Despite challenges with poor emissions and fuel economy, gasoline two stroke engines continue to be developed for a number of applications. The primary reasons for the choice of a gasoline two stroke engine includes its low cost, mechanical simplicity and high specific power output. Some applications for the gasoline two stroke engine include small capacity motorcycles and scooters, off road recreational vehicles, hand held power tools and unmanned aerial vehicles. New technologies, which are already mature in four stroke engines, are now being applied to two stroke engines. Such technologies include direct fuel injection, electronic engine management and exhaust gas after treatment. To implement these new technologies computation models are being continuously developed to improve the design process of engines. Multi-dimensional computational fluid dynamics modelling is now commonly applied to engine research and development, it is a powerful tool that can give great insight into the thermofluid working of an engine. Multi-dimensional tools are however computationally expensive and quasi-dimensional modelling methods are often better suited for the analysis of an engine, for example in transient engine simulation. This thesis reports the development of a new quasi-dimensional combustion model for a loop scavenged two stroke engine. The model differs from other quasi-dimensional models available in the literature as it accounts for a bulk motion of the flame front due to the tumble motion created by the loop scavenge process. In this study the tumble motion is modelled as an ellipsoid vortex and the size of the vortex is defined by the combustion chamber height and a limiting elliptical aspect ratio. The limiting aspect ratio has been observed in experimental square piston compression machines and optical engines. The new model also accounts for a wrinkled flame brush thickness and its effects on the interaction between flame front and combustion chamber. The new combustion model has been validated against experimental engine tests in which the flame front propagation was measured using ionization probes. The probes were able determine the flame front shape, the bulk movement of the flame front due to tumble and also the wrinkled flame brush thickness.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background: Various randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke. Methods: Literature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models. Results: We identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR = 1.31; 95% CI 0.98–1.74, p = 0.06) and 3-month BI (MD = 6.92; 95% CI − 0.92, 14.75; p = 0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR = 1.59; 95% CI 1.19–2.12, p = 0.002; I2 = 58%) and 3-month BI (MD = 12.37; 95% CI 5.60, 19.14, p = 0.0003; I2 = 47%), whereas reduced the 3-month NIHSS (MD − 2.84; 95% CI − 5.55, − 0.13; p = 0.04; I2 = 86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion. Conclusions: Although data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients. / Revisión por pares / Revisión por pares

Prior work demonstrated that impairments in fine motor function produced by a controlled ischemic lesion in monkey primary motor cortex were ameliorated by treatment with a cell drug product, CNTO 0007. This drug contains human umbilical tissue-derived cells, in a proprietary thaw and inject formulation. Brain tissue sections from subjects with and without CNTO 0007 therapy were processed immunohistochemically to identify neurons expressing c-Fos as a marker for neuronal activity. Neurons expressing c-Fos were quantified using unbiased stereology. The number of c-Fos positive neurons in dorsal pre-motor cortex ipsilateral to the lesion were greater in treated animals but only approached statistical significance. These findings suggest that cortical reorganization in the dorsal pre-motor cortex may underlie the observed functional recovery. However, c-Fos expressing neurons in other motor areas, such as the ventral pre-motor cortex, remain to be studied.

Focal ischemic stroke cause alterations of the brain’s inherent excitation – inhibition balance in neurons around the infarct, and in distant areas connected to the damaged region. These widespread changes contribute to symptomatology and reduce activity in areas that have the capacity to functionally compensate for the effect of the focal lesion. The ability to control excitability in specific brain areas after stroke could restore normal excitability and promote functional recovery. Non-invasive brain stimulation techniques have the potential to produce targeted change in excitability in neural tissue. One such technique, transcranial direct current stimulation (tDCS), modulates cortical excitability in a lasting, polarity-specific manner. The hypotheses of this study were that 1) focal unilateral ischemic damage to the parietal cortex would produce repeatable alterations in the inhibitory network in ipsilateral and contralateral brain areas, and 2) tDCS applied after ischemia would alter the size of the lesion change the inhibitory networks. A unilateral non-invasive photothrombic stroke was produced under isoflurane anesthesia, and cathodal (n=5), anodal (n=5), or sham (n=6) tDCS (5 minutes, 10.0mA) was subsequently administered to the site. Four additional animals were assigned to sham operation groups that did not undergo photothrombosis. Animals recovered for 24 hours, after which their brains were cut, and prepared for single- and double-labeled immunocytochemistry to analyze the functional activity of excitatory neurons and inhibitory interneurons, astrogliosis, and neuronal degeneration. Results demonstrate that unilateral ischemic injury does not produce a hyperexcitability of the contralateral cortex or otherwise alter the activation status of immunohistochemcially-defined inhibitory or disinhibitory neurons, a finding discrepant with the rationale used to treat ischemic injury in humans. Similar findings were identified in the ipsilateral cortex. Results did show that ischemia activated white matter neurons, as well as neurons in layer III ipsilateral to the lesion extending 1-2mm into the intact cortex. Neurons degenerating as observed by Fluoro-Jade B revealed clusters of pyramidal-shaped neurons in layer V which extended quite far from the lesion site. Addition of cathodal, but not anodal tDCS produced an overall decrease in the lesion size, but this decrease was not statistically reliable. Stimulation also did not obviously alter the activation status of inhibitory or disinhibitory neurons. Both types of stimulation prevented the appearance of degenerating cells in layer V, and anodal tDCS reduced the activation of excitatory layer III excitatory neurons. These findings illustrate the utility of using tDCS during the production of a lesion to mitigate the size and impact of lesion and raises questions on the rationale rationale for applying brain stimulation to the contralesional cortex to treat stroke, at least in the acute stage. Finally, the series of studies here illustrate the extent to which the lesion causes widespread and specific neural circuits, and highlights the potential of tDCS use in manipulating the activity of these circuits.

Given the difficulty in predicting outcomes in persons with stroke-induced aphasia (PWA), neuroimaging-based biomarkers of recovery could provide invaluable predictive power to stroke models. However, the neural patterns that constitute beneficial neural organization of language in PWA remain debated. Thus, in this work, we propose a novel network theory of aphasia recovery and test our overarching hypothesis, i.e., that task-specific language processing in PWA requires the dynamic engagement of intact tissue within a bilateral network of anatomically-segregated but functionally and structurally connected language-specific and domain-general brain regions. We first present two studies in which we examined left frontotemporal connectivity during different language tasks (i.e., picture naming and semantic feature verification). Results suggest that PWA heavily rely on left middle frontal gyrus (LMFG)-driven connectivity for tasks requiring lexical-semantic processing and semantic control whereas controls prefer models with input to either LMFG or left inferior frontal gyrus (LIFG). Both studies also revealed several significant associations between spared tissue, connectivity and language skills in PWA. In the third study, we examined bilateral frontotemporoparietal connectivity and tested a lesion- and connectivity-based hierarchical model of chronic aphasia recovery. Between-group comparisons showed controls exhibited stronger left intra-hemispheric task-modulated connectivity than did PWA. Connectivity and language deficit patterns most closely matched predictions for patients with primarily anterior damage whereas connectivity results for patients with other lesion types were best explained by the nature of the semantic task. In the last study, we investigated the utility of lesion classification based on gray matter (GM) only versus combined GM plus white matter (WM) metrics. Results suggest GM only classification was sufficient for characterizing aphasia and anomia severity but the GM+WM classification better predicted naming treatment outcomes. We also found that fractional anisotropy of left WM association tracts predicted baseline naming and treatment outcomes independent of total lesion volume. Finally, results of a preliminary multimodal prediction analysis suggest that combined structural and functional metrics reflecting the integrity of regions and connections comprise optimal predictive models of behavior in PWA. To conclude this dissertation, we discuss how multimodal network models of aphasia recovery can guide future investigations. / 2020-10-23T00:00:00Z

Background: Chinese populations have been reported to have a higher stroke incidence as well as different stroke epidemiology compared with white populations. However, reliable comparisons have been precluded by a lack of methodologically robust studies. I aimed to systematically evaluate the incidence of stroke, the distribution of its main types/subtypes, and risk factor distributions among stroke types/subtypes in Chinese, and to compare these with data from white populations. Methods: I performed a series of systematic reviews and meta-analyses of studies conducted since 1990 which had data on (1) incidence of stroke, (2) pathological types of stroke or ischaemic stroke subtypes, and (3) frequency of risk factors among pathological types of stroke or ischaemic stroke (IS) subtypes in Chinese populations, and in white populations for comparison. I calculated age-standardized stroke incidence and the proportions of each pathological type and ischaemic subtype. For each risk factor, I calculated study-specific and pooled odds ratios (ORs) using a random effects model for intracerebral haemorrhage (ICH) versus IS, for each IS subtype versus other subtypes, and for overall IS patients, comparing findings for Chinese versus Whites. In addition, I conducted individual patient analyses of data from the National Taiwan University Hospital (NTUH) Stroke Registry, which consecutively recruited 6675 acute stroke patients from 2006-2011, comparing risk factor profiles among stroke types and subtypes and using logistic regression to adjust for potential confounding factors. Results: From my systematic reviews, I found a younger onset of stroke, a slightly higher overall stroke incidence and higher proportion of ICH in Chinese versus white populations. Although the overall proportion of lacunar infarct appeared higher in Chinese from hospital-based studies than white populations, confirming the different distributions of ischaemic subtypes will need further comparable population-based studies. In my meta-analyses comparing risk factors for ICH versus IS, in Chinese - but not Whites – hypertension (HTN) and alcohol intake were significantly more frequent, while mean age was lower in ICH than IS. In IS, the overall prevalence of hypertension, diabetes, smoking, and alcohol intake were similar between Chinese and white IS patients, whereas hypercholesterolaemia, ischaemic heart disease (IHD) and atrial fibrillation (AF) were less common in Chinese IS patients. As for IS subtypes, the relative frequencies of risk factors were mostly qualitatively similar (although different in size) in Chinese and white populations. Compared with other ischaemic subtypes: large artery atherosclerosis (LAA) strokes were associated with diabetes; cardioembolic (CE) strokes were associated with AF and IHD; small vessel disease (SVD) strokes or lacunar strokes were associated with hypertension and diabetes. Analyses of NTUH individual patient data showed that HTN and alcohol intake were independent risk factors for ICH versus IS in a Chinese population in Taiwan, regardless of age, sex, or other risk factors. The results were consistent with my previous risk factor meta-analyses for ICH versus IS. In IS analyses, the prevalence of hypertension, diabetes, AF, and hyperlipidaemia in overall IS patients based in Taiwan were higher than the pooled results in my risk factor meta-analysis for IS for all Chinese populations including mainland China. In terms of risk factor associations with IS subtypes, the findings after controlling for potential confounders were mostly close to my previous meta-analysis results with the exception of stronger associations of hypertension and diabetes with SVD (lacunar) strokes. Conclusion: I have shown a younger onset of stroke, a higher overall stroke incidence, an around twofold higher proportion of ICH and different distribution of IS subtypes, as well as some differences in risk factor distributions among pathological types of stroke and IS subtypes in Chinese compared with white populations. My results help to inform us of different stroke mechanisms in different populations, to guide further well-designed research in this area, and to direct better strategies for stroke prevention in Chinese populations.

The remapping of cortical networks after stroke is hypothesized to be one of the mechanisms subserving functional recovery. Our understanding of cortical remapping remains limited due to the inability to resolve which cells are active while performing motor tasks with high temporal and spatial specificity. The experiments presented in the first chapter of this thesis evaluate the ability of the inducible Arc-CreERT2:Rosa-YFPf/f model to label cells in the motor cortex activated by a motor-related behaviour. Through the modification of previously published 4-hydroxytamoxifen treatment paradigms, this model can differentiate between animals that performed the rotarod task at two time points and home cage controls. In addition, 65% of cells active at the first behavioural time point are reactivated. Taken together, these data suggest that the Arc-CreERT2:Rosa-YFPf/f model is able to reliably label networks used to perform the same behavioural task at two time points. The second chapter of this thesis details a pilot study in which the Arc-CreERT2:Rosa-ChR2:YFPf/f model was used to test the effect of daily optogenetic stimulation of the contralateral cortex on functional recovery. The results of this chapter suggest that stimulating the contralesional motor cortex may impair functional recovery. Overall, the results of this thesis lay the foundation to use this model to investigate motor networks in both naïve and pathological conditions, such as stroke.

The original description of the ischaemic penumbra asserted that both cerebral blood flow and metabolism would be required to monitor therapeutic intervention in acute ischaemic stroke. However, imaging in stroke trials has predominantly used biomarkers of infarction or perfusion-weighted signal to identify the pathophysiological processes that occur. This approach has neither identified novel treatment targets, nor been shown to consistently select patients who might benefit from intervention. The aim of this thesis was to use magnetic resonance imaging (MRI) biomarkers to identify and describe the pathophysiology of acute ischaemic stroke in patients. Patients admitted to the John Radcliffe Hospital in Oxford were recruited into a clinical imaging study. Serial imaging data were acquired, predominantly in the first hours after symptom onset, to capture the early dynamics of brain pathophysiology. Tissue status was meticulously defined over time to ensure robust interpretation of the novel imaging biomarkers: multiple post labeling delay arterial spin labeling to measure cerebral blood flow (CBF), and amide proton transfer to generate an intracellular pH-weighted signal. At a group level, the regions with the most severe injury had the lowest mean CBF and the greatest acidosis at presentation. There was a gradient of mean CBF and pH-weighted signal from the most ischaemic tissue to healthy tissue, but at the level of the individual there was considerable overlap in both parameters. The dynamics of perfusion were not sufficient to explain tissue outcome. Both acidosis and alkalosis were observed up to 24 hours in tissue that infarcted, and the nature of the pH change correlated with the timing of infarction. These data show that single imaging biomarkers cannot explain the pathophysiology of stroke and tissue fate. There is heterogeneity of pathophysiology both within and between patients, and the dynamics of these processes vary. Insight from pH-weighted imaging highlights the limitations of using perfusion imaging alone to assess tissue status, and supports the use of complementary metabolic imaging in the investigation of ischaemic stroke.

Engine manufactures are currently seeking to develop spark ignition engines that are more fuel efficient, more refined and produce lower amounts of polluting emissions. To achieve these objectives an improved understanding of the factors governing the combustion process is required. Engine in-cylinder fluid motion is known to fundamentally affect fuel–air mixture preparation and flame propagation. Therefore, characterisation and quantification of the in-cylinder flow is an important step in the process of achieving the conditions necessary for optimal combustion. This thesis reports the application of two-colour Particle Image Velocimetry (PIV) to measure extended velocity fields within the combustion chamber of a firing production geometry optical engine. Two-colour PIV was used to obtain high spatial resolution fluid velocity maps for a range of crank angles and engine conditions. PIV measurements were obtained in the unburned gas ahead of the propagating flame and a combustible seeding material was used to clearly define the burned gas region. Data is presented for both the normal 2-valve running conditions and with one inlet port deactivated for both open-valve and closed-valve fuel injection timing.

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