Animal models of ischaemic stroke and characterisation of the ischaemic penumbra

Over the past forty years, animal models of focal cerebral ischaemia have allowed us to identify the critical cerebral blood flow thresholds responsible for irreversible cell death, electrical failure, inhibition of protein synthesis, energy depletion and thereby the lifespan of the potentially salvageable penumbra. They have allowed us to understand the intricate biochemical and molecular mechanisms within the ‘ischaemic cascade’ that initiate cell death in the first minutes, hours and days following stroke. Models of permanent, transient middle cerebral artery occlusion and embolic stroke have been developed each with advantages and limitations when trying to model the complex heterogeneous nature of stroke in humans. Yet despite these advances in understanding the pathophysiological mechanisms of stroke-induced cell death with numerous targets identified and drugs tested, a lack of translation to the clinic has hampered pre-clinical stroke research. With recent positive clinical trials of endovascular thrombectomy in acute ischaemic stroke the stroke community has been reinvigorated, opening up the potential for future translation of adjunctive treatments that can be given alongside thrombectomy/thrombolysis. This review discusses the major animal models of focal cerebral ischaemia highlighting their advantages and limitations. Acute imaging is crucial in longitudinal pre-clinical stroke studies in order to identify the influence of acute therapies on tissue salvage over time. Therefore, the methods of identifying potentially salvageable ischaemic penumbra are discussed

Concert recording 2016-01-26

[Track 01]. Three poems of Fiona MacLeod, op. 11. Three poems of William Sharp / Charles T. Griffes -- [Track 02]. South of north, images of Canada. Eight poems of Richard Outram / Srul Irving Glick -- [Track 03]. Songs of eternity and sorrow, op. 36a. Four poems of A.E. Housman / Ian Venables -- [Track 04]. Another reason why I don\u27t keep a gun in the house. Six songs on poems of Billy Collins / Tom Cipullo -- [Track 05]. Encore

Concert recording 2019-02-12

[Track 1] Luoghi sereni e cari ; [Track 2] Vaghissima semianza ; [Track 3] O del mio amato ben / Stefano Donaudy -- [Track 4] Ideale ; [Track 5] Non t’amo piu ; [Track 6] L’ultima canzone / Francesco Paolo Tosti -- [Track 7] The songs of travel. The vagabond ; [Track 8] Let beauty awake ; [Track 9] The roadside fire ; [Track 10] Youth and love ; [Track 11] In dreams ; [Track 12] The infinite shining heavens ; [Track 13] Whither must I wander? ; [Track 14] Bright is the ring of words ; [Track 15] I have trod the upward and the downward slope / Ralph Vaughan Williams

Concert recording 2019-02-07a

[Track 1]. Luoghi sereni e cari [Track 2]. Vaghissima semianza [Track 3]. O del mio amato ben / Stefano Donaudy -- [Track 4]. Ideale [Track 5]. Non t\u27amo piu [Track 6]. L\u27ultima canzone / Francesco Paolo Tosti -- [Track 7]. The Songs of Travel . The vagabaond [Track 8]. Let beauty awake [Track 9]. The roadside fire [Track 10]. Youth and love [Track 11]. In dreams [Track 12]. The infinite shining heavens [Track 13]. Whither must I wander? [Track 14]. Bright is the ring of words [Track 15]. I have trod the upward and the downward slope / Ralph Vaughan Williams

Concert recording 2018-02-05

[Track 1]. Come scoglio from Cosi fan tutte / Wolfgang Amadeus Mozart -- [Track 2]. Nell [Track 3]. Aprés un rêve [Track 4]. Fleur jeté / Gabriel Fauré -- [Track 5]. Depuis le jour from Louise / Gustave Charpentier -- [Track 6]. Und gestern hat er mir Rosen gebracht [Track 7]. Selige Nacht [Track 8]. Hat dich die Liebe berührt / Joseph Marx -- [Track 9]. Song to the moon from Rusalka / Antonin Dvořák -- [Track 10]. I shall not live in vain from Faces of love / Jake Heggie -- [Track 11]. Love went a-riding / Frank Bridge -- [Track 12]. Vicino a te from Andrea Chénier / Umberto Giordano

Concert recording 2016-10-20a

[Track 1]. A questo seno deh vieni, K. 374 / Wolfgang Amadeus Mozart -- [Track 2]. Alma del core / Antonio Caldara -- [Track 3]. Amarilli / Giulio Caccini -- [Track 4]. Se floridna è fedele / Alessandro Scarlatti -- [Track 5]. Già il sole dal gange / Scarlatti -- [Tracks 6-10]. On this island, op. 11 / Benjamin Britten -- [Tracks 11-13]. Selection from Acht Lieder aud letzte Blätter, op. 10 / Richard Strauss -- [Tracks 14-17]. Vier duette, op. 78 / Robert Schumann -- [Tracks 18-19]. Deux duos, op. 10 / Gabriel Faure

Combined antiapoptotic and antioxidant approach to acute neuroprotection for stroke in hypertensive rats

We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO+control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO+Ngb-expressing CAV-2, CAVNgb; tMCAO+SP600125; tMCAO+CAVNgb+SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression+SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb+SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb+SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats

Impact of stroke co-morbidities on cortical collateral flow following ischaemic stroke

Acute hyperglycaemia and chronic hypertension worsen stroke outcome but their impact on collateral perfusion, a determinant of penumbral life span, is poorly understood. Laser-speckle contrast imaging (LSCI) was used to determine the influence of these stroke comorbidities on cortical perfusion after permanent middle cerebral artery occlusion (pMCAO) in spontaneously hypertensive stroke prone rats (SHRSP) and normotensive Wistar rats. Four independent studies were conducted. In animals without pMCAO, cortical perfusion remained stable over 180 min. Following pMCAO, cortical perfusion was markedly reduced at 30 min then gradually increased, via cortical collaterals, over the subsequent 3.5 h. In the contralateral non-ischaemic hemisphere, perfusion did not change over time. Acute hyperglycaemia (in normotensive Wistar) and chronic hypertension (SHRSP) attenuated the restoration of cortical perfusion after pMCAO. Inhaled nitric oxide did not influence cortical perfusion in SHRSP following pMCAO. Thus, hyperglycaemia at the time of arterial occlusion or pre-existing hypertension impaired the dynamic recruitment of cortical collaterals after pMCAO. The impairment of collateral recruitment may contribute to the detrimental effects these comorbidities have on stroke outcome

An immunoturbidimetric assay for bovine haptoglobin

In cattle, the serum protein haptoglobin (Hp) is a major acute phase protein (APP) that rises in concentration over a thousand fold following stimulation by pro-inflammatory cytokines. As such, this APP is a valuable biomarker for infection, inflammation and trauma in cattle. The assay for bovine Hp is becoming more commonplace in clinical pathology and in experimental studies when a biomarker of innate immunity is required. The most widely used assay for Hp utilises its binding to haemoglobin (Hp-Hb binding assay), which at low pH enables the preservation of the native peroxidase activity in the haemoglobin. This assay is used for all species, including species such as dog, cat and pig where the level of Hp is higher in healthy animals of these species than in healthy cattle, and therefore a bovine-specific immunoassay that can be automated would be desirable. Thus, a novel-automated species-specific immunoturbidimetric (IT) assay has been developed. Validation studies showed intra- and inter-assay CVs of below 5% and 9% respectively and a recovery of 99% from samples spiked with bovine Hp and a limit of quantification of 0.033 g/L. The assay is not affected by icterus or lipaemia but had moderate interference from haemoglobin and showed a significant correlation with the Hp-Hb binding assay. This novel IT assay for bovine Hp will allow automated analysis of this important bovine APP to identify changes in the Hp concentration not detectable by current Hp-Hb binding assays. It will enable the incorporation of this assay into herd health assessments, animal welfare analysis and for bovine medicine and research

Positive impact of pre-stroke surgery on survival following transient focal ischemia in hypertensive rats

We describe a positive influence of pre-stroke surgery on recovery and survival in a commonly used experimental stroke model. Two groups of male, stroke-prone spontaneously hypertensive rats (SHRSPs) underwent transient middle cerebral artery occlusion (tMCAO). Group 1 underwent the procedure without any prior intervention whilst group 2 had an additional general anaesthetic 6 days prior to tMCAO for a cranial burrhole and durotomy. Post-stroke recovery was assessed using a 32 point neurological deficit score and tapered beam walk and infarct volume determined from haematoxylin–eosin stained sections. In group 2 survival was 92% (n = 12) versus 67% in group 1 (n = 18). In addition, post-tMCAO associated weight loss was significantly reduced in group 2. There was no significant difference between the two groups in experimental outcomes: infarct volume (Group 1 317 ± 18.6 mm<sup>3</sup> versus Group 2 332 ± 20.4 mm<sup>3</sup>), and serial (day 0–14 post-tMCAO) neurological deficit scores and tapered-beam walk test. Drilling a cranial burrhole under general anaesthesia prior to tMCAO in SHRSP reduced mortality and gave rise to infarct volumes and neurological deficits similar to those recorded in surviving Group 1 animals. This methodological refinement has significant implications for animal welfare and group sizes required for intervention studies