Using Dental Pulp Stem Cells for Stroke Therapy

Stroke is a leading cause of permanent disability world-wide, but aside from rehabilitation, there is currently no clinically-proven pharmaceutical or biological agent to improve neurological disability. Cell-based therapies using stem cells, such as dental pulp stem cells, are a promising alternative for treatment of neurological diseases, including stroke. The ischaemic environment in stroke affects multiple cell populations, thus stem cells, which act through cellular and molecular mechanisms, are promising candidates. The most common stem cell population studied in the neurological setting has been mesenchymal stem cells due to their accessibility. However, it is believed that neural stem cells, the resident stem cell of the adult brain, would be most appropriate for brain repair. Using reprogramming strategies, alternative sources of neural stem and progenitor cells have been explored. We postulate that a cell of closer origin to the neural lineage would be a promising candidate for reprogramming and modification towards a neural stem or progenitor cell. One such candidate population is dental pulp stem cells, which reside in the root canal of teeth. This review will focus on the neural potential of dental pulp stem cells and their investigations in the stroke setting to date, and include an overview on the use of different sources of neural stem cells in preclinical studies and clinical trials of stroke

A systematic review: efficacy of botulinum toxin in walking and quality of life in post-stroke lower limb spasticity.

BACKGROUND: Improved walking is one of the highest priorities in people living with stroke. Post-stroke lower limb spasticity (PSLLS) impedes walking and quality of life (QOL). The understanding of the evidence of improved walking and QOL following botulinum toxin (BoNTA) injection is not clear. We performed a systematic review of the randomized control trials (RCT) to evaluate the effectiveness of BoNTA injection on walking and QOL in PSLLS. METHODS: We searched PubMed, Web of Science, Embase, CINAHL, ProQuest Thesis and Dissertation checks, Google Scholar, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov , Cochrane, and ANZ and EU Clinical Trials Register for RCTs looking at improvement in walking and QOL following injection of BoNTA in PSLLS. The original search was carried out prior to 16 September 2015. We conducted an additional verifying search on CINHAL, EMBASE, and MEDLINE (via PubMed) from 16 September 2015 to 6 June 2017 using the same clauses as the previous search. Methodological quality of the individual studies was critically appraised using Joanna Briggs Institute's instrument. Only placebo-controlled RCTs looking at improvement in walking and QOL were included in the review. RESULTS: Of 2026 records, we found 107 full-text records. Amongst them, we found five RCTs qualifying our criteria. No new trials were found from the verifying search. Two independent reviewers assessed methodological validity prior to inclusion in the review using Joanna Briggs Institute's appraisal instrument. Two studies reported significant improvement in gait velocity (p = 0.020) and < 0.05, respectively. One study showed significant improvement in 2-min-walking distance (p < 0.05). QOL was recorded in one study without any significant improvement. Meta-analysis of reviewed studies could not be performed because of different methods of assessing walking ability, small sample size with large confidence interval and issues such as lack of power calculations in some studies. Findings from our systematic and detailed study identify the need for a well-designed RCT to adequately investigate the issues highlighted. CONCLUSIONS: This review could not conclude there was sufficient evidence to support or refute improvement on walking or QOL following BoNTA injection. Reasons for this are discussed, and methods for future RCTs are developed

Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation

Little is known about innate immunity and components of inflammasomes in airway epithelium. This study evaluated immunohistological evidence for NLRP3 inflammasomes in normal and inflamed murine (Balb/c) airway epithelium in a model of ovalbumin (OVA) induced allergic airway inflammation. The airway epithelium of control mice exhibited strong cytoplasmic staining for total caspase-1, ASC, and NLRP3, whereas the OVA mice exhibited strong staining for active caspase-1, with redistribution of caspase-1, IL-1β and IL-18, indicating possible activation of the NLRP3 inflammasome. Active caspase-1, NLRP3, and other inflammasome components were also detected in tissue eosinophils from OVA mice, and may potentially contribute to IL-1β and IL-18 production. In whole lung, inRNA expression of NAIP and procaspase-1 was increased in OVA mice, whereas NLRP3, IL-1β and IL-18 decreased. Some OVA-treated mice also had significantly elevated and tightly correlated serum levels of IL-1β and TNFα. In cultured normal human bronchial epithelial cells, LPS priming resulted in a significant increase in NLRP3 and II-lp protein expression. This study is the first to demonstrate NLRP3 inflammasome components in normal airway epithelium and changes with inflammation. We propose activation and/or luminal release of the inflammasome is a feature of allergic airway inflammation which may contribute to disease pathogenesis

Plasmin Generation Potential and Recanalization in Acute Ischaemic Stroke; an Observational Cohort Study of Stroke Biobank Samples

Rationale More than half of patients who receive thrombolysis for acute ischaemic stroke fail to recanalize. Elucidating biological factors which predict recanalization could identify therapeutic targets for increasing thrombolysis success. Hypothesis We hypothesize that individual patient plasmin potential, as measured by in vitro response to recombinant tissue-type plasminogen activator (rt-PA), is a biomarker of rt-PA response, and that patients with greater plasmin response are more likely to recanalize early. Methods This study will use historical samples from the Barcelona Stroke Thrombolysis Biobank, comprised of 350 pre-thrombolysis plasma samples from ischaemic stroke patients who received serial transcranial-Doppler (TCD) measurements before and after thrombolysis. The plasmin potential of each patient will be measured using the level of plasmin-antiplasmin complex (PAP) generated after in-vitro addition of rt-PA. Levels of antiplasmin, plasminogen, t-PA activity, and PAI-1 activity will also be determined. Association between plasmin potential variables and time to recanalization [assessed on serial TCD using the thrombolysis in brain ischemia (TIBI) score] will be assessed using Cox proportional hazards models, adjusted for potential confounders. Outcomes The primary outcome will be time to recanalization detected by TCD(defined as TIBI ≥4). Secondary outcomes will be recanalization within 6-h and recanalization and/or haemorrhagic transformation at 24-h. This analysis will utilize an expanded cohort including ∼120 patients from the Targeting Optimal Thrombolysis Outcomes (TOTO) study. Discussion If association between proteolytic response to rt-PA and recanalization is confirmed, future clinical treatment may customize thrombolytic therapy to maximize outcomes and minimize adverse effects for individual patients

Transient ischaemic attack (TIA) knowledge in general practice: a cross-sectional study of Western Adelaide general practitioners

Extent: 9p.Background: With evidence to support early assessment and management of TIAs, the role of the general practitioner (GP) needs to be considered in developing a TIA service in Western Adelaide. We thus aimed to determine GP knowledge of TIA assessment and management and identify perceived barriers, in order to tailor subsequent GP education and engage primary care in the co-ordinated care of TIA patients. Findings: A self-administered questionnaire was mailed to all GPs (n = 202) in the Adelaide Western General Practice Network. Response frequencies were calculated for all variables, and associations examined by univariate analysis. 32 GPs responded. All respondents correctly identified early risk of stroke following a TIA. Difficulty accessing neurological expertise was identified as a barrier (40.6 %), as was a lack of GP knowledge (18.8 %). Areas for improvement included access to neurologists (36.7 %), relevant guidelines and education (43.3 %). Conclusions: Diagnosis of TIA is difficult and this study highlights the need for further education and practical guidelines for GPs. With this training, GPs could be better equipped to assess and manage TIAs effectively in the community in consultation with stroke physicians.Elaine Stephanie Leung, Monica Anne Hamilton-Bruce, Cate Price and Simon A. Kobla

Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis.

AIM: To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis. METHODS AND RESULTS: We have generated a mouse model of endothelial-specific (Cdh5-driven) depletion of the Notch effector recombination signal binding protein for immunoglobulin kappa J region (RBPJ) [(ApoE-/-); homozygous RBPJk conditional mice (RBPJflox/flox); Cadherin 5-CreERT, tamoxifen inducible driver mice (Cdh5-CreERT)]. Endothelial-specific deletion of RBPJ or systemic deletion of Notch1 in athero-susceptible ApoE-/- mice fed a high-cholesterol diet for 6 weeks resulted in reduced atherosclerosis in the aortic arch and sinus. Intravital microscopy revealed decreased leucocyte rolling on the endothelium of ApoE-/-; RBPJflox/flox; Cdh5-CreERT mice, correlating with a lowered content of leucocytes and macrophages in the vascular wall. Transcriptome analysis revealed down-regulation of proinflammatory and endothelial activation pathways in atherosclerotic tissue of RBPJ-mutant mice. During normal Notch activation, Jagged1 signalling up-regulation in endothelial cells promotes nuclear translocation of the Notch1 intracellular domain (N1ICD) and its physical interaction with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This N1ICD-NF-κB interaction is required for reciprocal transactivation of target genes, including vascular cell adhesion molecule-1. CONCLUSIONS: Notch signalling pathway inactivation decreases leucocyte rolling, thereby preventing endothelial dysfunction and vascular inflammation. Attenuation of Notch signalling might provide a treatment strategy for atherosclerosis.This study was funded by grants SAF2013-45543R, RD12/0042/0005 (RIC) and RD12/0019/0003 (TERCEL) from the Spanish Ministry of Economy and Competitiveness (MINECO) to J.L.dlP, RD12/0042/0028 (RIC) to V.A. and RD12/0042/0053 (RIC) and SAF2012-40127 to J.M.G. M.N. held a Sara Borrell post-doctoral contract (CD09/00452) and D.M. holds a post-doctoral contract associated with grant RD12/0042/0005, both awarded by The Instituto de Salud Carlos III; B.M.P. holds a Juan de la Cierva post-doctoral contract (JCI-2010-06343). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a ‘Severo Ochoa’ Center of Excellence (MINECO award SEV-2015-0505).This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/cvr/cvw19

Calculating the speed of city bus trips: The case of Ljubljana, Slovenia

In promoting the use of public transport, an understanding of the passengers’ perspective on the provided service plays an important role. A series of factors influence people’s selection of transport mode, among which the competitiveness of travel time, or travel speed, is vital. Thanks to the widespread use of electronic payment systems, data collected through user validation can be used to calculate this speed. Thus, the actual trips made can be used to estimate their speed. This study focused on the Ljubljana bus system to analyse all trips made on a typical day. The input and output trip data were used to calculate the distance travelled, and the time and speed of the trips. In addition, an estimate was also made of how quickly the distances travelled by bus could have been travelled by bicycle or on foot. The findings showed that the speed of the bus trips analysed depends on the length of the journey: it increases with longer journeys. Bicycles are generally faster for all distances, but they become a less acceptable choice for longer distances. With regard to distances shorter than 2 km, in terms of speed, walking is competitive on only a few routes. The analyses performed using the data collected through the electronic service payment system provided useful insight into the efficiency of the public transport system from the passenger perspective, which in the future may prove useful in planning system improvements