Vascular receptor changes in ischemic stroke

The present thesis aimed to examine how ischemic stroke affects the vascular endothelin and angiotensin systems in cerebral arteries. To study vascular receptor changes in ischemic stroke transient focal ischemia was induced in rats. In addition, rat cerebral arteries and arterial smooth muscle cells were cultured for further analysis of cerebrovascular receptor regulation. For functional studies of cerebral arteries, sensitive myographs were used. mRNA levels were quantitatively measured by real time PCR and protein density was studied by immunohistochemistry. Main results: 1. Ischemic stroke in rat induces a contractile endothelin ET(B) receptor mediated response in the ipsilateral middle cerebral artery (MCA), which is accompanied by an increased expression of ET(B) receptors. 2. Organ culture of rat MCAs induces a time-dependent upregulation of contractile ET(B) receptors. The phenomenon is due to de novo transcription of the receptors and is partly dependent on PKC. 3. bFGF increases the ET(A) and ET(B) receptor mRNA expression in rat cerebral smooth muscle cells. 4. TNF-alpha and EGF can potentiate the ET(B) receptor mediated contraction in the rat MCA, whereas bFGF enhances the maximal ET(A) receptor mediated contraction and increases the mRNA and protein levels for the ET(B) receptors. 5. Ischemic stroke in rat enhances the contractile response to angiotensin II in the ipsilateral MCA. This contraction is mediated by angiotensin AT1 receptors. In addition the mRNA levels for angiotensin converting enzyme were increased, which may suggest an enhanced production of angiotensin II. 6. A low dose of the AT1 receptor blocker candesartan (0.05 mg/kg and day) in the acute phase of ischemic stroke can decrease the size of brain damage significantly. Our hypothesis suggests that ischemic stroke can activate contractile mediators in cerebral arteries, and that this phenomenon may be detrimental if it implies a decreased perfusion of the already ischemic hemisphere. The present thesis confirms that there is indeed an increased ET(B) and AT1 receptor mediated contraction in the ipsilateral MCA after ischemic stroke

Study protocol: a multi-professional team intervention of physical activity referrals in primary care patients with cardiovascular risk factors-the Dalby lifestyle intervention cohort (DALICO) study

Background: The present study protocol describes the trial design of a primary care intervention cohort study, which examines whether an extended, multi-professional physical activity referral (PAR) intervention is more effective in enhancing and maintaining self-reported physical activity than physical activity prescription in usual care. The study targets patients with newly diagnosed hypertension and/or type 2 diabetes. Secondary outcomes include: need of pharmacological therapy; blood pressure/plasma glucose; physical fitness and anthropometric variables; mental health; health related quality of life; and cost-effectiveness. Methods/Design: The study is designed as a long term intervention. Three primary care centres are involved in the study, each constituting one of three treatment groups: 1) Intervention group (IG): multi-professional team intervention with PAR, 2) Control group A (CA): physical activity prescription in usual care and 3) Control group B: treatment as usual (retrospective data collection). The intervention is based on self-determination theory and follows the principles of motivational interviewing. The primary outcome, physical activity, is measured with the International Physical Activity Questionnaire (IPAQ) and expressed as metabolic equivalent of task (MET)-minutes per week. Physical fitness is estimated with the 6-minute walk test in IG only. Variables such as health behaviours; health-related quality of life; motivation to change; mental health; demographics and socioeconomic characteristics are assessed with an electronic study questionnaire that submits all data to a patient database, which automatically provides feed-back to the health-care providers on the patients' health status. Cost-effectiveness of the intervention is evaluated continuously and the intermediate outcomes of the intervention are extrapolated by economic modelling. Discussions: By helping patients to overcome practical, social and cultural obstacles and increase their internal motivation for physical activity we aim to improve their physical health in a long- term perspective. The targeted patients belong to a patient category that is supposed to benefit from increased physical activity in terms of improved physiological values, mental status and quality of life, decreased risk of complications and maybe a decreased need of medication

Protein kinase C inhibition attenuates vascular ET(B )receptor upregulation and decreases brain damage after cerebral ischemia in rat

BACKGROUND: Protein kinase C (PKC) is known to be involved in the pathophysiology of experimental cerebral ischemia. We have previously shown that after transient middle cerebral artery occlusion, there is an upregulation of endothelin receptors in the ipsilateral middle cerebral artery. The present study aimed to examine the effect of the PKC inhibitor Ro-32-0432 on endothelin receptor upregulation, infarct volume and neurology outcome after middle cerebral artery occlusion in rat. RESULTS: At 24 hours after transient middle cerebral artery occlusion (MCAO), the contractile endothelin B receptor mediated response and the endothelin B receptor protein expression were upregulated in the ipsilateral but not the contralateral middle cerebral artery. In Ro-32-0432 treated rats, the upregulated endothelin receptor response was attenuated. Furthermore, Ro-32-0432 treatment decreased the ischemic brain damage significantly and improved neurological scores. Immunohistochemistry showed fainter staining of endothelin B receptor protein in the smooth muscle cells of the ipsilateral middle cerebral artery of Ro-32-0432 treated rats compared to control. CONCLUSION: The results suggest that treatment with Ro-32-0432 in ischemic stroke decreases the ischemic infarction area, neurological symptoms and associated endothelin B receptor upregulation. This provides a new perspective on possible mechanisms of actions of PKC inhibition in cerebral ischemia

Inhibition of PKC activity blocks the increase of ET(B )receptor expression in cerebral arteries

BACKGROUND: Previous studies have shown that there is a time-dependent upregulation of contractile endothelin B (ET(B)) receptors in middle cerebral arteries (MCA) after organ culture. This upregulation is dependent on mitogen-activated protein kinases and possibly protein kinase C (PKC). The aim of this study was to examine the effect of PKC inhibitors with different profiles on the upregulation of contractile ET(B )receptors in rat MCA. Artery segments were incubated for 24 hours at 37°C. To investigate involvement of PKC, inhibitors were added to the medium before incubation. The contractile endothelin-mediated responses were measured and real-time PCR was used to detect endothelin receptor mRNA levels. Furthermore, immunohistochemistry was used to demonstrate the ET(B )receptor protein distribution in the MCA and Western blot to measure which of the PKC subtypes that were affected by the inhibitors. RESULTS: The PKC inhibitors bisindolylmaleimide I, Ro-32-0432 and PKC inhibitor 20–28 attenuated the ET(B )receptor mediated contractions. Furthermore, Ro-32-0432 and bisindolylmaleimide I decreased ET(B )receptor mRNA levels while PKC inhibitor 20–28 reduced the amount of receptor protein on smooth muscle cells. PKC inhibitor 20–28 also decreased the protein levels of the five PKC subtypes studied (α, βI, γ, δ and ε). CONCLUSION: The results show that PKC inhibitors are able to decrease the ET(B )receptor contraction and expression in MCA smooth muscle cells following organ culture. The PKC inhibitor 20–28 affects the protein levels, while Ro-32-0432 and bisindolylmaleimide I affect the mRNA levels, suggesting differences in activity profile. Since ET(B )receptor upregulation is seen in cerebral ischemia, the results of the present study provide a way to interfere with the vascular involvement in cerebral ischemia

Att stärka elevers självkänsla på lågstadiet

This paper is an examination of how you as pedagogue can strengthen students self-esteem. I have acknowledge that there are possibilities to do this by the art of dancing. I want to with this paper to give a deeper understanding that shows of how you as a pedagogue can strengthen students self-esteem by using dance at junior level. To answer this question I have used this questions: - Can dance strengthen students self-esteem by the art of dancing and if that is so how can this be done? - What pedagogical attitude can be to an advantage when the goal is to strengthen students self-esteem. I have chosen to use ten qualitative interviews which brings up my questions at hand. My intention with the questions were not to bring up any direct question about self-esteem but to investigate if self-esteem is relevant in the interviewees teaching. Through dace students in the junior level have their self-esteem strengthened. The younger one is the easier one has to as a student have the courage to let ones inhabitations go and as a pedagogue one has a great influence on the teachings. With the help from the art of dancing one can emphasis the individual and at the same time strengthen the group and then it is important that one as a pedagogue has a good structure and is well-aware of what one wants with ones dance teachings. Keywords - Dance - Self-esteem - Pedagogue - Securit

Increased monoaminergic neurotransmission improves compliance with physical activity recommendations in depressed patients with fatigue.

Clinical studies have shown that moderately intense physical activity effectively treats various types of depression. Beneficial effects have been reported in the acute phase of the disease as well as in a long-term perspective. In addition, epidemiological studies have shown that inactivity increases the risk of depression and that exercise prevents relapse. Depressed patients are often prescribed antidepressants, with or without psychotherapy. Some studies have, however, suggested that the most frequently used antidepressants, selective serotonin reuptake inhibitors (SSRIs), contribute to fatigue, which is a common residual symptom associated with depression and the target of the proposed study. Profound fatigue may in turn decrease the ability and motivation to perform the beneficial physical activity, e.g. via executive dysfunction. Fatigue and impaired executive function are commonly linked to disturbed cerebral dopaminergic and noradrenergic neurotransmission. This kind of dysfunction is hard to overcome, even when the major symptoms of depression are alleviated. Interestingly, physical activity has been suggested to improve the dopamine and norepinephrine neurotransmission. Furthermore, the favorable effects may be reciprocal; improved dopamine and norepinephrine transmission in the brain may hypothetically increase the ability and motivation to exercise, since some parts of the brain (e.g. the prefrontal cortex, striatum and cerebellum) that control movement and initiative receive dopaminergic and noradrenergic projections. Based on these findings and assumptions, our hypothesis is that increased dopaminergic and noradrenergic neurotransmission, via intake of a dopamine- and norepinephrine-enhancing agent, improves the compliance with prescribed physical activity in patients with depression and residual fatigue. We also believe that the increased physical activity can prevent relapse into depression, even after interruption of medication. Since increased physical activity also has been shown to improve executive cognitive function, we suggest that executive function should be examined as a secondary outcome together with other possibly related variables such as quality of life, sick leave and BMI

Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries.

Cerebral ischemia results in a local inflammatory response that contributes to the size of the lesion, however, the involvement of the cerebral vasculature is unknown. We hypothesise that the expression of inflammatory genes (Il6, iNOS, cxcl2, TNF-α and Il-1β) and extracellular-matrix-related genes (MMP9, MMP13) is induced in cerebral arteries following cerebral ischemia via activation of mitogen activated kinases (MAPKs). This hypothesis was tested in vivo by experimental subarachnoid haemorrhage (SAH) and temporal middle cerebral artery occlusion (MCAO), and by organ culture of isolated cerebral arteries with quantitative real time PCR (mRNA expression) and immunohistochemistry (localization of protein expression). The gene promoters were investigated in silica with computer analysis. The mRNA analysis revealed that the ischemic models, SAH and MCAO, as well as organ culture of isolated cerebral arteries resulted in transcriptional upregulation of the abovementioned genes. The protein expression involved phosphorylation of three different MAPKs signalling pathways (p38, ERK 1/2 and SAPK/JNK) and the downstream transcription factors (ATF-2, Elk-1, c-Jun) shown by immunohistochemistry and quantified by image analysis. All three models revealed the same pattern of activation in the cerebrovascular smooth muscle cells. The in silica analysis demonstrated binding sites for said transcription factors. The results suggest that cerebral ischemia and organ culture induce activation of p38, ERK 1/2 and SAPK/JNK in cerebral arteries which in turn activate the transcription factors ATF-2, Elk-1 and c-Jun and the expression of inflammatory and extracellular-matrix-related genes in the wall of cerebral arteries