Stem cell transplantation for ischemic stroke

Background Stroke is a leading cause of morbidity and mortality worldwide, with very large healthcare and social costs, and a strong demand for alternative therapeutic approaches. Preclinical studies have shown that stem cells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benefits of stem cell transplantation in people with ischemic stroke is lacking. This is the first update of the Cochrane review published in 2010. Objectives To assess the efficacy and safety of stem cell transplantation compared with control in people with ischemic stroke. Search methods We searched the Cochrane Stroke Group Trials Register (last searched August 2018), CENTRAL (last searched August 2018), MED-LINE (1966 to August 2018), Embase (1980 to August 2018), and BIOSIS (1926 to August 2018). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched August 2018). We also contacted individuals active in the field and stem cell manufacturers (last contacted August 2018). Selection criteria We included randomized controlled trials (RCTs) that recruited people with ischemic stroke, in any phase of the disease (acute, subacute or chronic), and an ischemic lesion confirmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation, regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. The primary outcome was efficacy (assessed as neurologic impairment or functional outcome) at longer term follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological deficit, infections, and neoplastic transformation). Data collection and analysis Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data. If needed, we contacted study authors for additional information. We performed random effects meta-analyses when two or more RCTs were available for any outcome. We assessed the certainty of the evidence by using the GRADE approach. Main results In this updated review, we included seven completed RCTs with 401 participants. All tested adult human non-neural stem cells; cells were transplanted during the acute, subacute, or chronic phase of ischemic stroke; administered intravenously, intra-arterially, intracerebrally, or into the lumbar subarachnoid space. Follow-up ranged from six months to seven years. Efficacy outcomes were measured with the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), or Barthel Index (BI). Safety outcomes included case fatality, and were measured at the end of the trial. Overall, stem cell transplantation was associated with a better clinical outcome when measured with the NIHSS (mean difference [MD]-1.49, 95% confidence interval [CI]-2.65 to-0.33; five studies, 319 participants; low-certainty evidence), but not with the mRS (MD-0.42, 95% CI-0.86 to 0.02; six studies, 371 participants; very low-certainty evidence), or the BI (MD 14.09, 95% CI-1.94 to 30.13; three studies, 170 participants; very low-certainty evidence). The studies in favor of stem cell transplantation had, on average, a higher risk of bias, and a sample size of 32 or fewer participants. No significant safety concerns associated with stem cell transplantation were raised with respect to death (risk ratio [RR] 0.66, 95% CI 0.39 to 1.14; six studies, participants; low-certainty evidence). We were not able to perform the sensitivity analysis according to the quality of studies, because all of them were at high risk of bias. Authors’ conclusions Overall, in participants with ischemic stroke, stem cell transplantation was associated with a reduced neurological impairment, but not with a better functional outcome. No obvious safety concerns were raised. However, these conclusions came mostly from small RCTs with high risk of bias, and the certainty of the evidence ranged from low to very low. More well-designed trials are needed

Balance between the reliability of classification and sampling effort: A multi-approach for thewater Framework Directive (WFD) ecological status applied to the Venice Lagoon (Italy)

The Water Framework Directive (WFD) requires Member States to assess the ecological status of water bodies and provide an estimation of the classification confidence and precision. This study tackles the issue of the uncertainty in the classification, due to the spatial variability within each water body, proposing an analysis of the reliability of classification, using the results of macrophyte WFD monitoring in the Venice Lagoon as case study. The level of classification confidence, assessed for each water body, was also used as reference to optimize the sampling effort for the subsequent monitorings. The ecological status of macrophytes was calculated by the Macrophyte Quality Index at 114 stations located in 11 water bodies. At water body scale, the level of classification confidence ranges from 54% to 100%. After application of the multi-approach (inferential statistics, spatial analyses, and expert judgment), the optimization of the sampling effort resulted in a reduction of the number of stations from 114 to 84. The decrease of sampling effort was validated by assessing the reliability of classification after the optimization process (54-99%) and by spatial interpolation of data (Kernel standard error of 22.75%). The multi-approach proposed in this study could be easily applied to any other water body and biological quality element

Risk of stroke and bleeding in relation to hypertension in anticoagulated patients with atrial fibrillation: a meta-analysis of randomised controlled trials.

Background and purpose Hypertension is common in patients with atrial fibrillation (AF) and carries an additional risk for complications, most notably stroke and bleeding. We assessed the history of hypertension, level of blood pressure control, and an interaction with the choice of oral anticoagulants on clinical outcomes. Methods We performed a systematic review and meta-analysis of studies that randomised patients to novel oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) and reported outcomes stratified by presence of hypertension. Collected outcomes were: ischaemic stroke or systemic embolism (SE), haemorrhagic stroke, intracranial haemorrhage and major bleeding. Log adjusted hazard ratios (HR) and corresponding standard error were calculated, and HRs were compared using Mantel-Haenszel random effects. Quality of the evidence was assessed with Cochrane risk of bias tool. Results Five high-quality studies were eligible, including 71.527 participants who received NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) or VKAs, with median follow-up of 1.8-2.8 years. Compared with patients without hypertension, those with hypertension had higher adjusted risk for ischaemic stroke/SE (HR: 1.25, 95%-CI:1.09, 1.43) and haemorrhagic stroke (HR:1.98, 1.24-3.16). On a continuous scale, the risk of ischaemic stroke/SE increased 6-7% per 10 mmHg increase in systolic blood pressure. No interactions were found between the efficacy or safety of NOACs versus VKAs in the presence or absence of hypertension. In both groups, the use of NOACs led to a lower risk of ischaemic stroke/SE, haemorrhagic stroke and intracranial haemorrhage compared with patients that used VKAs. Conclusions Adequate blood pressure management is vital to optimally reduce the risk of stroke in patients with atrial fibrillation. The benefits of NOACs over VKAs, also apply to patients with elevated blood pressure

A New Multi-Index Method for the Eutrophication Assessment in Transitional Waters: Large-Scale Implementation in Italian Lagoons

Eutrophication represents one of the most impacting threats for the ecological status and related ecosystem services of transitional waters; hence, its assessment plays a key role in the management of these ecosystems. A new multi-index method for eutrophication assessment, based on the ecological index MaQI (Macrophyte Quality Index), the trophic index TWQI (Transitional Water Quality Index), and physicochemical quality elements (sensu Dir. 2000/60/EC), was developed including both driver and impact indicators. The study presents a large-scale implementation of the method, which included more than 100 Italian lagoon sites, covering a wide variability of lagoon typologies and conditions. Overall, 35% of sites resulted in eutrophic status, 45% in mesotrophic, and 25% in oligotrophic status

Microalgal biostimulants and biofertilisers in crop productions

Microalgae are attracting the interest of agrochemical industries and farmers, due to their biostimulant and biofertiliser properties. Microalgal biostimulants (MBS) and biofertilisers (MBF) might be used in crop production to increase agricultural sustainability. Biostimulants are products derived from organic material that, applied in small quantities, are able to stimulate the growth and development of several crops under both optimal and stressful conditions. Biofertilisers are products containing living microorganisms or natural substances that are able to improve chemical and biological soil properties, stimulating plant growth, and restoring soil fertility. This review is aimed at reporting developments in the processing of MBS and MBF, summarising the biologically-active compounds, and examining the researches supporting the use of MBS and MBF for managing productivity and abiotic stresses in crop productions. Microalgae are used in agriculture in different applications, such as amendment, foliar application, and seed priming. MBS and MBF might be applied as an alternative technique, or used in conjunction with synthetic fertilisers, crop protection products and plant growth regulators, generating multiple benefits, such as enhanced rooting, higher crop yields and quality and tolerance to drought and salt. Worldwide, MBS and MBF remain largely unexploited, such that this study highlights some of the current researches and future development priorities

Cardiovascular Risk Factors Associated With the Metabolically Healthy Obese (MHO) Phenotype Compared to the Metabolically Unhealthy Obese (MUO) Phenotype in Children

Background: In pediatric age the prevalence of obesity is high. Obese children who do not have other risk factors than excess weight have been defined as \u201cmetabolically healthy obese\u201d (MHO). Aim: The aim of this study is to evaluate, in a population of obese children, the prevalence of the MHO and \u201cmetabolically unhealthy obese\u201d (MUO) phenotype. Furthermore, we evaluated the distribution of Uric Acid, HOMA index and Waist-Height ratio (W-Hr) in the MHO and MUO sub-groups and the impact of these non-traditional risk factors on the probability to be MUO. Methods: In 1201 obese children and adolescents [54% males, age (\ub1SD) 11.9 (\ub13.0) years] weight, height, waist circumference, systolic (SBP) and diastolic (DBP) blood pressure, pubertal status, glucose, insulin, HDL cholesterol, triglycerides and Uric Acid serum values were assessed. MUO phenotype was defined as the presence of at least one of the following risk factors: SBP or DBP 65 90th percentile, glycaemia 65 100 mg/dl, HDL cholesterol <40 mg/dl, triglycerides 65100 mg/dl (children <10 years) or 65130 mg/dl (children 6510 years). A multivariate logistic regression analysis was used to estimate the association between MUO phenotype and non-traditional cardiovascular risk factors. Results: The prevalence of the MUO status was high (61%). MUO subjects were more often male, older and pubertal (p < 0.001). The levels of the three non-traditional risk factors were significantly higher in MUO children compared to MHO children (p < 0.001) and all of them were independent predictors of the fact of being MUO [OR 1.41 (95% CI 1.24\u20131.69); 1.15 (95% CI 1.06\u20131.23) and 1.03 (95% CI1.01\u20131.05) for Uric Acid, HOMA index and W-Hr, respectively]. About 15% of MHO subjects had serum Uric Acid, HOMA index and W-Hr values within the highest quartile of the study population. Conclusion: The prevalence of MUO subjects in a large pediatric population is high and serum Uric Acid, HOMA index and W-Hr values are independent predictors of the probability of being MUO. A non-negligible percentage of subjects MHO has high values of all three non-traditional risk factors

Validation protocols for blood pressure measuring devices: the impact of the European Society of Hypertension International Protocol and the development of a Universal Standard

In the last three decades protocols for the validation of blood pressure measuring devices have been developed by the US Association for the Advancement of Medical Instrumentation, the British Hypertension Society, the German Hypertension League, the European Society of Hypertension Working Group on blood pressure Monitoring and the International Organization for Standardization. The European Society of Hypertension International Protocol required much smaller sample size than the other protocols, aiming to reduce the time, resources and cost of validation studies and thereby increase the number of validated devices. Given its specifications, the European Society of Hypertension International Protocol was adequate for ‘high- and low-accuracy’ devices, yet assessment of ‘moderate accuracy’ devices had high uncertainty with resultant high rate of device failure. Thus, devices validated using the European Society of Hypertension International Protocol should be considered to be as accurate as those validated with the previous Association for the Advancement of Medical Instrumentation or British Hypertension Society protocols. However, the European Society of Hypertension International Protocol did not allow subgroup evaluation (arm sizes, special populations, etc). The mission of the European Society of Hypertension International Protocol to promote the concept of validation has been well achieved, as almost double studies have been published using it than all the other protocols together. However, the maintenance of different validation protocols is confusing and therefore experts from the Association for the Advancement of Medical Instrumentation, European Society of Hypertension International Protocol and International Organization for Standardization have now developed the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) as the recommended 21st-century procedure for worldwide application. The European Society of Hypertension Working Group has published a practical guide for using the Universal Standard. It is in the interests of all scientific bodies to propagate the Universal Standard and ensure its wide implementation

Uptake-release by MSCs of a cationic platinum(II) complex active in vitro on human malignant cancer cell lines

In this study, the in vitro stability of cisplatin (CisPt) and cationic platinum(II)-complex (caPt(II)-complex) and their in vitro activity (antiproliferative and anti-angiogenic properties) were investigated against three aggressive human tumor cell lines. caPt(II)-complex shown a high stability until 9 days of treatment and displayed a significant and higher activity than CisPt against both NCI-H28 mesothelioma (19.37 \ub1 9.57 \u3bcM versus 34.66 \ub1 7.65 \u3bcM for CisPt) and U87 MG glioblastoma (19.85 \ub1 0.97 \u3bcM versus 54.14 \ub1 3.19 for CisPt). Mesenchymal Stromal Cells (AT-MSCs) showed a significant different sensitivity (IC50=71.9 \ub1 15.1 \u3bcM for caPt(II)-complex and 8.7 \ub1 4.5 \u3bcM for CisPt) to the antiproliferative activity of caPt(II)-complex and CisPt. The ability of MSCs to uptake both the drugs in a similar amount of 2.49 pM /cell, suggested a possible development of new therapies based on cell mediated drug delivery

Interpreting and acting upon home blood pressure readings: A qualitative study

This article is made available through the Brunel Open Access Publishing Fund. Copyright @ 2013 Vasileiou et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Recent guidelines recognize the importance of home blood pressure monitoring (HBPM) as an adjunct to clinical measurements. We explored how people who have purchased and use a home blood pressure (BP) monitor make sense of, and act upon, readings and how they communicate with their doctor about the practice of home monitoring. Methods: A qualitative study was designed and participants were purposively recruited from several areas in England, UK. Semi-structured in-depth interviews were conducted with 18 users of home BP monitors. The transcribed data were thematically analysed. Results: Interpretation of home BP readings is complex, and is often characterised by uncertainty. People seek to assess value normality using ‘rules of thumb’, and often aim to identify the potential causes of the readings. This is done by drawing on lay models of BP function and by contextualising the readings to personal circumstances. Based on the perceived causes of the problematic readings, actions are initiated, mostly relating to changes in daily routines. Contacting the doctor was more likely when the problematic readings persisted and could not be easily explained, or when participants did not succeed in regulating their BP through their other interventions. Most users had notified their doctor of the practice of home monitoring, but medical involvement varied, with some participants reporting disinterest or reservations by doctors. Conclusions: Involvement from doctors can help people overcome difficulties and resolve uncertainties around the interpretation of home readings, and ensure that the rules of thumb are appropriate. Home monitoring can be used to strengthen the patient-clinician relationship

Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects