Stuart Howell

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.

Allogeneic Mesenchymal Precursor Cells Promote Healing in Postero-lateral Annular Lesions and Improve Indices of Lumbar Intervertebral Disc Degeneration in an Ovine Model

Study Design. In-vivo ovine model of intervertebral disc degeneration (IVD) to evaluate treatment with stem cells. Objective. To determine if stem cells delivered to the nucleus pulposus (NP) or the annulus fibrosus (AF) of degenerated lumbar IVDs leads to improved indices of disc health. Summary of Background Data. Previous studies assessing the efficacy of stem cell injections into degenerated IVDs have reported positive findings. However, studies have been limited to small animals, targeting solely the NP, with short term follow-up. Methods. Mesenchymal precursor cells (MSC) were obtained from the iliac crest of 8-week-old sheep. IVD degeneration was induced by postero-lateral annulotomy at three lumbar levels in eight 2-year-old sheep. Six months later, each degenerated IVD was randomized to one of three treatments: Injection of MSC into (i) previously incised AF (AFI), (ii) NP (NPI), or (iii) no injection (negative control, NC). The adjacent IVD received injection of phosphate buffered saline into NP (positive control, PC). Radiographs and magnetic resonance imaging scans were obtained at baseline, 6, 9, and 12 months. Discs were harvested at 12 months for biochemical and histological analyses. Results. IVD degeneration was consistently observed postannulotomy, and characterized by reduced disc height index (DHI), disc height (DH), glycosaminoglycan (GAG) content, and increased grade of disc degeneration. Six months after stem cell injection, DHI and DH had recovered in AFI and NPI groups when compared with NC group (P < 0.01). Mean Pfirrmann grade improved from 3.25 to 2.67 (AFI group) and from 2.96 to 2.43 (NPI group). Mean histopathological grade improved for both AFI (P < 0.002) and NPI (P < 0.02) groups. Both AFI and NPI groups demonstrated spontaneous repair of the postero-lateral annular lesion. Conclusion. In this large animal model, injection of MSCs into the annulus fibrosus or the nucleus pulposus of degenerated IVD resulted in significant improvements in disc health. Level of Evidence: N/A

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

BackgroundImproved 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.MethodsWe 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.ResultsOf 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.ConclusionsThis 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.

Self-reported fitness of American Society of Anesthesiologists class 3 patients undergoing endovascular aneurysm repair predicts patient survival

BACKGROUND Most patients undergoing elective endovascular aneurysm repair (EVAR) are classified American Society of Anesthesiologists (ASA) 3. However, the severity of systemic disease among these patients can vary, resulting in markedly different levels of fitness. In this study, we explored the hypothesis that ASA 3 patients with good self-reported exercise tolerance have better survival after EVAR. METHODS Data for EVAR patients classified ASA 3 were extracted retrospectively from a prospectively collected registry database. Patients were split into two groups according to fitness level, based on their self-reported ability to climb stairs or to walk briskly for 1 km. Patient survival for each group was assessed by Cox proportional hazards models. RESULTS During follow-up of 392 patients for a mean of 1.9 years, there were 64 deaths (16.3%), 13.4% in the more physically able group and 21.6% in the less able group. Self-reported inability to walk or to climb stairs was associated with increased risk of all-cause mortality (hazard ratio, 3.55; P < .0001). Following risk adjustment for a number of possible confounding variables, fitness remained significant (hazard ratio, 3.03; P = .0011). CONCLUSIONS This study has shown that among ASA 3 patients, self-reported exercise capacity is an excellent means of predicting survival. Physicians should consider the physical fitness of their ASA 3 patients when discussing treatment options.

Bone Marrow Recovery by Morphometry during Induction Chemotherapy for Acute Lymphoblastic Leukemia in Children

Bone marrow architecture is grossly distorted at the diagnosis of ALL and details of the morphological changes that accompany response to Induction chemotherapy have not been reported before. While marrow aspirates are widely used to assess initial response to ALL therapy and provide some indications, we have enumerated marrow components using morphometric analysis of trephine samples with the aim of achieving a greater understanding of changes in bone marrow niches. Morphometric analyses were carried out in the bone marrow trephine samples of 44 children with ALL, using a NanoZoomer HT digital scanner. Diagnostic samples were compared to those of 32 control patients with solid tumors but without marrow involvement. Samples from patients with ALL had significantly increased fibrosis and the area occupied by bony trabeculae was lower than in controls. Cellularity was higher in ALL samples due to leukemic infiltration while the percentage of normal elements such as megakaryocytes, adipocytes, osteoblasts and osteoclasts were all significantly lower. During the course of Induction therapy, there was a decrease in the cellularity of ALL samples at day 15 of therapy with a further decrease at the end of Induction and an increase in the area occupied by adipocytes and the width of sinusoids. Reticulin fibrosis decreased throughout Induction. Megakaryocytes increased, osteoblasts and osteoclasts remained unchanged. No correlation was found between clinical presentation, early response to treatment and morphological changes. Our results provide a morphological background to further studies of bone marrow stroma in ALL.

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

Evaluation of human coronary vasodilator function predicts future coronary atheroma progression

Objective Coronary vasodilator function and atherosclerotic plaque progression have both been shown to be associated with adverse cardiovascular events. However, the relationship between these factors and the lipid burden of coronary plaque remains unknown. These experiments focus on investigating the relationship between impaired coronary vasodilator function (endothelium dependent (salbutamol) and endothelium independent (glyceryl trinitrate)) and the natural history of atheroma plaque progression and lipid burden using dual modality intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. Methods 33 patients with stable chest pain or acute coronary syndrome underwent serial assessment of coronary vasodilator function and intracoronary plaque IVUS and NIRS imaging. Coronary segmental macrovascular response (% change segmental lumen volume (ΔSLV)), plaque burden (per cent atheroma volume (PAV)), lipid core (lipid-rich plaque (LRP) and lipid core burden index (LCBI)) were measured at baseline and after an interval of 12–18 months (n=520 segments). Results Lipid-negative coronary segments which develop into LRP over the study time period demonstrated impaired endothelial-dependent function (−0.24±2.96 vs 5.60±1.47%, P=0.04) and endothelial-independent function (13.91±4.45 vs 21.19±3.19%, P=0.036), at baseline. By multivariate analysis, endothelial-dependent function predicted ∆LCBI (β coefficient: −3.03, 95% CI (−5.81 to −0.25), P=0.033) whereas endothelial-independent function predicted ∆PAV (β coefficient: 0.07, 95% CI (0.04 to 0.10), P<0.0001). Conclusions Epicardial coronary vasodilator function is a determinant of future atheroma progression and composition irrespective of the nature of clinical presentation. Trial registration number ACTRN12612000594820, Post-results.