Motivation: Ischemic heart disease is the eighth leading cause of death in an African population. Silent ischemia can be defined as an ischemic episode without associated pain. The clinical significance of silent ischemia is growing and can now be considered as a risk factor in the development of coronary disease. Hypertension and associated risk factors, hypercholesterolemia and diabetes are associated with silent ischemia. Other factors such as higher pulse pressure, double product, heart rate and higher carotid intima-media thickness are also associated with silent ischemia. Urbanisation is rising in South-Africa. This new lifestyle is associated with several risk factors including: poor diets, lower physical activity levels, hypertension and increased smoking and alcohol abuse. The prevalence of stroke is high among Africans, which can be due to a higher prevalence of hypertension, diabetes and obesity. Purpose: The purpose of this study was to determine the associations between silent ischemia and cardiovascular function in African men. The focus fell on hypertension and associated risk factors, higher total cholesterol levels, and increased pulse pressure, heart rate and sub-clinical atherosclerosis. vi Methodology: This study constituted a population study in the North-West province carried out on urbanized African male teachers aged between 20-60 years. The SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) sub-study consisted of a total of 80 African male volunteers. The Cardiotens apparatus was placed on each participant on the first morning. This apparatus took ambulatory blood pressure measurements as well as Electrocardiogram measurements. Hereafter, participants continued with their normal work day until 1700. After an overnight stay at the Metabolic unit of the North-West University Potchefstroom campus, the apparatus was removed at 0600. During statistical analyses, the African males were divided into groups of participants with silent ischemia (SI) and those without silent ischemia (nSI), as determined by the ambulatory electrocardiogram. Statistical analyses were performed by means of the Statistica version 10 software program. Results: In comparison with the nSI men, the SI showed the following: above normal high sensitivity C-reactive protein and glucose, higher ambulatory blood pressure, heart rate, pulse pressure, resting ST-segment depression and carotid intima-media thickness. Multiple regression analyses indicated that ambulatory silent ischemia is associated with sub-clinical atherosclerosis, possibly increasing their stroke risk. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2012.

Implications for the endocannabinoid system in global cerebral ischemia has not been clearly defined. Ischemia produces an excitotoxic environment that is severely damaging to neurons, causing degradation of cell membrane and ultimately cell death. Contradicting research suggests both the benefits and adverse effects of endocannabinoids on neurological injury. Due to the excitotoxic nature of ischemic injury, and the mechanisms at play with endocannabinoid agonists, such as increased transmission of dopamine and glutamate, it is suspected that endocannabinoid antagonists, such as AM251, may a provide cell protection.40 male Wistar rats were separated into 4 groups (n=10/group). The first group of rats were administered AM251 (2 mg/kg, i.p) 30 minutes prior to global cerebral ischemia (four vessel occlusion), while the second group were given AM251, 30 minutes prior to sham surgery. Finally the last two groups were given a vehicle control instead of AM251 and given either ischemia or the sham surgery. Behavioural testing, open field test and elevated plus maze, took place after a five day recovery period following ischemia. Immunohistochemical analyses were performed using to mark tyrosine hydroxylase (TH) and dopamine receptor 1(DRD1) to compare dopamine function amongst groups. Cell survival was also evaluated using thionin staining. Ischemia induced significant reduction in dopamine within the mesolimbic circuit, including: ventral tegmental area, nucleus accumbens, CA3 & CA1 of the hippocampus, and basolateral amygdala. These reductions in dopamine transmission by global ischemia were partially or fully reversed when AM251 was given beforehand. Furthermore, cell survival was increased in the CA1 from treatment of AM251. Behavioural results show similar results that AM251 reversed emotional irregularities associated with ischemia insult. The endocannabinoid antagonist AM251 improves deficits in dopamine function, prevents cell death and regulates emotionality when given prior global cerebral ischemia.

Motivation: Ischemic heart disease is the eighth leading cause of death in an African population. Silent ischemia can be defined as an ischemic episode without associated pain. The clinical significance of silent ischemia is growing and can now be considered as a risk factor in the development of coronary disease. Hypertension and associated risk factors, hypercholesterolemia and diabetes are associated with silent ischemia. Other factors such as higher pulse pressure, double product, heart rate and higher carotid intima-media thickness are also associated with silent ischemia. Urbanisation is rising in South-Africa. This new lifestyle is associated with several risk factors including: poor diets, lower physical activity levels, hypertension and increased smoking and alcohol abuse. The prevalence of stroke is high among Africans, which can be due to a higher prevalence of hypertension, diabetes and obesity. Purpose: The purpose of this study was to determine the associations between silent ischemia and cardiovascular function in African men. The focus fell on hypertension and associated risk factors, higher total cholesterol levels, and increased pulse pressure, heart rate and sub-clinical atherosclerosis. vi Methodology: This study constituted a population study in the North-West province carried out on urbanized African male teachers aged between 20-60 years. The SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) sub-study consisted of a total of 80 African male volunteers. The Cardiotens apparatus was placed on each participant on the first morning. This apparatus took ambulatory blood pressure measurements as well as Electrocardiogram measurements. Hereafter, participants continued with their normal work day until 1700. After an overnight stay at the Metabolic unit of the North-West University Potchefstroom campus, the apparatus was removed at 0600. During statistical analyses, the African males were divided into groups of participants with silent ischemia (SI) and those without silent ischemia (nSI), as determined by the ambulatory electrocardiogram. Statistical analyses were performed by means of the Statistica version 10 software program. Results: In comparison with the nSI men, the SI showed the following: above normal high sensitivity C-reactive protein and glucose, higher ambulatory blood pressure, heart rate, pulse pressure, resting ST-segment depression and carotid intima-media thickness. Multiple regression analyses indicated that ambulatory silent ischemia is associated with sub-clinical atherosclerosis, possibly increasing their stroke risk. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2012.

Tyrimo tikslas: ištirti kavos rūgšties fenetilo esterio (CAFE) poveikį išemijos paveiktų žiurkės inkstų mitochondrijų funkcijoms. Uždaviniai: įvertinti tiesioginį in vitro CAFE poveikį inkstų mitochondrijų funkcijoms; CAFE poveikį išemijos (20 min) in vitro paveiktų inkstų mitochondrijų funkcijoms; kvėpavimo grandinės I komplekso aktyvumui; mitochondrijų gebėjimui kaupti Ca2+. Metodai. Wistar veislės žiurkių patinėliai buvo skirstomi į 4 grupes: kontrolinė grupė, 20 min trukmės išemijos, CAFE 22 mg/kg ir CAFE 34 mg/kg. CAFE buvo leidžiamas 1,5 h prieš sukeliant išemiją. Mitochondrijos buvo išskiriamos diferencinio centrifugavimo būdu. Mitochondrijų kvėpavimo greitis mitochondrijoms oksiduojant I ir II komplekso substratus buvo registruojamas poliarografiškai Klarko tipo elektrodu. Ca2+ sugėrimas buvo matuojamas fluorimetriškai. Mitochondrijų kvėpavimo grandinės I komplekso aktyvumas buvo tiriamas spektrofotometriškai. Rezultatai: CAFE (0,7 – 4,5 M) didina mitochondrijų kvėpavimo greitį 2-oje metabolinėje būsenoje nuo 15 % iki 34 % ir neveikė mitochondrijų kvėpavimo greičio 3-ioje metabolinėje būsenoje (VADP). Didesnės koncentracijos (5,2 - 6,5 µM) slopina mitochondrijų kvėpavimo greitį VADP (16 % ir 43 % atitinkamai). Tiriant CAFE poveikį 20 min išemijos in vitro paveiktų mitochondrijų funkcijoms, nustatyta, jog 22 mg/kg ir 34 mg/kg CAFE, intraperitonealinė injekcija 1,5 h prieš sukeliant inkstų išemiją, 20 % (p<0,05) pagerino mitochondrijų kvėpavimo greitį VADP bei... [toliau žr. visą tekstą] / The aim of investigation: to analyse the effect of caffeic acid phenethyl ester (CAPE) on kidney mitochodrial functions. Objectives: to evaluate direct in vitro effect of CAPE on kidney mitochondrial functions; the impact of CAPE on ischemia (20 min) in vitro affected kidney mitochondrial functions; on the mitochondrial respiratory chain complex I activity and on the mitochondria capability to accumulate Ca2+. Methods. Wistar rats were pretreated intraperitoneal with 22 mg/kg and 34 mg/kg of CAPE. Animals were divided into 4 groups: control group, 20 min of ischemia, CAPE 22 mg/kg group and CAPE 34 mg/kg group. Mitochondria were isolated by means of differential centrifugation. The mitochondrial respiration rate while oxidizing complex I and II dependent substrates was registered polarographically with Clark-type electrode. Ca2+ accumulation was measured fluorometrically. Activity of complex I was measured spectrophotometrically. Results: the results shown that CAPE 0,7 - 4,5 µM increases mitochondrial State 2 respiration rate by 15 - 34 % and has no effect on the State 3 respiration rate. Higher concentrations (5,2 - 6,5 µM) decreased mitochondrial State 3 respiration rate by 16% and 43%, respectively. Pretreatment with CAPE (22 mg/kg and 34 mg/kg) increased (by 20%) the ischemia suppressed mitochondrial State 3 respiration rate and respiratory control index. CAPE had no effect on succinate oxydation. Pretreatment with CAPE (22 mg/kg and 34 mg/kg) increased Ca2+... [to full text]

The present thesis investigated the effects of a western diet (WD) on cell death and functional outcome following global ischemia in rats. Experiment 1 assessed the effects of a 60-day WD regimen on temperature, activity and glucose levels in normal rats. Experiment 2 evaluated the influence of a 60-day WD regimen on hippocampal CA1 injury and cognition following global ischemia. Results from experiment 1 revealed significant differences in activity levels only; animals fed the WD were less active than control diet animals. Results from experiment 2 suggested that a WD did not aggravate CA1 injury or behavioral deficits. The second portion of my thesis examined the effects of a 120-day WD regimen on stroke severity and cognition following global ischemia. Briefly, the surgical protocol used to induce a global ischemic insult did not produce consistent damage across all animals. Plausible reasons for this surgical variability and future directions are discussed.

No description available.

Referred pain is frequently associated with misdiagnosis and unnecessary therapy directed to the pain location instead of its origin. When craniofacial pain is the sole symptom of myocardial ischemia, failure to recognize its cardiac source can endanger the patient. In particular, patients with acute myocardial infarction (AMI) who do not experience chest pain run a very high risk of misdiagnosis and death. Pain that is limited to the craniofacial region during myocardial ischemia has so far been described only in case reports and its overall prevalence is unknown. Experimental research in animals suggests a vagal involvement in the pathological mechanisms of cardiac pain referred to the face. The aim of this study was to gain knowledge about the prevalence, clinical characteristics and possible mechanisms of craniofacial pain of cardiac origin, in order to improve the clinician’s ability to make a correct diagnosis. It was hypothesized that the quality of craniofacial pain from cardiac versus dental origin would differ, implying a high diagnostic validity. It was also hypothesized that craniofacial pain can be the sole symptom of a prodromal (pre-infarction) angina episode and that this pain location would be especially associated with cardiac ischemia in the areas more densely innervated by vagal afferent fibres. The study group was comprised of consecutive patients who experienced craniofacial pain of a verified cardiac (n=326) or dental (n=359) origin. Demographic details on age, gender and pain characteristics (location, quality and intensity) were assessed in both groups. Cardiovascular risk factors, cardiac diagnosis and ECG signs of ischemia were also assessed in the cardiac pain group. Ethics approval and informed consent for each patient was obtained. Craniofacial pain was found to be the sole symptom of myocardial ischemia in 6% of patients and was the sole symptom of an AMI in 4% of patients; this craniofacial pain was more prevalent in women (p=0.031). In those patients without chest pain, it was the most frequent pain location and was the only symptom of prodromal angina in 5% of AMI patients. The craniofacial pain included the throat, the jaws, the temporomandibular joints/ears and the teeth, mainly bilaterally. The pain quality descriptors “pressure” and “burning” were statistically associated with pain of cardiac origin, while “throbbing” and “aching” were associated with an odontogenic cause (p&lt;0.001). In myocardial ischemia patients, the occurrence of craniofacial pain was associated with an inferior localization of ischemia in the heart (p&lt;0.001). In conclusion, this study showed that pain in the craniofacial region could be the sole symptom of cardiac ischemia and AMI, particularly in women. Craniofacial pain of cardiac origin was commonly bilateral, with the quality pain descriptors “pressure” and “burning”, and pain provocation with physical activity and pain relief at rest. The association between the presence of craniofacial pain and inferior wall ischemia suggests a vagal involvement in the mechanisms of cardiac pain referred to the craniofacial region. Since the possibility of misdiagnosis and death in this group of patients is high, awareness of this clinical presentation needs to be brought to the attention of researchers, clinicians and the general public.

Stroke is the third largest cause of death, and the leading cause of disability worldwide. Treatments are sought to reduce mortality, and increase survival time following an ischaemic stroke. Hypoxia-ischaemia (HI) is the combination of cerebral ischaemia and global hypoxia that can lead to neuronal damage, particularly perinatally. The complex neurodegenerative cascade following ischaemic stroke and HI activates many stress pathways, including heme oxygenase (HO). HO metabolises free heme to release iron, carbon monoxide, and biliverdin, which is subsequently metabolised to bilirubin. This thesis aims to elucidate the role HO plays following HI, and assess any neuroprotective mechanisms using HO modulators. The 26 day old rat model of HI was used to induce the neurodegenerative cascade. All animals were sacrificed 3 days post-insult. Immunohistochemistry and Western blotting demonstrated that HO-1 was increased in the ipsilateral hemisphere of both HI (by 1.7 � 0.1 fold: p = 0.016, n = 4) and middle cerebral artery occlusion (MCAO) brains (by 1.6 � 0.1 fold: p = 0.037, n = 4), compared to controls. HO-2 was constitutively expressed throughout the control brain, but HI upregulated HO-2 expression (by 1.7 � 0.2 fold: p = 0.027, n = 4) ipsilaterally, whereas MCAO did not alter HO-2 expression. Administration of the HO inhibitor tin protoporphyrin (SnPP; 30[mu]mol/kg intraperitoneally) daily, beginning 1 day prior to HI until sacrifice, reduced infarct volume to 50% � 10 of saline-treated animals (p = 0.039, n = 6-8). The HO inducer ferriprotoporphyrin (FePP; 30[mu]mol/kg) had no effect on infarct volume. HO activity and protein expression were not significantly altered following treatment with SnPP. Therefore, the neuroprotective actions of SnPP may be through alternative mechanisms. SnPP treatment increased HI + saline-induced total nitric oxide synthase (NOS) activity by 1.5 � 0.06 fold (p < 0.001, n = 6-8). Conversely, SnPP inhibited both inducible NOS (50% � 7 of HI + saline; p = 0.045, n = 7-8) and cyclooxygenase (COX) activity (32% � 6 of HI + saline; p = 0.049, n = 4-8). SnPP treatment also increased mitochondrial complex I activity by 1.6 � 0.25 fold (p = 0.04, n = 4-8) and complex V activity by 1.7 � 0.26 fold (p = 0.046, n = 4-8) in the ipsilateral hemisphere. It appears that SnPP is acting on inflammatory and mitochondrial enzymes to produce neuroprotection. In vitro analysis of cultured RAW264.7 macrophages exposed to lipopolysaccharide (LPS; 10[mu]g/mL) treated with SnPP (dose range: 10⁻�⁰M - 10⁻⁵M) did not alter nitrite levels or cell viability. However, high dose SnPP (10⁻⁵M) in the absence of LPS increased nitrite levels from control cells by 2.7 � 0.7 fold (p = 0.043, n = 6), complementing the in vivo total NOS data. Other mechanisms such as NMDA receptor activation were not affected by 100[mu]M SnPP or 100[mu]M SnCl₂ in patch clamped cortical pyramidal neurons. Overall, the role that HO plays following HI remains unclear, but this thesis provides definitive evidence that SnPP (an established HO inhibitor) provides neuroprotection. This neuroprotection may be due to its effects on inducible pathways such as NOS and COX. Therefore, further experimentation is required to fully elucidate the role that HO plays following cerebral ischaemia, and additional in vivo evidence will be necessary to establish HO inhibitors as a putative candidate for cerebral ischaemia neuroprotection.

More than 15 million people worldwide will suffer a stroke each year two thirds will die or be left permanently disabled. Accordingly, stroke represents an enormous financial burden on the community, due to the cost of hospitalisation, treatment and rehabilitation of stroke patients. Despite the significance of this public health problem, a safe and widely applicable stroke therapeutic remains elusive. Cerebral oedema is widely recognised as a common and often fatal complication of stroke that is associated with worsened outcome. However, the exact mechanisms of oedema formation remain unclear, with current therapies largely ineffective in addressing the mechanisms of cerebral swelling, and also being associated with their own negative side-effect profile. This thesis characterises the role of neurogenic inflammation and the neuropeptide, substance P (SP), in mediating the development of blood brain barrier breakdown, cerebral oedema and resultant functional deficits following stroke, using a rodent model of reversible cerebral ischaemia. The findings of this thesis demonstrate that increased SP immunoreactivity, particularly of the penumbral tissue vasculature, is a feature of tissue perfusion following stroke, but not in non-reperfused infarcts. The central role for SP in the breakdown of the BBB following stroke and the associated deleterious effects of such breakdown was confirmed by studies using an NK₁ receptor antagonist. These antagonists conferred a profound attenuation of BBB breakdown, cerebral oedema formation, neuronal death and injury, and the associated development of functional deficits following reversible stroke. Similarly, depletion of all neuropeptides by capsaicin pre-treatment also reduced both histological abnormalities and functional deficits following stroke, confirming the central role of neuropeptides in the secondary injury process after stroke. The NK₁ receptor antagonist was able to be safely combined with the currently approved treatment for stroke, tPA, producing a synergistic effect of greater protection from the ischaemic insult. In particular, histological and functional outcome were markedly improved, as well as a reduction in the risk of intracerebral haemorrhage and death. Furthermore, the NK₁ receptor antagonist was effective even when administered up to 8 h following the onset of ischaemia, and in a variety of stroke severities. We conclude that SP plays a central role in the secondary injury that occurs following stroke, in particular, the genesis of BBB breakdown and cerebral oedema. Accordingly, combination therapy of tPA and an NK₁ receptor antagonist may offer a novel therapeutic strategy for the clinical management of ischaemic stroke of varying severity. / http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1298280 / Thesis (Ph.D.) -- The University of Adelaide, School of Medical Sciences, 2007

Abstract Background The prognosis after an ischaemic stroke is determined largely by how much damage is done to the brain. Currently physicians possess only a few therapies that can improve outcome. Early changes in common physiological variables, such as blood pressure, temperature and blood glucose levels, represent a potential therapeutic target, and manipulation of these variables may eventually yield an effective and potentially widely applicable range of therapies for optimising stroke recovery. However, the natural history and determinants of physiological change require clarification before the effects of manipulating physiology can be assessed. Previous research suggests that blood pressure and glucose falls over the first few days and temperature rises over this time. Some of the determinants of this change have been identified, for example stroke severity, but their influence has not been accurately quantified. The lack of detail in previous attempts to characterise these relationships is partly due to a reliance on traditional cross-sectional statistical techniques. My aims were to use the most apposite statistical technique, namely mixed-effects modelling, to accurately characterise the temporal patterns of post-stroke blood pressure, temperature and glucose, and to identify baseline factors that represent determinants of change in these three physiological variables. Methods A cohort of ischaemic stroke patients was recruited within 48 hours of stroke onset, and their blood pressure, temperature and glucose was recorded at least every 4 hours until 48 hours post-stroke. Factors representing potential determinants of change in these physiological variables were also recorded, including stroke severity and the presence of infection. There were no protocols dictating the treatment of these physiological variables, but if this occurred, those treatments were also recorded. In each analysis, mixed-effects models were generated with serial measures of physiology as the outcome factors and the potential determinants of physiological change as the explanatory factors. These determinants included time, representing the temporal patterns of change. Patients with diabetes were excluded from the analysis of glucose, for several reasons including the excessive impact on glycaemia made by dietary intake in patients with diabetes. Results There were 157 eligible patients overall. The analysis of blood pressure (n=157) revealed a linear systolic blood pressure fall of 14.9 mmHg (95% Confidence Interval (CI) 6.2, 22.6 mmHg) and a diastolic blood pressure fall of 6.1 mmHg (95%CI 1.6, 10.5 mmHg) over the first 48 hours after stroke. Patients with post-stroke infection exhibited a slight rise in systolic blood pressure of about 4 mmHg. Higher systolic blood pressures were seen in older patients and in those with pre-existing or previously treated hypertension, previous strokes or transient ischaemic attacks, in regular alcohol users and in those with mild to moderately severe stroke. Systolic blood pressures were 4.6 mmHg (95%CI 2.35,6.85 mmHg) lower in current smokers than in non-smokers. Of the 156 patients eligible for the temperature analysis, temperature rose by 0.17 deg C in patients with mild stroke (National Institutes of Health Stroke Score (NIHSS)≤6) and 0.35 deg C in patients with moderate to severe stroke (NIHSS≥6) over the first 48 hours after stroke. Temperatures were higher in those who required paracetamol. Temperatures were 0.33 deg C (95%CI 0.07, 0.58) higher in patients with infection and the effect was fixed during the 48 hour observation period. Blood glucose remained static in the 124 patients without diabetes during the first 48 hours after stroke. Glucose levels where higher in those requiring glucose lowering therapy, and in those with more severe stroke. Conclusions I have quantified the amount by which blood pressure falls and temperature rises over the first 48 hours after stroke. In addition, I have shown that mean glucose levels remain static during this time, suggesting that previous reports of acutely resolving post-stroke hyperglycaemia may have represented misinterpretation of regression to the mean. Several determinants of change in post-stroke physiological variables were identified, with unexpected findings in several cases. Higher systolic blood pressures were seen with stroke of moderate severity but not mild or severe stroke. This relationship was fixed during the first 48 hours after stroke, but while more severe stroke was also associated with higher temperatures, the latter effect became more marked as time passed. Conversely, infection was associated with a fixed elevation in temperature, but was associated with systolic blood pressures that rose slightly during the observation period. These apparent inconsistencies require clarification in future work, for example studies of whether markers of the inflammatory or neuroendocrine stress responses evolve in parallel with the changes in physiological variables. This work provides fundamental information regarding the natural history and determinants of changes in physiological variables post-stroke, and will improve the design of future studies investigating the prognostic significance of untreated and treated physiological variables after stroke. This will ultimately lead to the refinement of clinical guidelines for the management of physiological variables post-stroke and to better outcomes for stroke patients.