression was analyzed using qPCR in CSF and plasma samples. We observed a significant decrease of C-reactive protein (CRP) concentration in plasma on the seventh day from the application of cells. Gene array results revealed decreased expression of gene sets responsible for neutrophil activation. Further analysis revealed moderate negative correlation between CRP level in CSF and clinical outcome. Brain-derived neurotrophic factor (BDNF) concentrations in both plasma and CSF significantly correlated with the favorable clinical outcome. On a micro-RNA level, we observed significant increase of miR-16-5p expression one week after transplantation in both body fluids and significant increase of miR-206 expression in plasma. Administration of Lin- cells may decrease inflammatory response and prevent neurodegeneration. However, these issues require further investigations.

Risk factors for ischemic stroke in patients with non-valvular atrial fibrillation and therapeutic international normalized ratio range.

INTRODUCTION: Atrial fibrillation (AF) is the most common cause of ischemic stroke (IS). Atrial fibrillation patients are recommended to use oral anticoagulants (OACs) as part of prevention against IS. However, despite having a therapeutic intensity of OAC therapy, IS can still occur in such patients. The aim of our study was to examine the configuration of IS risk factors in patients with non-valvular atrial fibrillation (NVAF) and within the therapeutic INR range (TINR). MATERIAL AND METHODS: Our retrospective study involved 1835 patients with a recent IS. The experimental group consisted of 154 patients with acute IS, NVAF and TINR. The control group consisted of 1681 patients with acute IS but without AF. RESULTS: Patients with IS, NVAF and TINR were significantly older and more often female than patients with IS without NVAF (p < 0.001 and p < 0.001, respectively). In these patients, diabetes mellitus, dyslipidemia, hypertension, coronary heart disease, smoking and previous IS were significantly more frequent than in the patients with IS without NVAF (p = 0.036, p = 0.002, p < 0.001, p < 0.001, p < 0.001, p = 0.003). Based on a univariable and multivariable logistic regression model, we found that in the group of patients who suffered a stroke despite TINR compared to patients with IS without AF there were more smokers (OR = 20.337; OR = 147.589) and patients with previous stroke (OR = 6.556; OR = 11.094), hypertension (OR = 3.75; OR = 2.75) and dyslipidemia (OR = 2.318; OR = 2.294). CONCLUSIONS: The group of patients with NVAF and TINR is significantly more burdened by other independent common risk factors for stroke.

Comparative assessment and monitoring of deterioration of articulatory organs using subjective and objective tools among patients with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of a rapid course. In 25% of ALS sufferers, speech disorders occur as prodromal symptoms of the disease. Impaired communication affects physical health and has a negative impact on mental and emotional condition. In this study, we assessed which domains of speech are particularly affected in ALS. Subsequently, we estimated possible correlations between the ALS patients' subjective perception of their speech quality and an objective assessment of the speech organs carried out by an expert. METHODS: The study group consisted of 63 patients with sporadic ALS. The patients were examined for articulatory functions by means of Voice Handicap Index (VHI) and the Frenchay Dysarthria Assessment (FDA). RESULTS: On the basis of the VHI scores, the entire cohort was divided into 2 groups: group I (40 subjects) with mild speech impairment, and group II (23 subjects) displaying moderate and profound speech deficits. In an early phase of ALS, changes were typically reported in the tongue, lips and soft palate. The FDA and VHI-based measurements revealed a high, positive correlation between the objective and subjective evaluation of articulation quality. CONCLUSIONS: Deterioration of the articulatory organs resulted in the reduction of social, physical and emotional functioning. The highly positive correlation between the VHI and FDA scales seems to indicate that the VHI questionnaire may be a reliable, self-contained tool for monitoring the course and progression of speech disorders in ALS. TRIAL REGISTRATION: NCT02193893 .

Influence of Lineage-Negative Stem Cell Therapy on Articulatory Functions in ALS Patients.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease, leading to loss of muscle strength and motor control. Impaired speech and swallowing lower the quality of life and consequently may induce acute respiratory failure. Bone marrow-derived stem and progenitor cells (SPCs) may be a valuable source of trophic factors. In this study, we assessed whether adjuvant cellular therapy could affect the levels of selected neurotrophins and proinflammatory factors in the cerebrospinal fluid (CSF) and subsequently prevent the deterioration of articulation. MATERIALS AND METHODS: The study group consisted of 32 patients with sporadic ALS who underwent autologous lineage-negative (Lin-) stem cell intrathecal administration to the spinal canal. Lin- cells were aspirated from the bone marrow and isolated using immunomagnetic beads and a lineage cell depletion kit. Patients were examined for articulatory functions by means of the Voice Handicap Index (VHI) questionnaire and Frenchay Dysarthria Assessment (FDA). In parallel, we carried out the analysis of selected trophic and proinflammatory factors in CSF utilizing multiplex fluorescent bead-based immunoassays. RESULTS: Of the 32 patients who received the Lin- progenitor cell therapy, 6 (group I) showed improvement in articulatory functions, 23 remained stable (group II), and 3 deteriorated (group III) on the 28th day. The improvement was particularly noticeable in a better cough reflex, laryngeal time, and dribble reflex. A statistically significant lower level of brain-derived neurotrophic factor (BDNF) was observed on day 0 in group I compared to group II. The CSF concentrations of C-reactive protein (CRP) in group I significantly decreased 7 days after Lin- SPC transplantation. On the contrary, a significant increase in the tumor necrosis factor receptor (TNF-R) level was confirmed among patients from group I with improvement of dribble and coughing reflex, tongue movements, and respiration on the 7th day, as well as on day 28 including dribble reflex solely. CONCLUSIONS: An application of Lin- stem cells could potentate the beneficial humoral effect. The prevention of deterioration of articulatory functions in ALS patients after applying adjuvant Lin- stem cell therapy seems to be promising. Although the procedure is safe and feasible, it requires further in-depth studies.

Beneficial effects of pre-stroke statins use in cardioembolic stroke patients with atrial fibrillation: a hospital-based retrospective analysis.

INTRODUCTION: Statins are widely used in stroke patients. The AHA/ASA guidelines recommend aggressive statin therapy in atherosclerotic stroke patients. Their beneficial effects are due to both their hypolipemic and pleiotropic properties. The aim of this study was to establish potential benefits from statin use in ischemic stroke patients with the diagnosis of atrial fibrillation (AF). MATERIAL AND METHODS: Ischemic stroke patients with AF were enrolled in the study. Group I, the statin group (n = 181), consisted of patients who had been treated with statins before stroke. Group II, the non-statin group (n = 153), consisted of patients who had not received such treatment in the last year. In-hospital mortality and neurological deficit on admission and at discharge were analyzed using the National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: Patients from the non-statin group had greater initial and discharge NIHSS scores (10 vs. 11.9, probability value p < 0.05; 7.6 vs. 9.5, p < 0.05 respectively). The improvement in NIHSS score was greater in the statin group (73.5% vs. 59.5%, p < 0.01). In-hospital mortality was more frequent in the non-statin group (9.9% vs. 18.3%, p < 0.05). CONCLUSIONS: Despite the predominant use of statins in atherothrombotic stroke patients, we demonstrated the beneficial effects of statins in cardioembolic stroke patients. Detailed cardiovascular screening for statin therapy should be carried out in all AF patients with regard to primary and secondary stroke prevention.

Elevated Inflammatory Parameter Levels Negatively Impact Populations of Circulating Stem Cells (CD133+), Early Endothelial Progenitor Cells (CD133+/VEGFR2+), and Fibroblast Growth Factor in Stroke Patients.

BACKGROUND: Endothelial Progenitor Cells (EPCs) are important players in neovascularization, mobilized through signalling by Angiogenic Growth Factors (AGFs) such as Vascular Endothelial Growth Factor (VEGF) and fibroblast growth factor (FGF). In vitro, inflammatory parameters impair the function and influence of EPCs on AGFs. However, this connection is not clear in vivo. To understand the mechanisms of augmented arteriogenesis and angiogenesis in acute ischemic stroke (AIS) patients, we investigated whether circulating stem cells (CD133+), early endothelial progenitor cells (CD133+/VEGFR2+), and endothelial cells (ECs; CD34¯/CD133¯/VEGFR2+) were increasingly mobilized during AIS, and whether there were correlations between EPC levels, growth factor levels and inflammatory parameters. METHODS: Data on demographics, classical vascular risk factors, neurological deficit information (assessed using the National Institutes of Health Stroke Scale), and treatment were collected from 43 consecutive AIS patients (group I). Risk factor control patients (group II) included 22 nonstroke subjects matched by age, gender, and traditional vascular risk factors. EPCs were measured by flow cytometry and the populations of circulating stem cells (CD133+), early EPCs (CD133+/VEGFR2+), and ECs (CD34¯/CD133¯/VEGFR2+) were analysed. Correlations between EPC levels and VEGF and FGF vascular growth factor levels as well as the influence of inflammatory parameters on EPCs and AGFs were assessed. RESULTS: Patient ages ranged from 54 to 92 years (mean age 75.2 ± 11.3 years). The number of circulating CD34¯/CD133¯/VEGF-R2+ cells was significantly higher in AIS patients than in control patients (p < 0.05). VEGF plasma levels were also significantly higher in AIS patients compared to control patients on day 7 (p < 0.05). FGF plasma levels in patients with AIS were significantly higher than those in the control group on day 3 (p < 0.05). There were no correlations between increased VEGF and FGF levels and the number of CD133+, CD133+/VEGFR2+, or CD34¯/CD133¯/VEGFR2+ cells. Leukocyte levels, FGF plasma levels, and the number of early EPCs were negatively correlated on day 3. High sensitivity C-reactive protein levels and the number of CD133+ and CD133+/VEGFR2+ cells were negatively correlated on day 7. In addition, there was a negative correlation between fibrinogen levels and FGF plasma levels as well as the number of early EPCs (CD133+/VEGFR2+). CONCLUSION: AIS patients exhibited increased numbers of early EPCs (CD133+/VEGFR2+) and AGF (VEGF and FGF) levels. A negative correlation between inflammatory parameters and AGFs and EPCs indicated the unfavourable influence of inflammatory factors on EPC differentiation and survival. Moreover, these correlations represented an important mechanism linking inflammation to vascular disease.

Reduced Hemoglobin Levels Combined with an Increased Plasma Concentration of Vasoconstrictive endothelin-1 are Strongly Associated with Poor Outcome During Acute Ischemic Stroke.

The association of poor outcome and mortality with low levels of hemoglobin (Hb) and hematocrit (HcT) in patients admitted after acute Ischemic Stroke (IS) was recently demonstrated. The mechanisms behind this still remain unclear. Our study aims to find out whether mRNA expressions and plasma concentrations of endothelin-1 (ET-l), endothelin-2 (ET-2) and endothelin-3 (ET-3) remain different in IS sufferers with low HcT and Hb levels in comparison with those whose HcT i Hb levels during a severe IS episode remain within the norm. The study included 60 patients treated consecutively for first-time IS. The assessment of mRNA gene expression and plasma concentration of ET-1, ET-2, ET-3 was conducted in the first, third and seventh day following the onset of stroke using qRT-PCR method and ELISA tests. We demonstrated that patients whose initial HcT and Hb levels were below the norm presented a deeper neurologic deficit on 1, 3 and 7 day following stroke with noticeable improvement no earlier than between day 3 and 7. We also found a negative correlation between the initial HcT and Hb and concentration of plasma ET-1 on the same days. The patients whose HcT and Hb levels were within normal limits showed a significant improvement in their neurologic condition on each consecutive day of the observation. Reduced levels of Hb and HcT combined with an increased plasma concentration of vasoconstrictive endothelin-1 are strongly associated with poor outcome and high mortality in acute ischemic stroke.

Effects of Angiotensin-Converting Enzyme Inhibition on Circulating Endothelial Progenitor Cells in Patients with Acute Ischemic Stroke.

BACKGROUND: Therapeutic neovascularization might represent an important strategy to salvage tissue after ischemia. Circulating bone marrow-derived endothelial progenitor cells (EPCs) were previously shown to augment the neovascularization of ischemic tissue. Angiotensin-converting enzyme inhibitors (ACEIs) might modulate EPC mobilization. We evaluated populations of circulating stem cells and early EPCs in acute ischemic stroke (AIS) patients and the effect of ACEI on circulating EPCs in these patients with respect to aspects of stroke pathogenesis. METHODS: We studied 43 AIS patients (group I), comprising 33 treated with ACEI (group Ia) and 10 untreated (group Ib). Risk factor controls (group II) included 22 subjects. EPCs were measured by flow cytometry. RESULTS: In AIS patients, the number of circulating stem cells and early EPCs upon admission was similar to that in control group individuals. There were no significant differences in the numbers of stem cells and early EPCs over subsequent days after AIS. There were also no significant differences in stem cell and early EPC numbers over the first 3 days between group Ia and group Ib. However, on day 7, these numbers were significantly higher in group Ib than in group Ia (p < 0.05). In AIS patients chronically treated with ACEI, there was a negative correlation between CD133+ cell number and neurological deficit on the first, third, and seventh days (p < 0.005). CONCLUSIONS: An increased number of circulating stem cells and early EPCs were not observed in stroke patients chronically treated with ACEI. In patients chronically treated with ACEI, a significant correlation was observed between decreased neurological deficit and higher levels of CD133+ cells; this could be due to the positive influence of these cells on the regeneration of the endothelium and improved circulation in the ischemic penumbra.