Cerebral ischemia elicits a wide range of events, including complex activation of various intracellular signaling pathways. This study aims to investigate the expression of vascular endothelial growth factor (VEGF) and the activation pattern of mitogen-activated protein kinases (MAPK) in reponse to focal cerebral ischemia. Furtermore, the functional roles of the p38 MAPK and the Src family kinases (SFKs) are investigated with specific signal transduction inhibitors in the rat in vivo. VEGF was found upregulated in several cell types including neurons, glia and vascular cells after both permanent and transient cerebral ischemia. VEGF-receptor 1 (VEGFR1) was expressed in a similar manner, while VEGFR2 expression was more restricted and confined to endothelial cells and glia.The main MAPK pathways, including extracellular-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, were differentially activated by cerebral ischemia. ERK activation was present in blood vessels, suggesting a potential role in neovascularization. JNK was also activated in blood vessels in the infarcted hemisphere, possibly reflecting an interaction with ERK, whereas p38 activity was absent in vessels. In neurons, ERK was activated in cortical cells up to days of survival, while no substantial JNK or p38 activation was seen in ischemic neurons. Invading macrophages showed distinct activation of p38 and to some extent also JNK but not ERK. Glia showed activation of all MAPK to a variable extent. Pretreatment with the p38-inhibitor SB203580 before transient cerebral ischemia (ischemia-reperfusion) was investigated with magnetic resonance imaging (MRI). The experiment group suffered worse infarcts and blood-brain barrier (BBB) damage than controls, which contrasts to previous studies. The results might be attributed to interference with protective effects of the vehicle or with preconditioning mechanisms. The SFK-inhibitor PP2 significantly reduced infarct size after cerebral ischemia-reperfusion, which is consistent with previously reported effects in permanent ischemia. Due to the multifunctional role of SFKs, it cannot be easily concluded in exactly what cellular context(s) SFKs are of importance to cerebral ischemia. In conclusion, the VEGF and MAPK systems of extra- and intracellular signaling are activated in focal cerebral ischemia. Manipulation of p38 as well as SFK in vivo can influence the course of transient cerebral ischemia, which may be of significance to the understanding of the pathology of cerebral ischemia and to the development of therapeutic strategies.

No description available.

<p>Cerebral ischemia elicits a wide range of events, including complex activation of various intracellular signaling pathways. This study aims to investigate the expression of vascular endothelial growth factor (VEGF) and the activation pattern of mitogen-activated protein kinases (MAPK) in reponse to focal cerebral ischemia. Furtermore, the functional roles of the p38 MAPK and the Src family kinases (SFKs) are investigated with specific signal transduction inhibitors in the rat <i>in vivo</i>. </p><p>VEGF was found upregulated in several cell types including neurons, glia and vascular cells after both permanent and transient cerebral ischemia. VEGF-receptor 1 (VEGFR1) was expressed in a similar manner, while VEGFR2 expression was more restricted and confined to endothelial cells and glia.The main MAPK pathways, including extracellular-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, were differentially activated by cerebral ischemia. ERK activation was present in blood vessels, suggesting a potential role in neovascularization. JNK was also activated in blood vessels in the infarcted hemisphere, possibly reflecting an interaction with ERK, whereas p38 activity was absent in vessels. In neurons, ERK was activated in cortical cells up to days of survival, while no substantial JNK or p38 activation was seen in ischemic neurons. Invading macrophages showed distinct activation of p38 and to some extent also JNK but not ERK. Glia showed activation of all MAPK to a variable extent.</p><p>Pretreatment with the p38-inhibitor SB203580 before transient cerebral ischemia (ischemia-reperfusion) was investigated with magnetic resonance imaging (MRI). The experiment group suffered worse infarcts and blood-brain barrier (BBB) damage than controls, which contrasts to previous studies. The results might be attributed to interference with protective effects of the vehicle or with preconditioning mechanisms. The SFK-inhibitor PP2 significantly reduced infarct size after cerebral ischemia-reperfusion, which is consistent with previously reported effects in permanent ischemia. Due to the multifunctional role of SFKs, it cannot be easily concluded in exactly what cellular context(s) SFKs are of importance to cerebral ischemia.</p><p>In conclusion, the VEGF and MAPK systems of extra- and intracellular signaling are activated in focal cerebral ischemia. Manipulation of p38 as well as SFK <i>in vivo </i>can influence the course of transient cerebral ischemia, which may be of significance to the understanding of the pathology of cerebral ischemia and to the development of therapeutic strategies. </p>

No description available.

<p>The aims of the present thesis were to evaluate the management of acute WAD and to develop, describe and evaluate a cognitive behavioural approach for the physiotherapy management of long-term WAD as well as to study the predictors and mediating factors for long-term disability and pain after a whiplash injury. </p><p>Two approaches for acute and chronic WAD were evaluated in experimental studies. Fifty-nine patients with acute whiplash injury (study I) and 33 patients with chronic WAD (study V), were randomised into experimental and control groups. In addition, three chronic WAD patients participated in an experimental single case study (study IV). Home exercise programmes for patients with acute WAD were used in study I. In study IV a physiotherapy management with integrated components of cognitive-behavioural origin was tried for chronic WAD patients. In study V physiotherapy treatment in primary care units and a physiotherapy management with integrated components of cognitive-behavioural origin was tried for chronic WAD patients. Study I showed that a home exercise programme including training of neck and shoulder range of motion (ROM), relaxation and general advice, appears to be a sufficient treatment for most acute WAD patients. Further, the results of study IV and V suggest that cognitive behavioural components m be useful in physiotherapy treatment for patients with chronic WAD, but its contribution is not yet fully understood. </p><p>Study III showed that the significance of coping as an explanatory factor for disability increased during the one-year period after a whiplash injury. In study V it was concluded that self-efficacy is related to patients' use of different coping styles. A model to study coping as a mediator between self-efficacy and disability was therefore introduced. In a path-analytic framework, data from subjects in study I were re-analysed to illustrate a theoretical standpoint that emphasises the process of coping. With regard to disability, the proportion of explained variance increased from 39% at three weeks after the accident, to 79% at one-year follow-up. These results also show that coping has a crucial and mediating role between self-efficacy and disability. Positive long- term outcomes in WAD-patients would therefore be improved by, shortly after an accident, boosting self- efficacy and teaching patients to use active, adaptive coping strategies to manage their problems. </p>

<p>Epidermolytic hyperkeratosis is a rare inherited disease of the skin caused by a dominant-negative mutation in keratin 1 (K1) or 10 (K10). Keratins are the major structural protein in epidermis and mutations causes instability of intermediate filament and keratinocyte fragility. No curative treatment is available, but some patients benefit from retinoid therapy. More knowledge is needed about the genotype/phenotype correlation in epidermolytic hyperkeratosis and the mechanism of action of retinoids including regulation of keratin expression. </p><p>Fifteen patients were identified in Scandinavia, 13 with a generalised disease and 2 with localised lesions. Different types of mutation were identified such as point, splice site, deletion, and deletion-insertion mutations. An association was found between mutation in K1 and the appearance of palmoplantar keratoderma. Only the patients with K10 mutation benefited from the treatment, although no differences in the mRNA levels for K1 and K10 were detected. However, retinoids caused a pronounce down-regulation of K2e in upper epidermis and upregulation of K4 not normally present in the skin. This was further investigated in normal healthy skin and in keratinocytes grown in a reconstructed skin model. By adding retinoids with different affinity for the nuclear receptors RAR and RXR to the culture, the most potent retinoids were found to be RARα agonist, the effect of which could be inhibited by addition of a pan RAR antagonist. </p><p>In conclusion, several novel keratin mutations have been shown to cause epidermolytic hyperkeratosis, and genotype/phenotype correlations have been found. Treatment with retinoids is only useful for patients with a K10 mutation, possibly because they are less vulnerable too the pronounce down-regulation of K2e also seen in normal skin. This effect and the upregulation of K4 seem to be mediated through RARα , expressed in the keratinocytes.</p>

The aims of the present thesis were to evaluate the management of acute WAD and to develop, describe and evaluate a cognitive behavioural approach for the physiotherapy management of long-term WAD as well as to study the predictors and mediating factors for long-term disability and pain after a whiplash injury. Two approaches for acute and chronic WAD were evaluated in experimental studies. Fifty-nine patients with acute whiplash injury (study I) and 33 patients with chronic WAD (study V), were randomised into experimental and control groups. In addition, three chronic WAD patients participated in an experimental single case study (study IV). Home exercise programmes for patients with acute WAD were used in study I. In study IV a physiotherapy management with integrated components of cognitive-behavioural origin was tried for chronic WAD patients. In study V physiotherapy treatment in primary care units and a physiotherapy management with integrated components of cognitive-behavioural origin was tried for chronic WAD patients. Study I showed that a home exercise programme including training of neck and shoulder range of motion (ROM), relaxation and general advice, appears to be a sufficient treatment for most acute WAD patients. Further, the results of study IV and V suggest that cognitive behavioural components m be useful in physiotherapy treatment for patients with chronic WAD, but its contribution is not yet fully understood. Study III showed that the significance of coping as an explanatory factor for disability increased during the one-year period after a whiplash injury. In study V it was concluded that self-efficacy is related to patients' use of different coping styles. A model to study coping as a mediator between self-efficacy and disability was therefore introduced. In a path-analytic framework, data from subjects in study I were re-analysed to illustrate a theoretical standpoint that emphasises the process of coping. With regard to disability, the proportion of explained variance increased from 39% at three weeks after the accident, to 79% at one-year follow-up. These results also show that coping has a crucial and mediating role between self-efficacy and disability. Positive long- term outcomes in WAD-patients would therefore be improved by, shortly after an accident, boosting self- efficacy and teaching patients to use active, adaptive coping strategies to manage their problems.

Epidermolytic hyperkeratosis is a rare inherited disease of the skin caused by a dominant-negative mutation in keratin 1 (K1) or 10 (K10). Keratins are the major structural protein in epidermis and mutations causes instability of intermediate filament and keratinocyte fragility. No curative treatment is available, but some patients benefit from retinoid therapy. More knowledge is needed about the genotype/phenotype correlation in epidermolytic hyperkeratosis and the mechanism of action of retinoids including regulation of keratin expression. Fifteen patients were identified in Scandinavia, 13 with a generalised disease and 2 with localised lesions. Different types of mutation were identified such as point, splice site, deletion, and deletion-insertion mutations. An association was found between mutation in K1 and the appearance of palmoplantar keratoderma. Only the patients with K10 mutation benefited from the treatment, although no differences in the mRNA levels for K1 and K10 were detected. However, retinoids caused a pronounce down-regulation of K2e in upper epidermis and upregulation of K4 not normally present in the skin. This was further investigated in normal healthy skin and in keratinocytes grown in a reconstructed skin model. By adding retinoids with different affinity for the nuclear receptors RAR and RXR to the culture, the most potent retinoids were found to be RARα agonist, the effect of which could be inhibited by addition of a pan RAR antagonist. In conclusion, several novel keratin mutations have been shown to cause epidermolytic hyperkeratosis, and genotype/phenotype correlations have been found. Treatment with retinoids is only useful for patients with a K10 mutation, possibly because they are less vulnerable too the pronounce down-regulation of K2e also seen in normal skin. This effect and the upregulation of K4 seem to be mediated through RARα , expressed in the keratinocytes.

<p>Epigenetic modifications were shown to play an essential role in tumorigenesis. Epigenetic mechanisms can alter transcription in several ways, through DNA methylation and/or through histone modification. DNA methylation at the TSS (transcriptional start site) has been implicated in tumor development and gene silencing. However, several examples of atypical methylation were shown. In Paper I we present the ICSBP/IRF8 gene that belongs to the IRF family and has characteristics of a tumor suppressor gene. The ICSBP/IRF8 is fully methylated in the promoter and TSS regions in U-937 and despite high expression of the gene. Presence of positive histone marks suggests that methylated DNA can be overridden by histone modification.</p><p>In Paper II a panel of 13 MM (multiple myeloma) cell lines and 9 primary patient tumors were analysed for methylation status of the ICSBP/IRF8 gene. In most cell lines (8/13) the gene was partially or fully methylated and partial methylation was also observed in 1/9 primary tumors. In vitro methylation analysis and treatment with 5-aza-2’deoxycytidine (DAC) proved that the ICSBP/IRF8 gene is silenced by methylation and may be associated with the malignant phenotype.</p><p>In Paper III and IV the NFκB signalling pathway was analysed and the role of ATRA and TNFα induction. In Paper III the data shows that activation of the NFκB pathway is essential in ATRA-induced terminal differentiation in the U-937 cell line and IκBα (S32A/S36A) inhibits ATRA-induced differentiation and G1 cell cycle arrest. This was accompanied by delayed down-regulation of several cyclins (A and E) and up-regulation of p21^WAF1/CIP1 (CDKN1A) and p27^KIP1 (CDKN1B).</p><p>TNFα alone did not induce expression of RA-induced genes analysed in Paper IV. However, ATRA in combination with TNFα showed enhanced activation of RA-induced genes. TNFα triggers demethylation of H3K9me3/H3K9me2 and H3K4me3 at RAR/RXR target genes, which were not accompanied by changes in the level of H3K9-ac. This decrease in H3 methylation by TNFα may pave way for the later ATRA-induced gene transcription.</p>

<p>The prevalence of respiratory symptoms and diseases like asthma and chronic obstructive pulmonary disease (COPD), seem to have increased the last decades. The reason for the increase in asthma related symptoms and allergy is uncertain. Some, but not all, of this increase might be ascribed to lowered threshold for use of the diagnosis by medical doctors, change in diagnostic criteria, and increased awareness of symptoms in the population. Studies have indicated that increased prevalence might be explained by a reduction during the last decades in exposure to environmental factors in infancy, These factors are supposed to stimulate the change from Th-2 to TH-1 helper cells (hygiene hypothesis), but even low level of allergen exposure seems to contribute to increase in risk for allergy. The increase in COPD in developed countries is closely related to the smoking pattern during the last two to four decades, and the increased therefore, is mainly seen in women. Further, studies have indicated that women are more vulnerable for the deleterious effects of tobacco smoking than men are; if this is true the current smoking pattern with increased female smoking, is worrying. </p> / Paper 1 reprinted with kind permission of Journal of Epidemiology and Community Health. Papers 2 and 3 reprinted with kind permission of European Respiratory Society Journals Ltd. Paper 4 reprinted with kind permission of John Wiley and Sons Limited.