Monica Anne Hamilton-Bruce

Human Adult Dental Pulp Stem Cells Enhance Poststroke Functional Recovery Through Non-Neural Replacement Mechanisms

Human adult dental pulp stem cells (DPSCs), derived from third molar teeth, are multipotent and have the capacity to differentiate into neurons under inductive conditions both in vitro and following transplantation into the avian embryo. In this study, we demonstrate that the intracerebral transplantation of human DPSCs 24 hours following focal cerebral ischemia in a rodent model resulted in significant improvement in forelimb sensorimotor function at 4 weeks post‐treatment. At this time, 2.3 ± 0.7% of engrafted cells had survived in the poststroke brain and demonstrated targeted migration toward the stroke lesion. In the peri‐infarct striatum, transplanted DPSCs differentiated into astrocytes in preference to neurons. Our data suggest that the dominant mechanism of action underlying DPSC treatment that resulted in enhanced functional recovery is unlikely to be due to neural replacement. Functional improvement is more likely to be mediated through DPSC‐dependent paracrine effects. This study provides preclinical evidence for the future use of human DPSCs in cell therapy to improve outcome in stroke patients.

Tissue Plasminogen Activator −7351C/T Enhancer Polymorphism Is a Risk Factor for Lacunar Stroke

Background and Purpose— Occlusive thrombosis is an important component of small- and large-vessel ischemic stroke. Endogenous tissue plasminogen activator (TPA) is the primary mediator of intravascular fibrinolysis and is predominantly expressed by the endothelium of small vessels. The acute release of TPA is influenced by the TPA −7351C/T polymorphism and therefore may play an important role in the pathogenesis of lacunar stroke. In this study, we investigated the risk of lacunar and nonlacunar ischemic stroke associated with the TPA −7351C/T polymorphism. Methods— We conducted a case-control study of 182 cases of ischemic stroke and 301 community controls. Participants were evaluated for known cerebrovascular risk factors, and the TPA −7351C/T genotype was established by a polymerase chain reaction (PCR) method. Logistic regression was used to determine the risk of lacunar and nonlacunar ischemic stroke associated with the TPA −7351C/T polymorphism. Results— The prevalence of the TPA −7351 CC, CT, and TT genotypes were 46%, 45%, and 9% for controls and 41%, 46%, and 13% for stroke patients, respectively. After adjustment for known cerebrovascular risk factors, the TT genotype was significantly associated with ischemic stroke (OR: 1.9; 95% CI: 1.01 to 3.6). Stratification for stroke subtype showed a significant association between the TT genotype and lacunar stroke but not nonlacunar stroke (OR: 2.7; 95% CI: 1.1 to 6.7). Conclusions— The TPA −7351C/T polymorphism is an independent risk factor for lacunar stroke. The findings suggest that impaired fibrinolysis may play a role in the pathogenesis of lacunar stroke.

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.

Genetic variation at 16q24.2 is associated with small vessel stroke

Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke.

Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: a systematic review and meta-analysis

Stem cells have demonstrated encouraging potential as reparative therapy for patients suffering from post-stroke disability. Reperfusion interventions in the acute phase of stroke have shown significant benefit but are limited by a narrow window of opportunity in which they are beneficial. Thereafter, rehabilitation is the only intervention available. The current review summarises the current evidence for use of stem cell therapies in stroke from early-phase clinical trials. The safety and feasibility of administering different types of stem cell therapies in stroke seem to be reasonably proven. However, the effectiveness needs still to be established through bigger clinical trials with more pragmatic clinical trial designs that address the challenges raised by the heterogeneous nature of stroke per se, as well those due to unique characteristics of stem cells as therapeutic agents.

TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke

Rationale Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability. Aims TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy; (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke; and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial. Methods and design TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task-specific rehabilitation. Advanced magnetic resonance and positron emission tomography neuro-imaging, and clinical assessment will be employed to probe any change afforded by stem cell therapy in combination with rehabilitation. Sample size estimates Nine participants will step-wise progress in Stage 2 to a dose of up to 10 million dental pulp stem cell, employing a cumulative 3 + 3 statistical design with low starting stem cell dose and subsequent dose escalation, assuming that an acceptable probability of dose-limiting complications is between 1 in 6 (17%) and 1 in 3 (33%) of patients. In Stage 3, another 18 participants will receive an intracranial injection with the maximum tolerable dose of dental pulp stem cell. Outcomes The primary outcomes to be measured are safety and feasibility of intracranial administration of autologous human adult DPSC in patients with chronic stroke and determination of the maximum tolerable dose in human subjects. Secondary outcomes include estimation of the measures of effectiveness required to design a future Phase 2/3 clinical trial.

Transient Ischaemic Attack (TIA) Knowledge in General Practice: a cross-sectional study of Western Adelaide general practitioners

BackgroundWith 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.FindingsA 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 %).ConclusionsDiagnosis 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.

Stem cell therapy clinical research: A regulatory conundrum for academia.

Abstract The encouraging pace of discovery and development in the field of regenerative medicine holds tremendous potential for bringing therapies to the clinic that may offer meaningful benefit to patients, particularly in diseases with no or suboptimal therapeutic options. Academic researchers will continue to play a critical role in developing concepts and therapies, thus determining whether regenerative medicine will be able to live up to this potential that clearly excites clinicians, researchers and patients alike. This review summarises recent developments in regulatory frameworks across different countries that aim to ensure adequate oversight of the development of regenerative medicine products, which are unique in structural and functional complexity when compared to traditional chemical drugs and fully characterised biological drugs. It discusses the implications of these developments for researchers aiming to make the challenging transition from laboratory to clinical development of these therapies and considers possible pragmatic solutions that could accelerate this process that is essential to maintain research credibility and ensure patient safety. Graphical abstract Figure. No Caption available.

The Origins of Compassion for Animals: Legal Privileging of Non-Wild Animals in Late Georgian Britain

In 1822, towards the end of the Georgian period in Britain, the first substantial law was enacted to protect some animals from human abuse: An Act to Prevent the Cruel and Improper Treatment of Cattle, brought before Parliament by Colonel Richard Martin. This article traces the origins and extension of compassion for animals in late Georgian Britain through visual media, bills, legislation, and other materials. These various forms of communication were all aimed at heightening public concern for mistreated animals and at relieving their suffering through legislative means. The analysis shows how non-wild and wild animals were perceived at the time and how the law reflected these views. Rather than offer hard and fast definitions of the terms “wild” and “non-wild,” we show how their meanings evolved in historical context. The article begins with a discussion of how compassion for animals was engendered through the printed works by William Hogarth and the writings of a number of early animal-welfare advocates, notably John Lawrence and Humphry Primatt. Their work is a useful gauge of what society knew about animal suffering at the time and which attitudes subsequently took hold. We then discuss how animal suffering began to be debated in the British Parliament, with Colonel Richard Martin and Lord Thomas Erskine leading the way. It is clear that Parliament did not seem particularly interested at the time in being compassionate to wild animals. Indeed, there was an effort to

Significant increase in thrombolysis therapy rates for stroke in South Australia

Andrew W. O. Moey, Monica A. Hamilton-Bruce, Stuart Howell, James M. Leyden, Woon K. Chong, Lizzie Dodd, Austin G. Milton, Simon A. Koblar, Timothy J. Kleinig, Andrew W. Lee, and Jim Jannes