Administration of CD4+CD25highCD127-FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (Tconv) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4+CD25highCD127-FoxP3+ T regulatory (Treg) cells may inhibit this destruction through suppressive activity exerted on Tconv cells. METHODS: We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous Treg cells for relapsing-remitting MS. The patients received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 106 Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 106 Treg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up. RESULTS: No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of Treg cells or Tconv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(-) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group. CONCLUSIONS: No serious adverse events were reported in the 14 patients with MS treated with Treg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety. TRIAL REGISTRATION: EudraCT: 2014-004320-22; registered 18 November 2014.

Cerebral and skin microcirculatory dysfunction in type 1 diabetes.

INTRODUCTION: An increase in cerebral pulsatility index (PI), measured by transcranial Doppler, reflects the presence of cerebral microangiopathy. A decrease in distance between skin capillaries (DISTANCE) and an increase in the ratio between the area of capillaries and total area of examined skin (COVERAGE), revealed by capillaroscopy, reflects skin microangiopathy. However, little is known about the association between the cerebral and skin microvasculature function in patients at risk of microcirculatory dysfunction. AIM: To assess PI of the middle cerebral artery by transcranial Doppler and the DISTANCE and COVERAGE of the nailfold capillaries by quantitative capillaroscopy in patients with type 1 diabetes and control subjects without diabetes, and to investigate relationships between these parameters. MATERIAL AND METHODS: The study group consisted of 51 patients with type 1 diabetes (median age: 37.5 years) and 23 volunteers free from chronic diseases (median age: 37.9 years). RESULTS: Median PI was higher in patients than in control subjects (0.82 vs. 0.75; p < 0.01). Median DISTANCE was lower in patients than in control subjects (220.9 µm vs. 239.7 µm; p = 0.03), while median COVERAGE was higher in patients than in control subjects (20.4% vs. 18.3%; p = 0.01). No correlations between PI and DISTANCE or COVERAGE were found, but PI was correlated with patients' age and diabetes duration. CONCLUSIONS: In spite of simultaneous presence of cerebral and skin microangiopathy, we found no association between cerebral and skin microvasculature dysfunction. This seems to indicate independent progression of microcirculatory injury in cerebral and peripheral vascular beds.

Cerebral thrombolysis in patients with ischemic stroke and heart failure.

BACKGROUND: Heart failure (HF) is common among patients with ischemic stroke (IS), however its impact on outcome after iv-thrombolysis has not been fully determined. Moreover, definition of HF has been recently modified, but majority of stroke studies classified patients regarding an old HF criteria. Thus, the aim of our study was to evaluate the relationship between both, newly and formerly defined HF and the long-term outcome, mortality and the presence of hemorrhagic complications in patients with acute IS treated with iv-thrombolysis. METHODS: We retrospectively evaluated data from 328 Caucasian patients with IS consecutively treated with iv-thrombolysis. HF was defined according to old and new definition; long-term outcome was assessed with modified Rankin Scale (mRS) score and mortality rate on 90th days after IS. RESULTS: The incidence of HF did not differ between patients with favorable (mRS 0-2) and unfavorable (mRS 3-6) functional outcome respectively for the old and for the new definition (10.4% vs. 15.5, p = 0.17; 17.4% vs. 18.1%, p = 0.88) and between those who survived and died within 90 days after IS (11.7% vs. 20.0%, p = 0.27; 17.2% vs. 25.0%, p = 0.38, respectively). Multivariate analysis showed no impact of HF diagnosis on outcome (p = 0.94) or mortality (p = 0.64). CONCLUSION: The presence of systolic HF, defined according to an old and a new definition, does not determine safety and efficacy of cerebral iv-thrombolysis in patients with IS.

CD271+, CXCR7+, CXCR4+, and CD133+ Stem/Progenitor Cells and Clinical Characteristics of Acute Ischemic Stroke Patients.

Ischemic stroke causes mobilization of various groups of progenitor cells from bone marrow to bloodstream and this correlates with the neurological status of stroke patients. The goal of our study was to identify the activity of chosen progenitor/stem cells in the peripheral blood of acute ischemic stroke patients in the first 7 days after the incident, through associations between the levels of the cells and clinical features of the patients. Thirty-three acute ischemic stroke patients and 15 non-stroke control subjects had their venous blood collected repeatedly in order to assess the levels of the CD45-CD34 + CD271+, the CD45-CD34 + CXCR4+, the CD45-CD34 + CXCR7+, and the CD45-CD34 + CD133+ stem/progenitor cells by means of flow cytometry. The patients underwent repeated neurological and clinical assessments, pulse wave velocity (PWV) assessment on day 5, and MRI on day 1 and 5 ± 2. The levels of the CD45-CD34 + CXCR7+ and the CD45-CD34 + CD271+ cells were lower in the stroke patients compared with the control subjects. Only the CD45-CD34 + CD271+ cells correlated positively with lesion volume in the second MRI. The levels of the CD45-CD34 + CD133+ cells on day 2 correlated negatively with PWV and NIHSS score on day 9. The patients whose PWV was above 10 m/s had significantly higher levels of the CD45-CD34 + CXCR4+ and the CD45-CD34 + CXCR7+ cells on day 1 than those with PWV below 10 m/s. This study discovers possible activity of the CD45-CD34 + CD271+ progenitor/stem cells during the first 7 days after ischemic stroke, suggests associations of the CD45-CD34 + CD133+ cells with the neurological status of stroke patients, and some activity of the CD45-CD34 + CD133+, the CD45-CD34 + CXCR4+, and the CD45-CD34 + CXCR7+ progenitor/stem cells in the process of arterial remodeling.

Length of stay in emergency department and cerebral intravenous thrombolysis in community hospitals.

OBJECTIVES: Current guidelines for the early management of patients with acute ischemic stroke recommend completion of an evaluation within 60 min of the patient's arrival at the emergency department (ED) because prolongation of ED length of stay (LOS) may reduce the efficacy of acute stroke treatment. AIM: To evaluate the LOS in EDs at the community-based Polish stroke centers, to determine logistic, social, epidemiological, and clinical factors responsible for its prolongation, and to assess the association between increased LOS and the implementation of cerebral intravenous (IV) thrombolysis. MATERIALS AND METHODS: This study carried out an evaluation of the medical records of 8398 patients with stroke and transient ischemic attack who consecutively reported to the Pomeranian Stroke Registry from 2010 to 2012. RESULTS: The median ED LOS in the studied cohort was 97 (44-196) min and was prolonged (>60 min) in 63.1% of patients. Prolongation of ED LOS contributed to a low (4.9%) IV thrombolysis rate. Functional status at discharge was worse in patients with prolonged versus nonprolonged LOS [modified Rankin scale: 2 (0-3) vs. 1 (0-3) points; P<0.001]. Multivariate analysis showed that onset-to-door time more than 270 min or unknown time of symptoms onset, referral to ED in urban areas, living alone, presence of diabetes, motor, sensory, visual, and gait deficits at stroke onset, and NIHSS score on admission contributed toward prolongation of ED LOS. CONCLUSION: A prolonged ED LOS, because of ineffective prehospital logistics, ED urban location, patients' risk factors, and cohabitation profile and stroke symptoms and severity, commonly exists among patients with stroke and transient ischemic attack and contributes toward a low rate of IV thrombolysis in Polish community hospitals.

IL-1ß, TNF-α, and IL-6 levels in gingival fluid and serum of patients with ischemic stroke.

It has been documented that an increase of immune cells in periodontitis may stimulate the process of atherosclerosis and lead to ischemic stroke. The aim of this study was to investigate whether there is any significant difference in serum and gingival crevicular fluid (GCF) cytokine concentrations between patients with early ischemic stroke (IS) and a control group. Eighty-six patients were consecutively enrolled for this study, 50 with ischemic stroke and 36 as a control group with no previous stroke. Only dentulous patients were included. In each patient, GCF was collected from the deepest periodontal pocket. Blood serum samples were also taken from all subjects. The collected material was analyzed for cytokine concentrations using the cytometric bead array technique. Cerebral ischemia was found to be correlated with higher serum levels of IL-1ß (13.01 ± 13.87 vs. 7.83 ± 2.11) and IL-6 (15.82 ± 16.64 vs. 6.64 ± 2.5) compared to the control group. The levels of IL-1, IL-6 and TNF-α in GCF were higher in patients with ischemic stroke but the difference was not significant. In conclusion, ischemic stroke was found to be associated with higher levels of IL-1ß and IL-6 in serum. The cytokine concentrations in GCF did not appear to be directly correlated with those in serum in patients with ischemic stroke.(J Oral Sci 58, 509-513, 2016).

Left ventricular ejection fraction and aortic stiffness are independent predictors of neurological outcome in acute ischemic stroke.

BACKGROUND: Stroke is a leading cause of disability and one of the major causes of death worldwide. The short-term prognosis in individual patients is highly variable and cannot be explained solely by stroke severity. We investigated the association of left ventricular ejection fraction with early neurological outcome in acute ischemic stroke. METHODS: In total, 216 patients enrolled in a prospective study, underwent echocardiography and applanation tonometry performed within 1 week after stroke onset. At day 10, favorable outcome was defined as a 4 or more point improvement from baseline National Institutes of Health Stroke Scale or final National Institutes of Health Stroke Scale of 0-1. RESULTS: In patients with favorable outcome, the ejection fraction was significantly higher comparing with patients with poorer prognosis (54.3 ±â€Š7.9 vs. 49.9 ±â€Š9.8%, P = 0.005). Favorable neurological outcome at day 10 was also associated with lower heart rate and lower pulse wave velocity at baseline. Univariate analyses showed that left ventricle ejection fraction and arterial stiffness were the strongest predictors of the poststroke improvement. In multivariate analysis, ejection fraction at least 50% remained significantly associated with favorable outcome after full adjustment for potential confounders (odds ratio 3.81, [95% confidence interval, 1.18-12.35]; P = 0.02). CONCLUSION: These findings provide evidence that in ischemic stroke, preserved ejection fraction and lower pulse wave velocity are associated with early favorable outcome, independently of other known prognostic factors, including blood pressure.

Renal Dysfunction in Post-Stroke Patients.

BACKGROUND: The presence of chronic kidney disease (CKD) is an indicator of a worse long-term prognosis in patients with ischemic stroke (IS). Unfortunately, not much is known about renal function in the population of post-IS subjects. The aim of our study was to assess the prevalence of renal damage and impaired renal function (IRF) in the population of post-IS subjects. METHODS: This prospective analysis concerned 352 consecutive post-IS survivors hospitalized in Pomeranian stroke centers (Poland) in 2009. In this group estimated glomerular filtration rate (eGFR) according to MDRD (modification of diet in renal diseases) and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formulas and urine albumin/creatinine ratio (ACR) were determined. RESULTS: Among survivors decreased eGFR (<60 mL/min./1.73m2 according to MDRD or CKD-EPI) or ACR≥30mg/g were detected in 40.38% (23.07% Men, 55.32% Women; P<0.01). The highest prevalence of IRF was noted in post-IS subjects with atheromatic and lacunar IS. In multivariate analysis the ACR≥30mg/g was predicted by older age, diabetes mellitus (DM) and physical disability (modified Rankin scale 3-5 pts.). The association with reduced eGFR was proved for sex (female), DM and physical disability. CONCLUSIONS: CKD is a frequently occurring problem in the group of post-IS subjects, especially after lacunar and atheromatic IS. Post-IS patients, mainly the elderly women, with physical disability and diabetes mellitus, should be regularly screened for CKD. This could reduce the risk of further cardiovascular events and delay the progression of IRF.

Acute hypertensive response in ischemic stroke is associated with increased aortic stiffness.

BACKGROUND AND AIMS: Acute hypertensive response (AHR) affects more than 60% of patients with ischemic stroke and is associated with poor outcomes. We hypothesized that its development is related to arterial stiffening. "The gold standard" estimate of arterial stiffness is carotid-femoral pulse wave velocity (CF-PWV). We compared CF-PWV and indirect indices of arterial stiffness (central augmentation index (cAIxHR), central systolic (cSBP) and pulse (cPP) pressures) between acute ischemic stroke patients who developed AHR and those who were normotensive in the early phase of stroke. METHODS: AHR was assessed through hourly BP measurements within 24 h from admission using an oscillometric device. The stiffness was assessed using applanation tonometry with a SphygmoCor(®) device (Atcor, Sydney, Australia) 7 ± 2 days after stroke. RESULTS: Among 102 patients with acute ischemic stroke, 73(71.5%) met AHR criteria. In an univariate analysis, CF-PWV, cAIxHR, cSBP and cPP were higher in those who developed AHR (10.9 vs. 8.3 m/s, p < 0.001; 30.8 vs. 23.9%, p = 0.004; 138.2 vs. 117.2 mmHg, p < 0.001; 54.6 vs. 44 mmHg, p = 0.005, respectively). In a multivariate logistic regression analysis, CF-PWV was independently associated with AHR after adjustment for age and peripheral mean blood pressure (pMBP) (p = 0.04), for age, pMBP and diabetes mellitus (DM) (p = 0.045), and age, pMBP, DM and hypertension (p = 0.047). CONCLUSION: This study revealed for the first time that AHR in ischemic stroke is associated with elevated aortic stiffness independently of other clinical factors including age and hypertension preceding stroke. A potential pathophysiological mechanism responsible for this relationship includes impaired baroreceptor function in stiff arteries resulting in impaired BP autoregulation.

Statin Use and Cognitive Impairment in Patients With Type 1 Diabetes: An Observational Study.

OBJECTIVE: We aimed to assess a wide range of cognitive functions in patients with type 1 diabetes (DM1) compared with healthy control subjects and to evaluate the effects of statins on cognitive functions in DM1 patients. MATERIALS AND METHODS: The sample studied consisted of 55 DM1 patients (80.0% with hyperlipidemia, 20% with statin treatment) and 36 age-matched control subjects (77.8% with hyperlipidemia) without diabetes or statin use. Their cognitive functions (attention, memory, and executive functions) were evaluated with the trail making test, controlled oral word association test (COWAT), Rey-Osterrieth complex figure test, brain damage test (diagnosticum für cerebralschädigung, DCS), Wisconsin card sorting test (WCST), and digit span and block design tests from the revised Wechsler adult intelligence scale. RESULTS: Cognitive performance was impaired in DM1 patients when compared with the control group with regard to semantic verbal fluency (COWAT_animals), visual learning (DCS), conceptual-level responses, executive functions (WCST random errors), and WCST trials to complete the first category. Subgroups of DM1 patients distinguished on the basis of statin therapy did not differ with regard to verbal fluency (COWAT_animals), visual learning (DCS), conceptual-level responses, executive functions (WCST random errors), and WCST trials to complete the first category. Multivariate analysis also does not show the impact of statin therapy on cognitive functioning regardless of the duration of education, microangiopathic evidence, the presence of hyperlipidemia, or antihypertensive therapy. CONCLUSIONS: We find impairment of cognitive functions in DM1 patients when compared with control subjects without diabetes. However, we show neither the effect of statins nor the significant influence of metabolic control, microangiopathic complications, or the presence of hyperlipidemia on cognitive functions in DM1 patients.

The role of additional computed tomography in the decision-making process on the secondary prevention in patients after systemic cerebral thrombolysis.

INTRODUCTION: Patients with ischemic stroke undergoing intravenous (iv)-thrombolysis are routinely controlled with computed tomography on the second day to assess stroke evolution and hemorrhagic transformation (HT). However, the benefits of an additional computed tomography (aCT) performed over the next days after iv-thrombolysis have not been determined. METHODS: We retrospectively screened 287 Caucasian patients with ischemic stroke who were consecutively treated with iv-thrombolysis from 2008 to 2012. The results of computed tomography performed on the second (control computed tomography) and seventh (aCT) day after iv-thrombolysis were compared in 274 patients (95.5%); 13 subjects (4.5%), who died before the seventh day from admission were excluded from the analysis. RESULTS: aCTs revealed a higher incidence of HT than control computed tomographies (14.2% vs 6.6%; P=0.003). Patients with HT in aCT showed higher median of National Institutes of Health Stroke Scale score on admission than those without HT (13.0 vs 10.0; P=0.01) and higher presence of ischemic changes >1/3 middle cerebral artery territory (66.7% vs 35.2%; P<0.01). Correlations between presence of HT in aCT and National Institutes of Health Stroke Scale score on admission (rpbi 0.15; P<0.01), and the ischemic changes >1/3 middle cerebral artery (phi=0.03) existed, and the presence of HT in aCT was associated with 3-month mortality (phi=0.03). CONCLUSION: aCT after iv-thrombolysis enables higher detection of HT, which is related to higher 3-month mortality. Thus, patients with severe middle cerebral artery infarction may benefit from aCT in the decision-making process on the secondary prophylaxis.

Interval analysis of interictal EEG: pathology of the alpha rhythm in focal epilepsy.

The contemporary use of interictal scalp electroencephalography (EEG) in the context of focal epilepsy workup relies on the visual identification of interictal epileptiform discharges. The high-specificity performance of this marker comes, however, at a cost of only moderate sensitivity. Zero-crossing interval analysis is an alternative to Fourier analysis for the assessment of the rhythmic component of EEG signals. We applied this method to standard EEG recordings of 78 patients divided into 4 subgroups: temporal lobe epilepsy (TLE), frontal lobe epilepsy (FLE), psychogenic nonepileptic seizures (PNES) and nonepileptic patients with headache. Interval-analysis based markers were capable of effectively discriminating patients with epilepsy from those in control subgroups (AUC~0.8) with diagnostic sensitivity potentially exceeding that of visual analysis. The identified putative epilepsy-specific markers were sensitive to the properties of the alpha rhythm and displayed weak or non-significant dependences on the number of antiepileptic drugs (AEDs) taken by the patients. Significant AED-related effects were concentrated in the theta interval range and an associated marker allowed for identification of patients on AED polytherapy (AUC~0.9). Interval analysis may thus, in perspective, increase the diagnostic yield of interictal scalp EEG. Our findings point to the possible existence of alpha rhythm abnormalities in patients with epilepsy.

Diabetic symmetric polyneuropathy is associated with increased aortal stiffening but not cerebral angiopathy in type 1 diabetes.

INTRODUCTION: Diabetic symmetric polyneuropathy (DSP) and cerebral microangiopathy are common complications of type 1 diabetes (T1DM). However, little is known about associations between DSP, cerebral microcirculation and macrovascular injury in T1DM. We aimed to assess relationships between those complications. MATERIAL AND METHODS: We examined 42 patients (25 females; mean age 37.1±5.6years) with T1DM (mean disease duration 20.6±6.1years). DSP was diagnosed with the use of quantitative vibration sensory testing (QVST) and Michigan Neuropathy Screening Instrument (MNSI). Cerebral microvasculature was evaluated with measurements of vasomotor reactivity reserve (VMR) and pulsatility index (PI) of middle cerebral artery, macroangiopathic injury by measuring intima-media complex thickness (IMT) in the common carotid artery and carotid-femoral pulse-wave velocity (PWV). RESULTS: Patients with DSP (33.3%) showed higher PWV than those without DPS (10.5 vs 9.1m/s; P=0.03); no differences concerning VMR, PI or IMT existed. There were correlations between PWV and vibration perception thresholds (VPT) (r=0.44; P=0.004) and MNSI score (r=0.43; P=0.003); VPT showed impact on PWV (beta 0.34; P<0.03). CONCLUSIONS: DSP is associated with systemic macroangiopathy, reflected by increased carotid-femoral PWV, but not with the cerebral macro- and microangiopathy.

Is there a bad time for intravenous thrombolysis? The experience of Polish stroke centers.

BACKGROUND AND PURPOSE: The outcome in acute stroke strongly depends on patient-related issues, as well as on the availability of human and diagnostic resources. Our aim was to evaluate safety and effectiveness of intravenous alteplase for stroke according to the time of admission to the hospital. MATERIALS AND METHODS: We analyzed the data of all acute stroke patients treated with alteplase between October 2003 and December 2010, contributed to the Safe Implementation of Thrombolysis for Stroke registry from 27 Polish stroke centers. According to the time of admission we distinguished between: (1) non-working days (Friday 14:30-Monday 08:00 plus national holidays); (2) out-of-office hours (non-working days plus 14:30-08:00 during working days); and (3) night hours (time from 23:00 to 06:00). Patients admitted during regular working hours (Monday 08:00-Friday 14:30, excluding national holidays) were used as the reference. RESULTS: Of 1330 patients, 448 (32.5%) were admitted on non-working days, 868 (65.3%) at out-of-office hours, and 105 (7.9%) during night hours. In multivariate logistic regression, none of the evaluated periods showed association with symptomatic intracranial hemorrhage, 7-day mortality, and neurological improvement ≥4 points in the National Institutes of Health Stroke Scale score at day 7. Patients admitted during night hours had lower odds (OR 0.53, 95% CI: 0.29-0.95, p=0.032) for achieving favorable outcome (modified Rankin Scale score 0-2). CONCLUSIONS: There is no bad time for thrombolysis. Stroke centers should feel confident about the treatment outside regular working hours, irrespective of equipment and staff availability. However, it may be reasonable to pay additional attention during nighttime.

Hypertension, brain damage and cognitive decline.

Loss of cognitive function is one the most devastating manifestations of ageing and vascular disease. Cognitive decline is rapidly becoming an important cause of disability worldwide and contributes significantly to increased mortality. There is growing evidence that hypertension is the most important modifiable vascular risk factor for development and progression of both cognitive decline and dementia. High blood pressure contributes to cerebral small and large vessel disease resulting in brain damage and dementia. A decline in cerebrovascular reserve capacity and emerging degenerative vascular wall changes underlie complete and incomplete brain infarcts, haemorrhages and white matter hyperintensities. This review discusses the complexity of factors linking hypertension to brain functional and structural changes, and to cognitive decline and dementia. The evidence for possible clinical markers useful for prevention of decreased cognitive ability, as well as recent data on vascular mechanism in the pathogenesis of cognitive decline, and the role of antihypertensive therapies in long-term prevention of late-life cognitive decline will be reviewed.

Heart rate variability and functional outcome in ischemic stroke: a multiparameter approach.

BACKGROUND AND PURPOSE: Heart rate variability (HRV) as a measure of autonomic function might provide prognostic information in ischemic stroke. However, numerous difficulties are associated with HRV parameters assessment and interpretation, especially in short-term ECG recordings. For better understanding of derived HRV data and to avoid methodological bias we simultaneously recorded and analyzed heart rate, blood pressure and respiratory rate. METHODS: Seventy-five ischemic stroke patients underwent short-term ECG recordings. Linear and nonlinear parameters of HRV as well as beat-to-beat blood pressure and respiratory rate were assessed and compared in patients with different functional neurological outcomes at 7th and 90th days. RESULTS: Values of Approximate, Sample and Fuzzy Entropy were significantly lower in patients with poor early neurological outcome. Patients with poor 90-day outcome had higher percentage of high frequency spectrum and normalized high frequency power, lower normalized low frequency power and lower low frequency/high frequency ratio. Low frequency/high frequency ratio correlated negatively with scores in the National Institutes of Health Stroke Scale and modified Rankin Scale (mRS) at the 7th and mRS at the 90th days. Mean RR interval, values of blood pressure as well as blood pressure variability did not differ between groups with good and poor outcomes. Respiratory frequency was significantly correlated with the functional neurological outcome at 7th and 90th days. CONCLUSION: While HRV assessed by linear methods seems to have long-term prognostic value, complexity measures of HRV reflect the impact of the neurological state on distinct, temporary properties of heart rate dynamic. Respiratory rate during the first days of the stroke is associated with early and long-term neurological outcome and should be further investigated as a potential risk factor.

Decreased reactivity of skin microcirculation in response to L-arginine in later-onset type 1 diabetes.

OBJECTIVE: The aim of our study was to evaluate the vasodilatory effect of l-arginine infusion on the skin microcirculation and to assess the relationship between this effect and the presence of microangiopathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Capillaroscopy was performed before and after l-arginine infusion in 48 diabetic patients (26 women and 22 men; age, 39.8 ± 6.3 years) and 24 volunteers free of any chronic disease (13 women and 11 men; age, 38.0 ± 6.7 years). The skin microcirculation reactivity, as expressed by the percentage of area covered by capillaries (coverage) and the distance between capillaries (distance), and the relationship between microcirculation reactivity and the presence of microangiopathic complications were assessed. RESULTS: The distance before l-arginine infusion was significantly lower in patients than in controls (221 [153-311] vs. 240 [185-356] µm; P = 0.02) and did not differ after l-arginine infusion (223.5 [127-318] vs. 242.5 [181-341] µm; P = 0.27). The difference between the coverage values obtained before and after l-arginine infusion (Δcoverage) was significantly different from zero in the control group but not in the diabetes group. Patients with later onset of diabetes were characterized by decreased skin microcirculation reactivity when compared with patients with earlier onset of diabetes (-1.18 [-5.07 to 11.60] vs. 1.36 [-6.00 to 8.06]; P = 0.02) despite the higher prevalence of retinopathy in patients with earlier onset of diabetes (64% vs. 26%; P = 0.02). CONCLUSIONS: Skin microvascular reactivity is impaired in patients with later onset of type 1 diabetes. Capillaroscopy with l-arginine infusion is useful for the identification of skin microangiopathy in type 1 diabetes.

Pulse wave velocity is associated with early clinical outcome after ischemic stroke.

BACKGROUND AND PURPOSES: Pulse wave analysis (PWV), a marker of aortic stiffness, has independent predictive value for cardiovascular morbidity and mortality in both healthy and high-risk populations, especially fatal stroke, and for long-term functional stroke prognosis. Whether arterial stiffness and wave reflection are related to stroke in-hospital short-term outcome has never been demonstrated. METHODS: In a prospective study, we enrolled 134 patients with acute ischemic stroke, aged 63.4 ± 12.5 years, mean ± SD, National Institutes of Health stroke scale (NIHSS) scored 7.1 ± 6.5 at admission. Carotid-femoral (CF) PWV and central augmentation index (cAIx) were measured (SphygmoCor) one week after stroke onset. At hospital discharge, favorable outcome was defined as a 4 or more point improvement from baseline NIHSS or NIHSS of 0-1. Data were analyzed with logistic regression. RESULTS: In univariate analysis, low CF-PWV (P = 0.000,001), but not cAIx, was significantly associated with early favorable outcome. In multivariate analysis, CF-PWV > 9.0 m/s remained significantly associated with favorable early outcome after adjustment for age, NIHSS and blood glucose level on admission, as well as heart rate, systolic and mean blood pressure, measured at day 7 (OR = 0.17 [95% CI, 0.05-0.60];P = 0.006). CONCLUSIONS: In ischemic stroke, low aortic stiffness (CF-PWV) is associated with early favorable outcome, independently of other known prognostic factors.

Angiogenin in middle-aged type 1 diabetes patients.

BACKGROUND: Angiogenin levels are increased in children and adolescent patients with type 1 diabetes, regardless of the extent of diabetic microangiopathy. However, little is known about the angiogenin concentrations in adults with type 1 diabetes. Thus we studied its level in middle aged subjects with the presence of diabetic nephro-, retino and neuropathy. METHODS: We investigated the data of 57 (age 39±6.6 years, 45.6% of males) patients with type 1 diabetes and 38 age-matched control subjects without diabetes (age 37.1±5.9 years, 42.1% of males), including medical histories, evidences of microangiopathy and serum angiogenin concentrations. RESULTS: Serum angiogenin level was lower in patients with type 1 diabetes [384.2(190.4-999.8) ng/ml] compared to controls [460.4(230.6-708.2) ng/ml], p=0.04. In patients with overt diabetic nephropathy the angiogenin level was higher when compared to patients without nephropathy [568.2(269.6-999.8) vs 369.4(190.4-999.8) ng/ml, p=0.01]. There were no differences between angiogenin levels in subgroups of patients distinguished by the presence of other microvascular complications or other concomitant vascular risk factors despite cigarette smoking [smokers: 516.2(294.4-999.8) vs. non-smokers: 372.1(190.4-924.8) ng/ml, p=0.01]. CONCLUSIONS: Regardless of the presence of diabetic microangiopathy, angiogenin level in middle-aged type 1 diabetes patients is lower than in controls. The presence of overt nephropathy and smoking habit in middle-aged patients with type 1 diabetes are associated with higher angiogenin level.