| 51. |
- Aili Fagerholm, Siri, 1980-
(författare)
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Insulin signaling in primary adipocytes in insulin sensitive and insulin resistant states
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Increasing numbers of people world-wide develops the disease type 2 diabetes. Development of type 2 diabetes is characterized by a shift from an insulin sensitive state to an insulin resistant state in peripheral insulin responding organs, which originates from the development of insulin resistance in the adipose tissue. Insulin resistance in combination with reduced pancreatic insulin secretion lead to overt type 2 diabetes.In this thesis, the insulin signaling network in primary adipocytes was analyzed. Key proteins and mechanisms were studied to gain deeper knowledge of signaling both in the insulin sensitive state and in the insulin resistant state produced by rapid weight gain as well as in type 2 diabetes.The surface of the adipocyte is dotted with invaginations in the cell membrane called caveolae that act as important metabolic and signaling platforms in adipocytes, and also harbor the insulin receptor. In paper I we show that insulin stimulation of primary adipocytes results in a rapid phosphorylation of the insulin receptor and caveolin-1, and that internalization of the proteins is mediated by endocytosis of caveolae.Weight gain due to overfeeding and obesity has been associated with the development of insulin resistance in insulin sensitive tissues such as the adipose tissue. In paper II we show that short-term overfeeding for one month of lean subjects results in an insulin resistant state. At the end of the study, the subjects had developed a mild systemic insulin resistance. Moreover, in isolated subcutaneous adipocytes we found several alterations of the insulin signaling pathway that mimicked alterations found in isolated subcutaneous adipocytes from subjects with type 2 diabetes.In paper III we present a first dynamic mathematical model of the insulin signaling network in human adipocytes that are based on experimental data acquired in a consistent fashion. The model takes account of insulin signaling in both the healthy, insulin sensitive state and in the insulin resistant state of type 2 diabetes. We show that attenuated mTORC1-mediated positive feedback to control of phosphorylation of IRS1 at Ser307 is an essential component of the insulin resistant state of type 2 diabetes. A future application of the model is the identification and evaluation of drug targets for the treatment of insulin resistance and type 2 diabetes.In paper IV we examine the protein kinase that catalyzes the insulin stimulated mTORC1- mediated feedback to IRS1. We find that the phosphorylation of IRS1 at Ser307 is not likely to be catalyzed by the kinases S6K1, mTOR or PKB. However, a catalyzing protein kinase for the in vitro phosphorylation of IRS1 at Ser307 was found to be associated with the complex mTORC1.In conclusion, this thesis provide new insights and characterize mechanisms of the intrinsically complex insulin signaling network of primary adipocytes, both in insulin sensitive and insulin resistant states.
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| 52. |
- Akanda, Nesar, 1972-
(författare)
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Voltage-dependent anion channels (VDAC) in the plasma membrane induce apoptosis
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Apoptosis, or programmed cell death, is essential for proper development and functioning of the body systems. During development, apoptosis plays a central role to sculpt the embryo, and in adults, to maintain tissue homeostasis by eliminating redundant, damaged or effete cells. Therefore, a tight regulation of this process is essential. Cell shrinkage associated efflux of K+ and Cl– through plasma membrane ion channels is an early event of apoptosis. However, little is known about these fluxes. The aim of this thesis was to investigate ion channels in the plasma membrane of neurons undergoing apoptosis. We studied differentiated (the mouse hippocampal cell line HT22, the human neuroblastoma cell line SK-N-MC, and rat primary hippocampal neurons) and undifferentiated (rat primary cortical neural stem cells cNSCs) cells with the patch-clamp technique. All cell types displayed a low electrical activity under control conditions. However, during apoptosis in differentiated neurons, we found an activation of a voltage-dependent anion channel. The conductance of the channel is 400 pS, the voltage dependence of the opening is bell shaped with respect to membrane voltage with a maximum open probability at 0 mV, and the Cl− to cation selectivity is >5:1. These biophysical properties remind about the voltage-dependent anion channel normally found in the outer mitochondrial membrane (VDACmt). Hence, we call our apoptosis-inducing plasma membrane channel VDACpl. The molecular identity of the channel was corroborated with the specific labelling of different anti-VDAC antibodies. Block of this channel either with antibodies or with sucrose prevented apoptosis, suggesting a critical role for VDACpl in the apoptotic process. VDACpl is a NADH (-ferricyanide) reductase in control cells. We found that the enzymatic activity is altered while the VDACpl channel is activated during apoptosis. Surprisingly, in cNSCs we did not find any activation of VDACpl, no VDACpl-specific labelling, no enzymatic activity, and no prevention of apoptosis with VDACpl-blocking strategies. Instead, we found an activation of a voltage-independent 37 pS ion channel, and that the Cl– channel blocker DIDS prevented apoptosis in cNSCs. Our finding that activation of VDACpl is critical for apoptosis in differentiated neurons hopefully can lead to new strategies in the treatment of several diseases related to apoptosis.
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| 53. |
- Al-Hawasi, Abbas, 1976-
(författare)
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Retinal ganglion cell examination with Optical Coherence Tomography reflects physiological and pathological changes in the eye and the brain.
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The retinal ganglion cell is situated in the inner retina and its axons, composing the retinal nerve fiber layer (RNFL), leave the eye to form the optic nerve. These cells develop embryologically from the forebrain and later during development re-establish connections with different parts of the brain serving different purposes. This unique position and connections make it possible to be investigated with different methods. Optical Coherence Tomography (OCT) is an accessible and easily operated clinical device that can provide a detailed image of this layer at a few micrometers level of precision in measurements. In this thesis we aimed to see whether examining these cells with OCT could reflect physiological and pathological changes in the eye and brain.In cases of optic neuritis (Paper I), the OCT examination showed early thickening of the peripapillary (pRNFL) followed by thinning which takes 6-9 months to reduce to below normal thickness without the ability to distinguish between the real from pseudo thinning. The ganglion cell -inner plexiform layer (GCL-IPL) layer, however, showed a thickness reduction within a few weeks to 3 months without pseudo thinning. In cases of Idiopathic Intracranial Hypertension (IIH) (Paper II), the GCL-IPL remained unchanged and there was no difference in pRNFL thickness compared to healthy controls, whereas the optic disc parameters of rim thickness, rim area, cup volume and cup/disc ratio differed significantly (P<0.05).In cases of benign multiple sclerosis (Paper IV), the OCT could detect that eyes which are not affected by optic neuritis had an annual thinning rate of the RNFL and GCL-IPL similar to a healthy population (P>0.05) which may indicate the benign course of the disease. In cases of physiological factors affecting the GCL in healthy population (Paper III) the OCT examination showed that there was a significant thinning rate of the layer with age (P<0.05), but the thinning was not significant when sex and axial length of the eye were taken into consideration. Males had a thicker GCL volume than females and with age a significant reduction in GCL volume was noted in females but not in males. A Longer axial length of the eye found to be associated with thinner GCL volume. In conclusion retinal ganglion cell changes detected with OCT can reflect physiological and pathological changes in the eye and brain.
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| 54. |
- Alehagen, Siw, 1953-
(författare)
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Fear pain stress hormones during labor
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the thesis were to develop a measure of fear during labor and to investigate women's experiences of fear and pain during labor and delivery as well as their levels of stress hormones. We also wanted to explore the associations between fear, pain, stress hormones and the duration of labor. Finally, we aimed to examine the relationships between pre-and postpartum fear, and fear and pain during labor.The measurement of fear was developed in two substudies. First we composed a list of 60 fear-related items and their contrasts and tested it in a group of 92 women in labor. After psychometrical analyses, 10 items were selected for the final scale. The scale was then tested in another group of 57 women in labor. Via semi-structured interviews the content of the items was documented and analyzed.Fifty-five nulliparous women participated in the investigation of women's experiences of fear, pain, levels of stress hormones and duration of labor. During gestation weeks 37-39, we measured levels of fear of childbirth, urinary catecholamines and salivary cortisol. During labor, hourly measurements were performed of fear, pain and levels of stress hormones. Finally, at two hours, two days and five weeks postpartum, fear of childbirth and stress hormones were measured.The questionnaire that measures fear during labor was called the Delivery Fear Scale (DFS). The DFS has an alpha coefficient of .8 and has good psychometric qualities in both nulliparous and parous women. It takes women in labor between 30 and 90 seconds to listen to and answer all the statements. We found that nulliparous women had higher fear during phase 1 of labor (cervix dilatation 3-Scm) than parous women. Fear during phase 1 of labor predicted the total amount of pain relief received during labor, but not the duration of remaining part of labor, nor the occurrence of instrumental vaginal delivery or emergency cesarean section.The results from the subsequently studies showed that there was an increase of the levels in stress hormones from pregnancy to labor. Epinephrine and cortisol increased more than 500% and norepinephrine approximately 50%. In women without EDA fear and cortisol increased throughout labor. In women with EDA cortisol did not increase, fear, pain and catecholamine levels first decreased after the administration of EDA but at the end of labor fear and pain increased. In phase 1, fear, but not pain, was more intensive in women who later subsequently received EDA than in those who did not. Fear and pain correlated positively during labor. A high level of epinephrine was associated with a shorter duration of phase 1 of labor. Postpartum fear of childbirth was higher in women who had received EDA during labor than in those who had not. Pre- and postpartum fear of childbirth correlated positively with fear but not with pain during phase 1 of labor.In conclusion, DFS is a new measure of fear during labor with good psychometric qualities. Childbirth is a stressful event associated with exceptionally high levels of stress hormones. In this study women's experiences of fear and pain were associated throughout labor. The administration of EDA heavily influenced the course of fear, pain and stress hormones. Women who later received EDA had higher scores of fear but not of pain early during labor than those who did not receive EDA. Late pregnant women who fear childbirth are prone to have a fearful delivery, as reported during the actual labor and postpartwn.
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| 55. |
- Alehagen, Urban, 1951-
(författare)
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Heart failure in primary health care : special emphasis on natriuretic peptides in the elderly
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: This thesis focuses on heart failure among elderly patients in the community who usually are not included in studies on heart failure. The heart failure syndrome is an increasing problem in Western society. Severe heart failure is often easy to diagnose compared with light to moderate heart failure, which is more frequent in patients in the community,Doppler echocardiography is the most commonly used method to objectively verify an abnormal cardiac function, mostly the systolic function. One goal of this thesis was to evaluate both the systolic and diastolic functions. Another goal was a study of the possible utility of the B-type natriuretic peptide, BNP (brain natriuretic peptide), and the amino terminal fragment of its precursor, proBNP (N-terminal proBNP) as tools in the diagnosis of heart failure in elderly patients.Methods: In a primary health care setting, 510 elderly patients (age range 65-82 years) with symptoms and signs possibly associated with heart failure were examined concerning patient history, ongoing pharmacological treatment, clinical examination, chest x-ray, electrocardiogram, Doppler echo cardiography, and selected biochemical measurements of blood samples. Additionally, the natriuretic peptide BNP and the aminoterminal fragment of proBNP were analyzed for a possible influence of gender, age, impaired cardiac function assessed using Doppler echocardiography, other diseases, and phannacological treatment. We followed our study population for six years, carefully registering mortality with death certificates. This information was used in analyzing the risk of cardiovascular death based on Cox proportional hazard regression. We present a model for estimating the risk of cardiovascular death in the individual patient.Results: Almost half of our study population [mean age 73 (SD 6) years] with symptoms of possible heart failure had signs of impaired cardiac function on Doppler echocardiography. Half of these individuals had isolated impairment of the diastolic function. Almost two thirds of the elderly patients who had an ejection fraction of less than 40% did not receive treatment with ACE inhibitors, one of the cornerstones in the treatment of heart failure.BNP and N-terminal proBNP were equally effective in detecting impaired cardiac function. As a response to increased filling pressure they probably provide earlier information on the haemodynamic situation than Doppler echocardiography does.In these elderly patients, functional class (NYHA class III: 7 times increased risk), in vivo examination by Doppler echo cardiography (EF<30%: 8 times increased risk) and the in vitro measurement of plasma BNP (>27.8 pmol/L: 11 times increased risk) and N-terminal proBNP (>109 pmol/L: 7 times increased risk) could be used as prognostic determinants in assessing the risk of cardiovascular death.Conclusion: The results indicate that a focused patient history and clinical examination provides important information that is often sufficient for the prognostic evaluation of a patient with heart failure symptoms. Additional information may be obtained with Doppler echo cardiographic examination and measurement of plasma BNP or N-terminal proBNP. The relationship between BNPIN-terminal proBNP concentration and risk of cardiovascular death may be analysed to define decision limits for the concentrations of these peptides as regards further diagnostic procedures and/or phannaceutical treatment.
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| 56. |
- Alexandersson, Kristina
(författare)
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Sickness absence in a Swedish county : with reference to gender, occupation, pregnancy and parenthood
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The occurrence of sickness absence in relation to gender, occupation, age, pregnancy and parenthood was analysed in a Swedish county. Data on all new sick-leave spells exceeding 7 days in the county of Östergötland (400,000 inhabitants) were recorded in 1985-1987. Information on diagnoses, occupation, age, gender, number of children etc. for each of the 45,000 persons sicklisted/year were included in the database. Incidence measures were obtained using census data as denominator.The largest and most consistent variation in occurrence of sickness absence concerned occupation and gender, When categorising the occupations according to degree of gender-segregation, women in the extremely maledominated group (>90% men) had exceptionally high sick-leave rates, while both men and women in the group of gender-integrated occupations had significantly lower sick-leave rates. These variations with male-and female domination of occupational groups were found for sickness absence in general as well as for sick-leave due to pregnancy-related diagnoses. Men with custody of young children had the lowest sickness absence, young women in the same situation the highest, while there were no gender differences in persons without young children. Sickness absence due to pregnancy-related diagnoses varied to a large degree with occupation, but was still high in occupations with a generally low sickness absence, and increased much more than in any otherdiagnostic group over the three years. About half of the gender differences in sickness absence could be explained by sickness absence among pregnant women.In conclusion, the occurrence of sickness absence was associated with gender, age, occupation, gender segregation of occupation, pregnancy and parenthood. Further research should focus on etiological studies and intervention trials.
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| 57. |
- Alexandrou, Christina, 1981-
(författare)
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MINISTOP 2.0 : a smartphone app integrated in primary child health care to promote healthy diet and physical activity behaviors and prevent obesity in preschool-aged children
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundChildhood overweight and obesity is currently estimated to affect 39 million children under the age of five worldwide. After the COVID-19 pandemic, further increases have been observed in several countries including Sweden, where an increased incidence was observed in 3- and 4-year-old children, especially in disadvantaged areas. This development emphasizes the urgent need for population-based childhood obesity prevention interventions, and Swedish primary child health care provides an ideal setting for primary preventive efforts during the preschool years. However, thus far, previous child health care-based obesity prevention interventions have demonstrated limited effectiveness. As previous interventions also have been face-to-face delivered and thus resource-demanding; new, and scalable ways of delivering interventions also need to be evaluated. Mobile health or mHealth refers to the use of mobile devices for medical and public health practice and provides opportunity for development and dissemination of digital interventions for various purposes and populations at scale. This thesis reports the results of the MINISTOP 2.0 project, which covers the development and evaluation of the MINISTOP 2.0 digital intervention, from adaptation and translation of the intervention to Somali, Arabic and English (Paper I), to evaluation of real-world effectiveness within the Swedish primary child health care setting (Paper II) followed by exploration of user experiences and implementation aspects (Paper III) and a cost-consequence analysis of the intervention costs (Paper IV). AimThe overall aim of this thesis was to evaluate whether a 6-month parent-oriented mHealth intervention (MINISTOP 2.0 app), embedded in the routine services of Swedish primary child health care, can be used to improve diet and physical activity behaviors, and decrease the prevalence of over-weight and obesity in 2.5-to-3-year-old children. MethodsThe MINISTOP 2.0 project utilized a hybrid type 1 effectiveness-implementation study design to enable simultaneous evaluation and exploration of intervention effectiveness, user experiences and implementation aspects. Paper I: A qualitative exploration of user requirements in an app-based parental support intervention was conducted through three focus group interviews with Somali- (n = 5), Arabic- (n = 4), and Swedish-speaking parents (n = 6), and individual interviews with child health care nurses (n = 15). Data was analyzed using thematic analysis. Paper II: A two-arm parallel randomized controlled trial was conducted at 19 child health care centers located in six Swedish regions. Participating parents (n = 552) were invited during their routine visit at 2.5/3-years at their primary child health care center. All baseline and follow-up procedures were conducted by the nurses. Parents that were randomized to the control group received standard care, while the intervention group received access to the MINISTOP 2.0 app for six months, alongside standard care. Prior to randomization, nurses measured the child’s height and weight for assessment of BMI, and parents answered a questionnaire about their child’s intake of fruit and vegetables, sweet and savory treats, and sweet drinks; time spent in moderate-to-vigorous physical activity (MVPA) and screen time; and parental self-efficacy (PSE) for promoting healthy diet, physical activity, and screen time behaviors. These baseline procedures were then repeated at a 6-month follow-up visit to the child health care center. Paper III: A qualitative exploration of user experiences, acceptability, and feasibility of the MINISTOP 2.0 intervention was conducted through individual interviews with parents (n = 24) with diverse backgrounds, and with child health care nurses (n = 15). Data was analyzed using content analysis. Paper IV: Data on all costs related to the MINISTOP 2.0 intervention, including costs for app and interface upkeep as well as salary costs for introduction and dissemination of the app by nurses, was collected retrospectively. A cost-consequence analysis was then performed to estimate the costs of the intervention. ResultsPaper I: Parents expressed several challenges related to promoting healthy eating behaviors, such as worrying about their child not eating enough, and difficulties balancing different food cultures. There were also requests for the app content to be accessible through alternative modes of delivery (e.g., audio/video) for parents with low literacy. Nurses underlined the importance of supporting parents early with health behavior interventions, and the value of a shared digital platform, available in several languages, to facilitate communication with parents. Paper II: Seventy-nine percent of the participating parents (n = 552) were mothers and 62% had a university degree. Among the children, 24% had two foreign-born parents. Children in the intervention group had lower in-takes of sweet and savory treats (-6.97 g/day; p = 0.001), sweet drinks (-31.52 g/day; p < 0.001), and screen time (-7.00 min/day; p = 0.012) com-pared to the control group at follow-up. Parents in the intervention group also reported higher total PSE (0.91; p = 0.006), PSE for promoting healthy diet behaviors (0.34; p = 0.008) and PSE for promoting healthy physical activity behaviors (0.31; p = 0.009) compared to the control group. For children’s MVPA or BMI z-score, no statistically significant effect was observed between groups. Finally, parents also reported high satisfaction with the app, and 54% reported using the app once a week or more. Paper III: Findings indicated that the app was well accepted and appreciated, as it increased knowledge and awareness around current health behaviors. Furthermore, evidence-based information available in one place and from a trusted source, was highly valued, especially when living in a country with a different culture than your own. The app was also acknowledged as a feasible support tool and a suitable complement to the standard care offered during visits. Finally, due to the accessibility in different languages and the possibility of disseminating the app at scale, both nurses and parents described the app as an appropriate tool for reaching larger populations of parents as well as parents in need of additional support. Paper IV: The total cost for the MINISTOP 2.0 intervention was 437 439 SEK based on the 277 families in the intervention group. The cost for child health care nurses introducing and registering families for the app represented only 9% of the total cost per family, which was considerably lower in comparison to other similar childhood obesity prevention interventions. Also, notably, for upscaling, sharing running costs for the user interface for larger populations of children, would result in much lower total costs per family. ConclusionsOverall, qualitative findings for adapting the intervention highlighted the need for early access to information, as well as the importance of adapting interventions to also be accessible for parents with migrant background and parents with lower literacy. When disseminated through primary child health care, the MINISTOP 2.0 intervention resulted in statistically significant reduced intakes of sweet and savory treats, sweet drinks, and screen time in children (primary outcomes) as well as increased PSE for promoting healthy diet and activity behaviors (secondary outcome). The app was well accepted and perceived as a feasible support tool for parents. Furthermore, accessibility in different languages was also appreciated. Finally, the relatively low salary costs in comparison to face-to-face interventions suggest that the MINISTOP 2.0 app and caregiver interface may be an affordable preventive effort for early promotion of healthy lifestyle behaviors in children when scaled up on a population level. Altogether, the results from the papers in this thesis support the large-scale implementation of the MINISTOP 2.0 app within the Swedish primary child health care setting for promotion of healthy lifestyle behaviours in 2.5-to-3-year-old children.
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| 58. |
- Alfredsson, Joakim
(författare)
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Management and Outcome in Non ST-Elevation Acute Coronary Syndromes : Similarities and Differences Between Women and Men
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Non ST-elevation Acute Coronary Syndromes are the most frequent manifestations of acute ischemic heart disease. Gender differences in treatment intensity, including differences in level of care, have been reported. Also differences in benefit from certain treatments, especially invasive treatment, have been discussed. Finally, difference in outcome between men and women, have been proposed. Results have been inconsistent, partly depending on if and how adjustment for differences in background characteristics has been made. The aims of the studies in this thesis were to assess differences between the genders in baseline characteristics, level of care, medical treatment and non-invasive and invasive cardiac procedures. The aims were also to determine gender differences in short and long-term mortality, including impact of level of care, and to determine differences between the genders in benefit from an invasive strategy, with special reference to benefit in women.Method: We used prospectively collected data from the RIKS-HIA registry in two studies (Paper I and IV). In one study we merged data from patients admitted to general wards in the south-east region of Sweden (The AKUT registry), with data from patients admitted to CCU´s (RIKS-HIA) at participating hospitals during the same time (Paper II). We also randomly assigned women to a routine invasive or a selective invasive treatment strategy, and performed a meta-analysis, to determine gender differences in benefit from a routine invasive strategy (Paper III).Results: Women were older than men and more likely to have a history of diabetes and hypertension, while men were more likely to have a history of myocardial infarction and revascularisation. Women were also more likely to have normal coronary arteries on the angiogram. After adjustment for baseline differences there were only minor, and directionally inconsistent, differences between women and men in pharmacological treatment. Men were more often referred for coronary angiography, even after adjustment. While CABG-rate was lower in women, after adjustment PCI-rate was similar or even higher compared to men. After adjustment for differences in age, longterm outcome was better in women. In our small but randomised trial there was no benefit from a routine invasive strategy in women. A meta-analysis indicated interaction between gender and treatment strategy, with lack of benefit in women, in contrast to in men. However, our large observational study indicated no gender difference with an invasive strategy. Moreover, benefit was similar in women and men with invasive treatment.Conclusion: There are substantial differences between women and men in baseline characteristics that affect management and outcome more than gender per se. After adjustment women have better long-term outcome than men. There appear to be a difference in benefit from a routine invasive strategy between the genders, with less benefit in women, but in routine clinical management there was no difference between women and men managed with an invasive strategy.
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| 59. |
- Alfredsson Ågren, Kristin, PhD Student, lecturer, 1971-
(författare)
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Internet use and digital participation in everyday life : Adolescents and young adults with intellectual disabilities
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Internet use is an integral part of everyday life in contemporary society, especially among young people. It is used to perform activities in everyday life by an increasing proportion of the population. However, knowledge about access to and use of the internet by adolescents and young adults with intellectual disabilities (ID) is scarce. More knowledge is needed about digital competencies and digital participation in their everyday lives.Aim: The overall aim of this thesis was to explore and describe internet access and use, and digital participation in everyday life among adolescents and young adults with intellectual disabilities.Designs and Methods: The thesis is based on results from three studies. In study I, the focus was on access to and use of the internet in the everyday settings of school/work, at home or during free time. Data was collected through observations, conversations, and follow-up interviews with 15 participants with ID, aged 13–24 years. The data was analysed using qualitative content analysis. In studies II and III, the design was cross-sectional and comparative, using national surveys on media and internet use from the Swedish Media Council, from which comparative data from reference groups could be gained. In study II, the national survey of adolescents on internet access and use was cognitively adapted for adolescents with intellectual disabilities, aged 13–20 years, in several steps. This made it accessible to a total selection of pupils from all the special schools in four diverse municipalities in two different regions of Sweden. In study III, the national survey of parents about opportunities and risks of internet use by their adolescents was used. The surveys were sent to a sample of n=318 adolescents with ID and their caregivers/parents. The responses were higher for the adolescents (n=114) than for the parents (n=99), and the response rate of the adolescents with ID was equivalent as that of the reference group, at 36% and 38% respectively. In study II, chi-square tests were used and, when necessary, Fisher’s exact test to analyse the data. In study III, analyses were carried out using Fisher’s exact test and logistic regression to control for confounding factors.Results: This thesis show that access to internet-enabled devices is lower for adolescents with ID than for the general population, except for tablets (study II). All internet activities, except playing games, are performed by fewer adolescents with ID compared to the reference group (study II) and the time spent on the internet activities is less (study III). Both environmental challenges and personal abilities present difficulties in internet access and use (study I) and affect digital participation for adolescents and young adults with ID. Furthermore, a significantly higher proportion of parents of adolescents with ID perceive opportunities associated with internet use and playing games, and a lower proportion perceive risks with negative consequences, or have concerns about online risks, compared with the reference group (study III). Significantly more parents of adolescents with ID state that their adolescent never uses smartphones or social media compared with the reference group. Strategies used to handle the digital environment and take part in internet activities were found and described, such as getting support from others, reducing the number of internet-enabled devices used and personalising them. Gaining access to internet content and performing internet activities was facilitated by picture-, word- and voice-based strategies, which were used by adolescents and young adults with both mild and moderate ID (study I).Conclusions: The conclusions are that the results show a lag in internet access and use and in digital participation by adolescents and young adults with ID. Adolescents and young adults with ID were accessing and using the internet in similar ways to the reference group, but to a lesser extent. The impact of the participants’ environment, together with their lack of certain abilities, make the development of digital competencies difficult for them. The result that parents of adolescents with ID perceive more opportunities and fewer risks associated with the internet provides new knowledge to support positive risk-taking in internet use and enable digital participation by adolescents and young adults with ID. Support can be developed in collaboration between the adolescent/young adult, their parents and teachers, and staff in community-based services and should involve physical, social and digital environmental adaptations. These can enable the development of digital competencies and minimise the lag in digital participation in everyday life, which is needed for participation in today’s digitalised society.
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| 60. |
- Ali, Zaheer, 1984-
(författare)
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Investigating mechanisms of angiogenesis in health and disease using zebrafish models
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis, the growth of blood vessels from an existing vasculature, can occur by sprouting from preexisting vessels or by vessel splitting (intussusception). Pathological angiogenesis drives choroidal neovascularization (CNV) in age related macular degeneration (AMD) which is commonly restricted under the retinal pigment epithelium (RPE), called occult CNV, but may also involve vessels penetrating through the RPE into the sub-retinal space. Pathological vessels are poorly developed, insufficiently perfused and highly leaky, phenotypes that are considered to drive disease progression and lead to poor prognosis. Currently, a number of anti-angiogenic drugs exists, the majority of which target vascular endothelial factor (VEGF), but although they often are highly beneficial for treating eye diseases in the short-term, they are generally of limited efficacy in other diseases such as cancer, and also have poorer efficacy when used for treatment of eye diseases in the long-term. A better understanding of the mechanisms underlying pathological angiogenesis can generate new targets for treatment leading to development of better drugs for cancer and retinopathies, but perhaps also other angiogenesis-dependent diseases, in the future. In this thesis mechanisms involved in developmental angiogenesis or pathological angiogenesis in the choroid, cornea or melanoma was identified. These findings highlight the need to further elaborate our knowledge related to angiogenesis in different tissues/conditions for a more targeted, and potentially effective treatment of diseases in the future.In paper I, we for the first time identified the choriocapillaries (CCs) in adult zebrafish and found that occult CNV could be induced by exposing the fish to severe hypoxia. Interestingly, we found that occult CNV relied on intussusception, involving not only de novo generation of intussusceptive pillars but also a previously poorly understood mechanism called pillar splitting. This involved HIF-VEGF-VEGFR2 signaling and evidence that this also occurred in both rats and humans suffering from AMD suggested that the mechanism was conserved and clinically relevant.In contrast, we found in paper II that the development of CCs in the zebrafish relies on sprouting angiogenesis, involve continuous remodeling, and delayed maturation of the vasculature in 2D. The initial development was found to occur by a unique process of tissuewide synchronized vasculogenesis. As expected, VEGFA via VEGFR2 was also critical for the development of these vessels in the zebrafish embryo, but surprisingly this was independent on hypoxia-inducible factor (HIF)-1.Inflammatory nuclear factor-kB (NF-kB) signaling is involved in the progression of angiogenesis, but this signaling pathway has mainly been studied in the inflammatory cells and the role of NF-kB in the endothelial cells during angiogenesis is poorly understood. In paper III, we found that blocking NF-kB signaling using a specific IKK2 blocker IMD0354, specifically blocks pathological as well as developmental angiogenesis by targeting endothelial cell NF-kB signaling in the endothelial cells. Using a rat model for suture-induced corneal neovascularization, IMD0354 treatment lead to reduced production of inflammatory C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 5 (CXCL5) and VEGF, and thereby reduced pathological corneal angiogenesis in this model.Using the zebrafish tumor xenograft model in paper IV, we found an association between Microphthalmia associated transcription factor (MITF) and pigment epithelium derived factor (PEDF), which was involved in pathological tumor angiogenesis and metastasis. Similarly, in paper V we used zebrafish transplantation models to study and investigate the use of biocompatible polymers for the delivery of pro-angiogenic FGF-2 as a potential treatment strategy for ischemic diseases such as myocardial infarction (MI). Conclusively, this thesis provides new insights into diverse fields of angiogenic assays using zebrafish, and reveals new mechanisms of angiogenesis in health and disease. This work will hopefully provide a foundation for further studies into occult CNV related to AMD, a process that has not been possible to study previously in pre-clinical models. In addition, zebrafish xenograft or other transplantation models used in this work will likely be important to study cancer biology and to develop more attractive pharmaceutical preparations based on biocompatible hydrogels formulated as microspheres in the future.
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