| 41. |
- Devenney, Irene, 1959-
(författare)
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Assessing eczema and food allergy in young children
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Atopic disease is an increasing problem. Eczema affects 10-20% of young children, and 33-37% of children with eczema are food allergic. Among other factors, nitric oxide (NO) is thought to play a role in eczema and food allergy. Following the atopic march, pproximately 80% of children with atopic eczema will become sensitized to aeroallergens and develop asthma and/or allergic rhinitis. Skin prick test is used for investigating sensitization and is considered a safe method. However, systemic allergic reactions may appear when the test is performed. In diagnosing food allergy and for evaluating achievement of tolerance, the oral food challenge is the method of choice, and the double-blind placebocontrolled fashion is 'the gold standard'.Skin prick test: We examined six cases of generalized allergic reactions in connection with skin prick testing in order to identify risk factors, and thereby increase safety, and we investigated the necessity of performing skin prick tests in duplicate. We found that all six children with generalized reactions were <6 months of age. When analyzing skin prick tests in duplicate, we found only 1.3% that showed diverging results, and in infants <6 months even fewer, 0.9%.Food challenge: We developed recipes and a protocol for low-dose oral food challenge to milk and egg to be used in young children outgrowing their food allergy so as to facilitate early re-/introduction of small amounts of milk and egg. We performed 52 challenges, both open and double-blind placebo controlled. The recipes were validated for blinding. The lowdose challenge was tolerated well by the children and was easy to perform. Four children had a positive challenge outcome, all reacting to very small amounts of milk. All but two of the non-reacting children were able to introduce milk and egg into their diet.Nitric oxide and eczema: We investigated the effect of eczema treatment on the NO levels in urine. The sum of nitrite and nitrate was measured in urinary samples from 94 infants at two visits, with an interval of 6 weeks, and the results were compared with clinical data. The levels of NO products increased significantly when the eczema improved.The atopic march: The aim was to evaluate the atopic march in children with eczema, from referral at <2 years until 4½ years of age. We followed 123 children with eczema, 78 sensitized and 45 not sensitized to milk and/or egg, with respect to eczema severity, other allergic manifestations, development of airway sensitization, and achievement of food tolerance. The difference in severity of eczema at referral was significant when comparing food-sensitized with non-sensitized children. At follow-up, 62% were still affected by eczema, although 56% only mildly so. Tolerance was achieved in 81% of the children allergic to milk and 68% of those allergic to egg. Fifty-eight percent of the food-sensitized children and 26% of the non-sensitized children had become sensitized to aeroallergens, a significant difference. The difference in airway symptoms was not significant. Very few children were exposed to tobacco smoke in their homes.Conclusions: Increased precautions should be considered when performing skin prick tests in infants <6 months of age. The use of a single prick, to avoid the risk of summation of reactions, is justified when performing skin prick tests. We report recipes and a protocol for standardized open and double-blind placebo-controlled low-dose food challenge in young children, enabling the introduction of small amounts of egg and milk into the diet during tolerance development. NO products in urine increases when eczema improves. This might be due to a Th2/Th1 shift induced by the eczema treatment and skin healing, and the variation in NO response may be due to individual variations in NO-induced feedback downregulation of Th1 and Th2 proliferation. The prognosis for achieving clinical tolerance is very good in children early sensitized and allergic to milk and egg, but they will become significantly more often sensitized to aeroallergens.
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| 42. |
- Droog Tesselaar, Erik, 1977-
(författare)
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Assessment of microvascular function by use of transdermal iontophoresis : methodological aspects
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Assessment of the microcirculation is of major importance in understanding the physiology of the vasculature and in assessing te vascular effects of pathological conditions such as diabetes, hypertension and sepsis. Transdermal iontophoresis can be used to non‐invasively introduce vasoactive drugs into the skin. The response to these drugs of the local cutaneous microvasculature can be measured by laser Doppler flowmetry methods. Although these techniques have been used together for over two decades, there are still important methodological issues to be resolved. This work is aimed at optimizing transdermal iontophoresis as a tool for microvascular assessment by focusing on the main methdological issues: non‐specific vasodilatation, drug delivery protocols and analysis of blood flow data.Non‐specific vasodilatation, an increase blood flow during iontophoresis of non‐vasoactive compounds, is an important problem as it interferes with the response to the administered drug. By investigating this effect in healthy volunteers, we found that the extent of the non‐specific response differs between the positive and negative electrode and that it is dependent on the voltage over the skin andon the ionic strength of the vehicle in which the drug is dissolved. We also found that the extent of the non‐specific response could be reduced by applying local anesthetics and by pre‐treatment with antihistamine drugs. These results suggest that non‐specific effects could be mediated by depolarization or hyperpolarisation of cells, triggering neural and histamine related mechanisms that finally lead to vasodilatation of the local microvasculature.To prevent non‐specific effects from occurring during the experiments, our results show that the current strength and the total electric charge during iontophoresis should be limited to 0.02 mA and12 mC, respectively. Furthermore, drug solutions at physiological ionic strengths should be used. Under these conditions, adequate responses to the most commonly used drugs, acetylcholine (ACh) and sodium nitroprusside (SNP), are obtained while no significant non‐specific vasodilatation occurs.The results of our investigations show that blood responses to ACh and SNP applied by a single iontophoretic pulse can well be escribed by conventional dose‐response models, which enables a more powerful analysis and comparison between drugs or possibly patient groups as compared with conventional aalysis methods. Finally, we have incorporated drug transport and physiological response to the local drug concentration during iontophoresis of vasoactve drugs into a single model. Validation of this model using measured responses to ACh and SNP shows that the commonly used assumption that the local drug concentration during iontophoresis is linearly proportional to the electric charge may not be valid.
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| 43. |
- Edvardsson, Anna, 1976-
(författare)
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Peptidyl-prolyl cis-trans Isomerases in the Chloroplast Thylakoid Lumen
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Sun is the ultimate energy source on Earth. Photosynthetic organisms are able to catalyze the conversion of solar energy to chemical energy by a reaction called photosynthesis. In plants, this process occurs inside a green organelle called the chloroplast. The protein complexes involved in the photosynthetic light reactions are situated in the thylakoid membrane, which encloses a tiny space called lumen. The Peptidyl-Prolyl cis-trans Isomerase (PPIase) family is the most abundant protein family in the thylakoid lumen. The three PPIase subfamilies, cyclophilins, FKBPs (FK506 binding proteins) and parvulins form a group by their enzymatic activity despite lack of sequence similarity between the subfamilies. Cyclophilins and FKBPs, collectively called immunophilins, were originally discovered as the targets of the immunosuppressive drugs cyclosporine A and FK506, respectively. By suppressing the immune response in humans, these immunophilin-drug complexes revolutionized the field of organ transplantation by preventing graft rejection. Cis-trans isomerization of peptide bonds preceding the amino acid proline is the rate-limiting step of protein folding and several immunophilins have been shown to be important for catalysis of protein folding in vivo. PPIases have been found to be part of large protein complexes as well as in functions such as signalling, protein secretion, RNA processing and cell cycle control. A picture is therefore emerging in which the actual interaction between the PPIase and its target is perhaps more important than the PPIase activity.In the present work, PPIases have been characterized in the chloroplast thylakoid lumen of Spinacia oleracea (spinach) and Arabidopsis thaliana (Arabidopsis). The most active PPIase in the spinach lumen was identified as the cyclophilin TLP20. AtCYP20-2, the Arabidopsis homologue of TLP20, was found to be upregulated at high light and attached to the thylakoid membrane, more precisely to the outer regions of photosystem II supercomplexes. In Arabidopsis, up to 5 cyclophilins and 11 FKBPs were predicted to reside in the lumen. Of these 16 immunophilins, only 2 were identified as active PPIases and significant differences were observed between the two plant species. AtCYP20-2, like TLP20, is an active isomerase although AtFKBP13 is the most active PPIase in the lumen of Arabidopsis. Mutant Arabidopsis plants deficient in AtCYP20-2 displayed no phenothypical changes or decrease in total lumenal PPIase activity. Being the only active PPIase in the mutants, the redox sensitive AtFKBP13 is proposed to compensate for the lack of AtCYP20-2 by oxidative activation. In agreement with the experimental data, the sequence analyses of catalytic domains of lumenal immunophilins demonstrate that only AtCYP20-2 and AtFKBP13 possess the amino acids found essential for PPIase activity in earlier studies of human cyclophilin A and FKBP12. It is concluded that with the exception of AtCYP20-2 and AtFKBP13 most immunophilins in the lumen of Arabidopsis lost their PPIase activity on peptide substrates and developed other specialized functions.
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| 44. |
- Ekbladh, Elin, 1974-
(författare)
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Return to Work : Assessment of Subjective Psychosocial and Environmental Factors
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduktion: Sjukfrånvaron i Sverige är hög och kunskap om vad som påverkar återgång i arbete efter sjukskrivning behöver utvecklas. I processen kring återgång i arbete är bedömning av arbetsförmåga en viktig del. Bristen på valida, reliabla och teoretiskt förankrade bedömningsinstrument inom området är dock ett bekymmer eftersom tillförlitliga bedömningar av arbetsförmåga är en förutsättning för utformning och genomförande av interventioner för att stödja återgång i arbete. Denna typ av interventioner kräver multidisciplinär kompetens där arbetsterapeuter utgör en viktig funktion. Vid bedömning av arbetsförmåga bör personens subjektiva uppfattning om sin situation beaktas, då den har betydelse för utfallet av återgång i arbete. Worker Role Interview (WRI) och Work Environment Impact Scale (WEIS) är två arbetsrelaterade intervjuinstrument, som har utvecklats i syfte att bedöma subjektiva psykosociala och miljömässiga faktorers påverkan på arbetsförmåga. Den teoretiska grunden till WRI och WEIS är Model of Human Occupation, som är en modell med fokus på aktivitetsutförande i relation till psykosociala faktorer. Inledande prövningar av WRI och WEIS reliabilitet och validitet har genomförts. Bedömningsinstrumenten har bearbetats och översatts till svenska och används främst av arbetsterapeuter, som arbetar med personer med arbetsrelaterad problematik.Syfte: Det övergripande syftet med avhandlingen är att undersöka användbarheten av bedömningsinstrumenten Worker Role Interview och Work Environment Impact Scale för identifiering av psykosociala och miljömässiga rehabiliteringsbehov av betydelse för återgång i arbete.Metod: Avhandlingen består av fem empiriska studier. I samtliga studier har erhållen information bearbetats kvantitativt. I studie IV har även kvalitativ bearbetning genomförts. Studie I, II och IV är tvärsnittsstudier och studie II och V är två års longitudinella studier. I studie I samlades information in via enkät. I studie II, III och V bestod den huvudsakliga informationen av skattningar utifrån WRI variabler och i studie IV var bedömningar utifrån WEIS i form av skattningar och nedskrivna kommentarer till skattningarna den huvudsakliga informationen.Resultat: I studie I undersöktes vilka teoretiska utgångspunkter och professionsspecifika modeller arbetsterapeuter i Sverige ansåg påverka den psykiatriska vården och den psykiatriska arbetsterapin. Det psykosociala perspektivet var den teoretiska utgångspunkt som hade störst påverkan både på psykiatrisk vård och på psykiatrisk arbetsterapi. Den arbetsterapeutiska modell som flest identifierade var Model of Human Occupation. Detta resultat indikerar att Model of Human Occupation verkar vara användbar inom arbetsterapi och motiverade vidare användning av modellen i denna avhandling. Det som dock också framkom i studie I var att arbetsterapeuter inom psykiatrisk vård använde professionsspecifika modeller i en relativt liten utsträckning. Ett sätt att öka tillämpningen av teori i praktik är att använda teoretiskt grundade bedömningsinstrument. I studie II, III, IV och V har endera av de Model of Human Occupation- baserade bedömningsinstrumenten WRI och WEIS använts och värderats.I studie II och V prövades WRI:s förmåga att predicera återgång i arbete efter långvarig sjukskrivning. Det område i WRI som uppvisade bäst prediktivitet var området ”Självuppfattning” vars variabler beaktar personens motivation för återgång i arbete i form av personens upplevelse av kompetens och effektivitet för att utföra arbetsuppgifter och hantera utmaningar i arbetet. De två WRI variabler som bäst kunde predicera vilka som skulle återgå respektive inte återgå i arbete vid uppföljning efter två år var: ”Tro på sin arbetsförmåga”, och ”Dagliga vanor och rutiner”. Resultaten tyder på att kunskap om hur tro på den egna förmågan stärks och kunskap om dagliga vanor och rutiners påverkan på utförande av arbete är central vid genomförande av interventioner i syfte att stödja personer att återgå till arbete efter sjukskrivning.I studie III prövades WRI:s konstrukturella validitet i en internationell studie. Samtliga variabler i WRI, förutom de som tillhör miljöområdet, uppvisade en god konstrukturell validitet dvs mätte psykosociala faktorers påverkan på arbetsförmågan. WRI:s skattningsskala verkar stabil och valid mellan olika länder och för personer med olika diagnoser. I analysen framkom att WRI kunde särskilja mellan personers psykosociala arbetsförmåga på tre olika nivåer.I studie IV undersöktes hur personer med erfarenhet av långtidssjukskrivning uppfattar att faktorer i arbetsmiljön stödjer respektive hindrar personens utförande av arbete och välbefinnande genom bedömningar utifrån WEIS. De faktorer som uppfattades som meststödjande var olika former av sociala interaktioner på arbetet samt uppfattningen om arbetets värde och mening. De faktorer som uppfattades som mest hindrande var olika krav i relation till arbetsgenomförandet samt den belöning som erhålls för arbetet.Konklusion: Sammanfattningsvis så kan WRI användas för bedömning av psykosociala faktorers påverkan på arbetsförmågan. I WRI ingår variabler som kan predicera återgång till arbete upp till två år efter genomförd bedömning. WEIS verkar användbart för att identifiera arbetsmiljöfaktorer som stödjer respektive hindrar personers välbefinnande och utförande av arbete. Att komplettera olika datainsamlingsmetoder är en förutsättning för att uppnå en så god bedömning av arbetsförmåga som möjligt. Den information som WRI- och WEISintervjuer genererar är värdefull, då den kan utgöra en viktig grund för planering av individspecifika rehabiliteringsinsatser. Bedömningsinstrumenten WRI och WEIS med sin teoretiska förankring i Model of Human Occupation kan anses vara användbara för att identifiera psykosociala och miljömässiga rehabiliteringsbehov i syfte att stödja personer i processen åter till arbete efter sjukskrivning.
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| 45. |
- Ekdahl, Christer, 1962-
(författare)
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Infective Endocarditis : aspects of pathophysiology, epidemiology, management and prognosis
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infective endocarditis (IE) is a rare but complex disease that is fatal if untreated. With a modern combination of antimicrobial therapy and heart valve surgery, mortality is still 10-20 %. The structure of the endocarditis vegetation impedes the penetration of phagocytic cells such as monocytes and granulocytes. This leads to high bacterial counts inside the vegetation and the need for long treatment courses with a combination of intravenously administered bactericidal antibiotics.The aim of this thesis was to study the changes in epidemiology, management, and mortality at our hospital between 1980 and 2001, and to identify prognostic factors associated with mortality. To assess the issue of referral bias, differences between referred episodes and episodes from our local community were studied. Additional aims were to study the occurrence of the pro-chemotactic cytokines IL-8 and TNF-α in heart valves and vegetations during the active phase of IE, and to study the effect of the glycopeptide antibiotic vancomycin in dense staphylococcal cultures in vitro. As it is a rare and complex disease, management of IE is usually complicated for non-specialists. For this reason a computerised decision support system for IE was developed and evaluated.Between 1980 and 2001, the occurrence of Staphylococcus aureus IE and the use of early heart valve surgery increased significantly, regardless of whether the episodes were referred or of local origin. Glycopeptide antibiotics, mainly vancomycin, were used more frequently, especially among referred patients. Referred patients were younger, predominantly male, had more complications, and received surgical treatment more often than patients from our local community. The reason for the lower frequency of female patients in the referral cohort cannot be explained by more comorbidity or fewer complications. The differences between referred and local episodes seen in our study highlight the need for assessment and adjustment for referral bias in IE studies (Paper I).In six patients who needed early heart valve surgery, the largest numbers of IL-8-containing cells, and the greatest amount of inflammation, were seen in patients with short preoperative antimicrobial treatment courses. No such relationships were seen with respect to TNF-α-containing cells. The IL-8-containing cells and the inflammatory cells were predominantly scattered in the heart valve stroma or in the margin of the vegetation (Paper II). The primary effect of IL-8 is to stimulate chemotaxis of polymorphonuclear neutrophil granulocytes. This indicates that there is no deficiency of IL-8 in the area close to the vegetation as a cause of the localised agranulocytosis often present inside the vegetation.Our study revealed a need for computerised decision support systems (DSSs) in the field of IE, but to be used in clinical practice these DSSs need be part of knowledge bases covering larger domains (Paper IV). Some of our initial ideas described in Paper III, especially the use of Internet technology and the combination of rule-based advice and explanatory hypertext, will probably be included in these knowledge bases.In vitro, there is a rapid reduction of free vancomycin in broth containing dense staphylococcal cultures. Consequently, there is a simultaneous increase in broth MICs, particularly in high inocula, which is not caused by a development of resistance (Paper V). These findings need further evaluation in vivo, but indicate that the dosing regimen of vancomycin is of particular importance in staphylococcal infections with dense inocula, e.g. infective endocarditis.Diabetes mellitus and moderate to severe heart failure were independent risk factors for 6-month mortality in left-sided, Duke definite IE episodes, regardless of referral or local origin of the episodes. Early heart valve surgery had a positive impact on the 6-month mortality in the referral cohort of episodes, which may be due to referral bias (Paper VI).
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| 46. |
- Ekholm Selling, Katarina, 1976-
(författare)
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Birth-characteristics, hospitalisations, and childbearing : Epidemiological studies based on Swedish register data
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the past decades there has been an improvement in the medical treatment of children born preterm or with reduced foetal growth. This has resulted in a much higher survival rate of these children, but also in a higher number of surviving children with chronic conditions. These changes have, in turn, increased interest in investigating the connection between birth-characteristics and outcomes in later life. The overall aim of the present thesis was to study the relations between birth-characteristics, subsequent hospitalisations, and childbearing by means of data available in Swedish population-based registries.The study population in this thesis consisted of women (and men in Paper III) born in 1973-75 according to the Medical Birth Register and the Total Population Register. Information available in other registries, such as the Hospital Discharge Register, was obtained by individual record linkage.In Paper I, 148,281 women, alive and living in Sweden at 13 years of age, were included. Of the women, 4.1% were born preterm and 5.4% were born small for gestational age, and approximately 30% of all women had given birth between 13 and 27 years of age. We found that reduced foetal growth and possibly preterm birth were related to the likelihood of giving birth during the study period. The intergenerational effects of preterm birth and reduced foetal growth were investigated in Paper II and the study population consisted of 38,720 mother-offspring pairs. An intergenerational effect of reduced foetal growth was found, and reduced foetal growth in the mother also increased the risk for preterm birth in the child.Paper III was concerned with 304,275 men and women living in Sweden at 13 years of age. Of these men and women, 30% were hospitalised during adolescence and early adulthood (i.e. between 12 and 23 years of age). We found that men and women born small for gestational age or preterm were more likely to be hospitalised, and that those born small for gestational age seemed to be more at risk compared to those born preterm. Finally, in Paper IV, the relation between hospitalisations during adolescence and the likelihood of giving birth was studied in 142,998 women living in Sweden at 20 years of age. We found that a majority of the causes of hospitalisation during adolescence were positively connected to the likelihood of giving birth between 20 and 27 years of age. The relations presented in Papers I-IV were evident although socio-economic characteristics were adjusted for.
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| 47. |
- Ekstedt, Mattias, 1976-
(författare)
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Non-Alcoholic Fatty Liver Disease : A clinical and histopathological study
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fatty liver has previously often been associated with excessive alcohol consumption. During the last two decades, the interest in fatty liver occurring in non-drinkers i.e. non-alcoholic fatty liver disease (NAFLD) has increased dramatically. Today, NAFLD is considered as the most common liver disease in the developed world. It is strongly associated with obesity, insulin resistance, and hypertension. Thus, NAFLD is considered as the hepatic manifestation of the metabolic syndrome.The spectrum of NAFLD includes: simple fatty liver without necroinflammatory activity; non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocellular injury, inflammation, and fibrosis; cirrhosis; and in some individuals hepatocellular carcinoma.The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the pathologist uses a four-graded scale: 0–3 or none, slight, moderate and severe. In this thesis we show that there is a considerable inter- and intraindividual variation in such scoring methods and that a more standardised and quantitative approach is preferable. The area/volume of fat in liver biopsies is greatly overestimated when assessed semiquantitatively. Moreover, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis.The long-term clinical and histopathological course of 129 consecutively enrolled NAFLD patients was studied. Mean follow-up (SD) was 13.7 (1.3) years. Survival of NASH patients was reduced compared with a matched reference population. These subjects more often died from cardiovascular and liver-related causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain.During follow-up, 17 patients had been prescribed a statin. At follow-up, patients on medication with statins had significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Although patients under statin treatment exhibited a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. It is concluded that statins can be prescribed safely in patients with elevated liver enzymes because of NAFLD.Alcohol consumption was evaluated with a validated questionnaire combined with an oral interview. In a multivariate analysis moderate alcohol consumption, particularly when frequency of heavy episodic drinking was analysed, consistent with the diagnosis of NAFLD to be set, was independently associated with fibrosis progression in NAFLD.The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. We evaluated the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in our cohort of NAFLD patients. Although the NAS was independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score was limited due to significant overlap in clinical development between NAS-score groups.
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| 48. |
- Elander, Nils
(författare)
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Inflammation-associated genes and genetic variations in colorectal cancer
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer is a major cause of morbidity and mortality around the world, each year affecting about one million individuals worldwide. The disease is characterized by an accumulation of genetic alterations, and a sequence of events leading to the development of an invasive and metastasising tumour. Chronic or dysregulated inflammation may contribute to tumour initiation and progression via the release and activity of various mediators – e.g. cytokines, prostaglandins, inducible nitric oxide synthase (NOS2), matrix metalloproteinases (MMPs), and vascular endothelial growth factors (VEGF). In the present thesis, genes and genetic alterations controlling these events were analysed and discussed within the context of colorectal cancer.Prostaglandins, being generated from arachidonic acid in reactions dependent on cyclooxygenases (COX-1, COX-2), have been implicated in carcinogenesis of many organs. Since the quite recent characterization of the terminal and specific prostaglandin synthases, which act downstream of COX enzymes, the search for molecular targets which selectively suppress individual prostanoids has been intensified. In papers I-II, the role and regulation of inducible prostaglandin E2 (PGE2) synthase - mPGES-1 - were explored within the context of intestinal cancer. mPGES-1 was genetically deleted in the ApcMin/+ mouse - yielding marked suppression of PGE2 generation in intestinal and tumour tissue. However, a shift towards enhanced generation of non-PGE2 prostanoids was observed in mPGES-1 knock out mice, and these mice developed more and larger instestinal tumours. These results therefore indicate that targeting mPGES-1 may paradoxically promote tumourigenesis, most likely by secondary effects on other potentially pro-tumoural mediators. We also explored the relation of the commonly mutated APC gene and mPGES-1 in colon tumour cells, and found that high expression of mPGES-1 was associated with the presence of wild type APC. Rather than by regulating putative β-catenin/Tcf binding sites of the mPGES-1 promoter, APC seems to influence the stabilisation of mPGES-1 mRNA.In papers III-V, the possible contribution of variations in regulatory regions of genes encoding NOS2, MMPs, and VEGF, was assessed in populations of colorectal cancer patients and healthy control individuals. A single nucleotide insertion (1G/2G) at -1607 upstream the transcription start site of the MMP-1 gene was identified to be a susceptibility factor for colorectal cancer development, although no relation with disease characteristics was observed. Except for a rather uncommon combination of two individual polymorphisms of the VEGF gene, investigated genetic variations of VEGF, other MMPs, and NOS2, were not associated with colorectal cancer susceptibility or clinicopathological characteristics. We therefore suggest that other molecular events play more significant roles for the dysregulation of these genes in colorectal tumours.In summary, accumulating evidence, including the results here presented, suggest significant albeit complex roles of inflammation-induced genes and mediators in colorectal tumourigenesis. The present results may aid in identifying or excluding potential biomarkers and drug targets within cancer-related inflammation.
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| 49. |
- Eliasson, Pernilla, 1979-
(författare)
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Live and Let Die : Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.
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| 50. |
- Elmerstig, Eva, 1969-
(författare)
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Painful Ideals : Young Swedish women´s ideal sexual situations and experiences of pain during vaginal intercourse
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many young women today are concerned about their sexual health; an increasing number of them consult gynaecologists, youth centres (YCs) and general practitioners with vulvar problems such as painful sensations associated with vaginal intercourse (VIC). It is known that some women continue to have VIC despite pain. Theoretically, repeated painful VIC might elicit vaginistic reactions, which may increase the pain and induce vicious circles. Since many clinicians and researchers nowadays notice that pain during VIC often starts at young age, it is important to investigate how pain during VIC starts and is maintained in younger populations. The overall aim of this thesis was to investigate young women’s experiences of ideal sexual situations and pain during VIC.Women aged 13-22 years participated in our studies, which used both quantitative (study I and IV) and qualitative (study II and III) methods. For paper I, a questionnaire was developed and used in a YC sample (n=300); informants for paper II were selected from that sample to participate in qualitative interviews (n=16). Another qualitative interview study for paper III with a complimentary research question was conducted in a different YC sample (n=14). For paper IV, a questionnaire was developed based on the results from study I, II and III to test the hypotheses derived from study II in a sample of female high school students (n=1566).The findings revealed that 65% of the women reported pain related to first VIC. Among those who reported VIC during the previous month, 49% had experienced pain and/or discomfort during VIC during that same period (paper I). In paper IV, 47% of the women reported experience of pain and/or discomfort during VIC, and among those, 47% continued to have VIC, 22% feigned enjoyment, and 33% omitted telling the partner about their pain. In paper II, the women’s reasons for continuing to have VIC despite pain were: striving to reach their ideal image of a woman, characterized as always willing to have VIC; being perceptive of their partner’s sexual needs; and being able to satisfy their partner. In paper IV the hypotheses derived from study II were confirmed and showed, for example that a significantly higher proportion of women who continue to have VIC despite pain than women who did not had difficulty refusing sex when the partner wants it, felt inferior to the partner during sex, regarded the partner’s satisfaction as more important than their own, felt dissatisfaction with their sex life, and feigned enjoyment despite pain. In a multivariate model, continuing to have VIC despite pain was associated with feelings of being inferior to the partner during sex (adjusted OR 1.82; CI 1.10-3.02), dissatisfaction with their own sex lives (adjusted OR 1.76; CI 1.14-2.72) and feigning enjoyment while having pain (adjusted OR 7.45; CI 4.37-12.69).The major reason for continuing to have VIC was that the partner’s enjoyment was prioritized higher than their own (paper IV). In paper III, we found that women without pain during VIC also felt pressure from social norms and demands and had experienced partners “driving their own race”. However, they managed to some extent to resist these unequal gender norms because of their urge to experience pleasure.In conclusion, pain during VIC is a common complaint among young Swedish women, and a high proportion of them continue having VIC despite pain. The women’s notion of prioritizing the partners´ enjoyment before their own illustrates that unequal gender regimes affect young women’s (hetero)sexuality negatively.
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