Doctoral Theses from Sahlgrenska Academy

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22q11 Deletion Syndrome. Neuropsychological and Neuropsychiatric Correlates. A Clinical Study of 100 Cases
(2007-11-12T12:18:31Z) Niklasson, Lena
Objectives: Examine the prevalence and type of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity-Disorder (AD/HD), Learning Disability (LD), behavioural profile, intellectual ability/profile, and executive function in 22q11 Deletion Syndrome (22q11DS) and to study the impact of AD/HD and ASD on these functions. Methods: One hundred individuals (58 female, 42 male; 1-35 years of age) with 22q11DS, confirmed by FISH analysis, were included. They were the first 100 referred 22q11DS cases, of whom 92 came from a multidisciplinary team as part of routine 22q11DS assessments, and 8 were referred directly to a Child Neuropsychiatric Clinic for learning and/or behaviour problems. Neuropsychological evaluation made use of a test battery designed to provide information concerning developmental/intellectual level and profile, visuomotor development, executive functions (planning ability and attention), and mentalisation skills. Neuropsychiatric assessments included structured and semistructured interviews with parent(s), an evaluation of the individual including psychiatric assessment, physical examination, and age-appropriate neurological examination. Parents completed the Autism Spectrum Screening Questionnaire, the Conners Brief Parent Rating Scale, the Child Behavior Checklist, and the Five To Fifteen (FTF) questionnaires. Comprehensive diagnoses of ASD and AD/HD were made by a psychiatrist according to the DSM-IV taking the results of the various examinations (interview, medical examinations, observation, and the FTF questionnaire) into account. Results: The prevalence of ASD and/or AD/HD with or without LD was 44%, of whom 21% had AD/HD “only”, 14% ASD “only”, and 9% a combination of these two diagnoses. In addition, 23% had LD “only”, meaning that there were 33% without any of these diagnoses. Autistic disorder was found to be quite rare (5%). Other psychiatric diagnoses were found mainly among the adults. Altogether 51% met criteria for LD, and the mean IQ was 71 with a normal distribution around this mean. Higher IQ for females compared to males and a negative trend for IQ with increasing age were found. An overrepresentation of girls was found only in the group without ASD/AD/HD/LD. In the school age group and in the adult group significantly higher verbal IQ than performance IQ was found. In contrast, in the youngest group the lowest result was found in the “Hearing and Speech” subscale (Griffiths´ Mental scale) reflecting a delay in expressive language in the early years. The strength within the verbal area was mainly due to good Vocabulary. Deficits in performance ability were found. The intellectual and the visuomotor impairments were related to 22q11DS per se while the presence of ASD/AD/HD had a negative impact on planning ability in children. The ability to sustain attention was found to be critically impaired in school age children with 22q11DS. According to results of the questionnaires a variety of behaviour problems were reported. A characteristic combination of initiating difficulties and a “lack of mental energy” was observed in the majority. Discussion and conclusions: The vast majority of all with 22q11DS had behaviour and/or learning problems and more than 40% met criteria for either ASD, AD/HD or both (even though typical autistic disorder was rather uncommon). Half the group had LD. The majority of the group with IQ in the normal to low normal range had learning difficulties. Many individuals with 22q11DS had social interaction difficulties that, in the presence of relatively good word skills, appeared to be related to initiation problems and language use deficits. Given the high rate and variety of problems found, a neuropsychiatric assessment, including neuropsychological testing, should be performed in all cases of 22q11DS. Such assessment will provide essential information about strengths and difficulties, crucial for providing optimal support for individuals with 22q11DS.
A gender perspective on irritable bowel syndrome: symptoms, experiences and the development of a person-centred support intervention
(2016-11-10) Björkman, Ida
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which affects approximately ten percent of the world’s population and which is more prevalent among women than men. The hallmark symptoms of IBS are abdominal pain and disturbed bowel habits and a number of differences, for example in symptom profiles, between men and women with IBS have been reported. Only a smaller number of studies have explored the patients’ perspective on everyday life and health care encounters in IBS, and never from a gender perspective. The present thesis aimed to explore symptoms, experiences from daily life and health care encounters in IBS from a gender perspective, and to develop and in a pilot study evaluate a nurse-led intervention for IBS. A multimethod design was applied where questionnaires on self-reported health were combined with interviews with patients. Among 557 patients diagnosed with IBS it was found that there were more similarities than differences when men and women were compared. However, there was a pattern of difference disfavoring the women, especially regarding health related quality of life. An interview study including 19 patients revealed that the experience of living with IBS was gendered, meaning that social norms on masculinity and femininity affected the experience of symptoms. A subsequent qualitative study including 10 patients with severe IBS showed that their experiences of health care encounters were mostly negative and that they struggled to protect themselves from stigmatizing labeling. The findings from these studies were used in the systematic development of an intervention for person-centred support in IBS. The intervention, which was tested in a pilot study including 17 patients, was found to be feasible, appreciated by the participants, and efficient in reducing IBS symptom severity, whilst there were no significant changes for general self-efficacy or gastrointestinal-specific anxiety. This thesis contributes to the existing knowledge on IBS through adding a sociocultural per-spective on gender/sex and by introducing person-centred care as a viable part of the clinical management of the disorder.
A meaningful work in a strained context - exploring midwives' work situation and professional role
(2021-11-09) Hansson, Malin
Midwives report a challenging work situation globally with a work force shortage, which is a large challenge for health-care organisations and can influence midwives’ professional role. The overall aim of this thesis was to explore midwives’ work situation and professional role in relation to models of care, salutogenic factors and job satisfaction and demands. The methods used in studies I-IV and the synthesis were classical grounded theory (I: n=27, III: n=12, synthesis) simultaneous mixed method (II: n=16/58) and statistical analyses of survey measurements (IV: n=1747). Data were collected by conducting focus group and face-to-face interviews and surveys, one of which was nation-wide. Results: In study I, other professions’ main concern were midwives marching to own drum and safeguarding midwifery and that the midwifery profession was veiled. The other professionals thus used unveiling strategies scrutinising, streamlining and collaborating admittance. All professionals co-existed in a strained baby factory context. In study II, a theoretical midwifery model of woman-centred care had the potential to strengthen midwives’ professional role and practice but not the strained work situation. In study III, the substantive theory of professional courage to create a pathway within midwives’ fields of work provided an explanation of health-promoting facilitative conditions in midwives’ work. However, there were vital organisational prerequisites that needed to be fulfilled, organisational resources, visualising midwifery and a reflective environment. In study IV possibilities for development, quality of work, role conflict, burnout and recognition, explained most of the variance in midwives’ job satisfaction (R2 =.626). Midwives demonstrated the largest mean difference from the reference population in terms of higher emotional demands, lower influence at work and a greater meaning in their work. The theoretical synthesis of the results of studies I-IV emerged as a ‘professional courage to maintain a meaningful work in a strained context’. The overall conclusion was that midwives report great meaningfulness in their work related to having a possibility to work based on the midwifery profession and having organisational prerequisites. Having a distinct professional role was facilitated by professional courage and by safeguarding a high-quality evidence-based midwifery care. These resources enhanced the motivational processes and job satisfaction. However, the midwives were found to work in a highly strained, factory-like, over-medicalised context with high demands and lack of organisational resources and support systems. Which in turn streamlined midwifery work, induced the impairment processes and adversely affected job satisfaction and occupational health.
A methodological platform to study molecular biocompatibility of biomaterials. Experimental and clinical studies
(2016-05-13) Lennerås, Maria
The aim of this project was to develop a methodological platform in order to advance our scientific understanding of the mechanisms of osseointegration. Screw-shaped, titanium implants, with different surface properties, were inserted in the rat tibia, or incubated in mono- or co-culture of human monocytes and MSCs. After different time points, the implant-adherent cells or the peri-implant bone were harvested and processed for different analyses. For in-vivo studies, qPCR, immunohistochemistry, histomorphometry, electron microscopy and removal torque analyses were used. In the in-vitro study, FACS, qPCR, ELISA and protein profiling were applied. Finally, qPCR was employed in a clinical study to analyse the abutment-adherent cells of osseointegrated fixtures. At the early time points in vivo, a higher gene expression of MSC recruitment and adhesion factors (CXCR4 and integrin-β1) was found in cells adhering to the oxidised compared to machined implant. This was corroborated by predominance of MSCs at the oxidised surface, as judged by immunohistochemistry and SEM. At the later time points, cells adhering to oxidised implants retained a higher expression of bone formation (ALP and OC) and bone remodelling (TRAP and CatK) genes. The qPCR findings correlated with histomorphometric, electron microscopy and removal torque measurements, revealing progressively increasing bone-implant contact and bone bonding and, as a result, an increase in the biomechanical stability of the oxidised implant. The enhanced RANKL/OPG expression ratio corresponded to the remodelling phase at the bone-implant interface. The qPCR analysis of FACS-sorted cells showed that the co-existence of monocytes and MSCs on the implant surface, in vitro, upregulates the gene expression of some cytokines in a cell-specific manner. The clinical study showed that bacterial colonisation was frequently detected on the skin, the abutment and in the bone canal. A higher expression of TNF-α was associated with positive cultures of S. aureus, whereas fixture loss was associated with lower expression of OC and IL-10. In conclusion, the present methodological platform enables detailed analyses of the events at the bone-implant interface. Employing this platform demonstrated that implant surface properties elicit a cellular and molecular cascade for rapid cell recruitment and enhanced bone formation and remodelling, which accelerates bone maturation and implant stability. Finally, the results of the thesis provide a first line of information on factors that could affect the performance of percutaneous implants.
A New Payment Model in Swedish Dental Care
(2015-11-04) Andrén Andås, Charlotte
The Public Dental Service introduced a new way of paying for dental care in 2007 in Region Västra Götaland, and in 2009 in all of Sweden. The new system, ‘Dental Care for Health’ (DCH), was based on capitation rather than the traditional fee-for-service (FFS) system. The overarching aim of this thesis was to conduct an evaluation of this new payment system with regard to patient attitudes, dental care and oral health. The specific aims of the four included manuscripts were: (I) to describe potential differences in views on oral health and oral health behavior between the patients who chose the respective schemes; (II) to map the experiences and attitudes among the prepayment scheme patients with regard to the agreement, the dental care received, and the financial arrangements; (III) to compare the amount and type of dental care received by patients in the two payment schemes, respectively, and to conclude about the financial net of the prepayment scheme; and (IV) to measure over six years the development of oral health in terms of manifest caries incidence, in the two payment schemes. Study I showed that patients who chose DCH reported themselves as being healthier and more engaged in health-promoting behaviors than patients in FFS. According to the qualitative analysis of interviews from study II, the DCH patients were satisfied with their choice and appreciated feeling secure when having an agreement with the PDS. Study III reported that DCH patients had more preventive treatment and less restorative treatment than FFS patients. The outcome for oral health, as described by the incidence of manifest caries from six years adherence to either of the payment schemes, showed, in study IV, a 50% increase in the risk for caries in FFS compared with DCH, when important background factors were controlled for.
A Podocyte view on RhoGTPases and actin cytoskeleton regulation
(2020-06-11) Bergwall, Lovisa
Proteinuria is a hallmark symptom of chronic kidney disease, that if left to persist constitutes a risk for progression of disease. Symptomatic treatment aiming at decreasing proteinuria is therefore standard practice. Curative treatments for the underlying cause of disease are however lacking and treatments currently in use to induce disease remission are associated with unfavorable side effects. Dysregulation of the podocyte actin cytoskeleton underlies the pathological process called foot process effacement (FPE), which is one of the leading causes of proteinuria. The studies included in this thesis have focused on podocyte actin cytoskeleton regulation and a group of proteins called RhoGTPases, known to be involved in actin cytoskeleton regulation in podocytes. In the first study, glomerular microarray analysis showed an increase in the expression of the melanocortin 1-receptor (MC1R) in renal diseases focal segmental glomerulosclerosis and membranous nephropathy. Subsequent mass spectrometry analysis in combination with pathway and biochemical analysis revealed the podocyte protective effects of MC1R stimulation in vitro. Activation of MC1R proved to be stabilizing the podocyte actin cytoskeleton through inhibition of the epidermal growth factor receptor (EGFR) and maintenance of the actin associated protein synaptopodin. In the second study, the depletion of the prenylation enzyme Geranylgeranyl transferase type I (GGTase-I) in podocytes led to the development of proteinuria and FPE in mice due to an imbalanced RhoGTPase activity and disruption of the actin cytoskeleton. These findings suggest that GGTase-I activity is essential for podocyte function. In the last study, a guanine nucleotide exchange factor (activator of RhoGTPases) named Bpix was identified to be modulated in podocytes following treatment with a renal stressor, using mass spectrometry analysis. Gene silencing of Bpix protected against actin cytoskeleton remodulation in a model of podocyte injury, demonstrating the importance of Bpix for podocyte actin cytoskeleton regulation. In conclusion, the results in this thesis confirm the importance of actin cytoskeleton regulation for podocyte integrity. Further on, the results provide new information on actin cytoskeleton regulatory pathways involving RhoGTPases in podocytes, which can be of importance for future attempts in finding targeted treatments of proteinuria and chronic kidney disease.
A prevention and health promotion programme for persons with overweight in Primary Health Care Patient outcomes and nurses’ experiences in terms of weight, lifestyle, health and risk factors
(2020-11-20) Bräutigam Ewe, Marie
Background: Primary Healthcare (PHC) is often the first point of contact for patients and thus considered the ideal place to address obesity and lifestyle issues. A weight reduction programme was developed to gain a better understanding of what those who are overweight or obese need in order to improve their health, weight reduction and weight maintenance. Aim: The overall aim was to describe and evaluate disease prevention and health promotion strategies in PHC for overweight persons related to weight, lifestyle, health and risk factors. Methods: Study II had a comparative cross-sectional design, while Study III had a prospective two-armed RCT-design. Studies I and IV had a descriptive design with qualitative content analysis and an inductive approach. In Study I, 19 participants answered five written open questions about their experiences of the programme. In Study II, 286 participants were included in the intervention group, while the two reference groups from studies performed by the National Health Survey (HLV) comprised 747 participants from Halland and 4,855 from Sweden as a whole. The data were collected by means of HLV questionnaires and analysed using descriptive statistics. In Study III, 286 women and men aged 40-65 years with a BMI of 28-35 were included. The participants were randomized to high or low-intensity groups. Blood samples, physical measurements as well as GHQ-12, HLV, SOC-13 and EQ5-D were analysed by means of analytical statistics. In Study IV, 13 PHC nurses participated in individual, semistructured, face-to-face inter-views about their experiences of working with patients burdened by overweight and lifestyle issues. Results: The participants in Study I appreciated the face-to-face meetings with the nurse because they felt seen and listened to. They believed that their life situation and self-discipline had an impact on how well they managed to follow the programme. Dietary advice on prescription (DaP) was deemed helpful for achieving behavioural change. People who succeeded in losing weight and sustaining the weight loss described the importance of support from partners and close friends. In Study II, the participants in the weight reduction programme were mostly women. They had a higher educational level, experienced worse general health than the overweight popula-tion and visited PHC more frequently than either of the two reference groups. They also felt more stressed, humiliated, reported more bodily pain and smoked less compared to the general population. They did not exercise less or have a lower fruit and vegetable intake than either of the two reference populations. In Study III, 182 (64%) participants allocated to a high or a low-intensity programme completed the 2-year follow up, leading to a significant overall weight reduction. No significant differences pertaining to weight were found between the groups. Anxiety/depression, self-rated health and sense of coherence improved in the whole group. Anxiety/depression, pain/discomfort and visits to the nurse decreased in the high intensity group and usual activities, fruit and vegetable intake increased. The PHC nurses in Study IV had a desire and a willingness to devote more time to overweight and lifestyle issues than was currently possible due to a lack of prioritization, resources, time and training. They felt that society should do more to stop the development of overweight. Structuring the conversations, tailoring them to each individual, without pointers, were crucial for weight management and strengthening the patients’ motivation to change. The nurses reported a lack of clarity about how to use and implement guidelines. They also pointed out the need for a Swedish national forum for nurses working with overweight and lifestyle issues that would provide lectures about the latest research in the area. Conclusion: To achieve and maintain weight reduction, it is important to individualize the programme in order to address each person’s life situation and unique difficulties. The total study population lost weight, although the high and low-intensity programmes did not result in significant differences in terms of weight. The high-intensity programme reported health benefits linked to lower levels of anxiety and depression, increased activity and intake of fruit and vegetables, as well as a reduction in the number of visits to nurses. The nurses considered overweight to be a complex condition that requires a holistic approach with individualized care. The development of a multidisciplinary team to care for this patient group was the nurses’ wishes. Implications: Despite only a small weight reduction, a weight reduction programme can contribute to improved health in the form of a better quality of life, reduced anxiety and a healthier lifestyle. The programme needs to be individualized with a range of dietary behaviour interventions, e.g. stress management, in order to achieve better compliance. The nurses’ dream scenario was a multidisciplinary team with allocated resources working together for a more holistic approach.
A prospective chohort study on bone formation and bone loss in ankylosing spondylitis
(2019-10-02) Deminger, Anna
Background and objectives: Patients with ankylosing spondylitis (AS) have an increased risk of bone loss with development of osteoporosis and vertebral fractures (VFs) but also spinal new bone formation with growth of bony spurs (syndesmophytes) between the vertebrae. Measurements of spinal bone mineral density (BMD) by the routine method dual-energy x-ray absorptiometry (DXA) in anteroposterior (AP) projection can be difficult to interpret due to the spinal new bone formation. The general aims of this thesis were to study the development of bone loss and new bone formation over 5 years in patients with AS and to assess factors associated with the changes. Methods: The studies included in this thesis are based on a cohort of patients with AS according to the modified New York criteria recruited from three rheumatology clinics in western Sweden. Patients completed the same protocol at baseline and at the 5-year follow-up with assessment of BMD with DXA at the hip (femoral neck, total hip), the spine (AP, lateral) and total radius and spinal radiographs for grading of AS related spinal alterations and VFs. A group of men were randomized in an age-adjusted algorithm to undergo high-resolution peripheral quantitative computed tomography (HRpQCT) at the ultra-distal radius and tibia for assessment of volumetric BMD (vBMD), cortical area and microarchitecture. Serum hepatocyte growth factor (s-HGF) was analyzed with enzyme-linked immunosorbent assay (ELISA) in the total cohort. Results: Over 5 years, there were significant decreases in femoral neck BMD and tibia vBMD. Decreases were associated with signs of inflammation. In contrast, BMD at the total hip and the spine AP and lateral projections increased. Use of bisphosphonates was associated with increases in BMD at all measured sites except tibia. Use of tumor necrosis factor inhibitors (TNFi) was associated with increases in BMD at AP spine and tibia. Only three patients developed new VFs. AS related spinal alterations increased significantly with higher increases in men compared to women. New predictors identified for spinal radiographic progression were obesity in both sexes and use of bisphosphonates and impaired mobility in women. Among previously known predictors, baseline AS related spinal alterations was shared by sexes, whereas baseline elevated CRP and smoking were predictors in men. The biomarker s-HGF was identified as a novel independent predictor of spinal radiographic progression in men. Conclusion: The studies in this thesis suggest that the best site to assess bone loss in patients with longstanding AS is at the femoral neck and that inflammation has a negative impact on bone loss and development of AS related spinal alterations and thus is an important treatment target. The studies give further reasons to counsel the patients to stop smoking and to encourage obese patients to weight loss. Treatments with bisphosphonates and TNFi had a positive impact on BMD. Further studies are suggested regarding the role of bisphosphonates in relation to spinal radiographic progression and whether s-HGF can be useful as a predictor for spinal radiographic progression.
A search for prognostic biomarkers in diffuse large B-cell lymphoma with proteomics and immunohistochemistry
(2021-11-18) Bram Ednersson, Susanne
Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in the Western world, can by gene expression profiling or immunohisto-chemistry (IHC), be divided into two subgroups according to its “cell-of-origin”. The subgroup ABC (or non-GCB) with similarities to active post-germinal centre B-cells, is associated with worse outcome. In addition, patients with primary refractory disease or early relapse have a very dismal prognosis. The aim of this thesis has been to identify novel prognostic biomarkers in a large retrospective DLBCL patient cohort by mass-spectrometry (MS)-based proteomics and IHC. Quantitative MS-based proteomics (QMS) revealed several differentially expressed proteins between refractory/relapsed patients (REF/REL) and patients with progression-free survival ≥5 years (CURED). Many ribosomal proteins were up-regulated in REF/REL patients while numerous proteins associated with the actin cytoskeleton were up-regulated in CURED patients. By using QMS we also found several up-regulated proteins in non-GCB DLBCL related to the tumour microenvironment, including interferon (IFN)-stimulated proteins. By using IHC we found a prognostic association for two proteins (CREBBP and TBLR1) that are frequently mutated in DLBCL, and for IFI16 and MNDA, both belonging to the pyrin and hematopoietic IFN-inducible nuclear (PYHIN) family. In conclusion, we have found increased expression of several proteins or groups of proteins not previously described in DLBCL and with potential prognostic impact. Further functional studies are warranted to elucidate their role in immunochemotherapy resistance.
A study of the contribution of mast cells to vaccination - Regulatory functions of Fc gamma receptors
(2013-08-23) Fang, Yu
This thesis aimed to explore the regulatory roles of mast cells in vaccination. Mast cells have been increasingly recognized as important orchestrators of immune regulation in both health and disease, in addition to their classically defined roles in allergic diseases. One of the recently appreciated beneficial roles of mast cells is their involvement in augmenting the adjuvant effects that are critically important in successful vaccination. This study has focused on the interaction of mast cells with an adjuvant complex composed of IgG and CTA1-DD, a fusion protein consisting of the Al subunit of cholera toxin (CT) linked to a synthetic dimer of fragment-D of Staphylococcus aureus protein A (DD). As the DD domain unspecifically binds immunoglobulins, CTA1-DD and IgG form complexes potentially able to activate mast cells through Fc  receptors. Indeed, CTA1-DD, in combination with polyclonal IgG, induced mast cell degranulation and the production of TNF-alpha, a cytokine important for the maturation and migration of antigen presenting cells, resulting in enhanced antigen-specific immune responses following immunization. Furthermore, only connective tissue mast cells (CTMCs), but not mucosal mast cells (MMCs), were found to be activated by CTA1-DD/IgG complexes. This effect was mediated by Fc gamma RIIIA, an activating receptor that has been described to be only expressed on connective tissue mast cells. Indeed, Fc gamma RIIIA-expressing connective tissue mast cells were found in the nasal submucosa. Responses to immunization facilitated by CTA1-DD/IgG were compromised in Fc gamma RIIIA-deficient mice, and in mice pre-treated with a CTMC inhibitor. Interestingly, MMCs, which were present in mouse nasal mucosa, were not entirely bystanders in CTA1-DD/IgG-mediated adjuvanticity. We discovered that a balanced expression of Fc gamma RIIB and Fc gamma RIIIA was required for mast cells to resist apoptosis mediated by IgG immune complexes. Therefore, MMCs, which only expressed Fc gamma RIIB, but not Fc gamma RIIIA, underwent apoptosis as a result of treatment by CTA1-DD/IgG. MMCs were capable of phagocytosing ovalbumin (OVA), and engulfment of these MMCs by antigen presenting cells (APCs) could occur if the MMCs were induced to apoptose. Finally, the APCs were able to present OVA peptide to OVA-specific T cells. Thus, MMCs may also contribute to vaccination through cross-presentation. Safety is always a prioritized concern for developing adjuvants, especially when mast cells are involved. Remarkably, CTA1-DD did not function as a superantigen to activate mast cells which had captured IgE molecules with their Fc epsilon RI, indicating that CTA1-DD is safe for use in allergic patients in which mast cell Fc epsilon RI is occupied by antigen-specific IgE molecules. Furthermore, CTA1-DD/IgG immune complexes administered intranasally did not trigger systemic anaphylaxis. In conclusion, CTA1-DD/IgG may target both CTMCs and MMC through Fc gammareceptors to enhance antigen-specific immune responses, probably through two distinct mechanisms. We propose that IgG immune complex-induced mast cell activation may be considered as a component of rationally designed mucosal adjuvants.
Abdominal Aortic Aneurysm, aspects on diagnosis and treatment
(2018-11-16) Smidfelt, Kristian
Background An abdominal aortic aneurysm (AAA) is an abnormal widening of the aorta with a risk of rupture if it grows to a large diameter. Rupture is associated with massive bleeding and a poor prognosis for survival. Aims The aim of this thesis was to evaluate the results of surgical intervention in patients with AAAs detected by population-based screening, including comparisons with the results in patients with aneurysms that were not detected by screening. A further aim was to investigate how common misdiagnosis is in the emergency department in patients seeking care for a ruptured AAA (rAAA), and how misdiagnosis affects the prognosis. A third aim was to investigate whether it is beneficial to treat patients with a primary open abdomen with delayed closure after open repair for rAAA. Methods Patients with AAA were identified in the Swedish Vascular Registry (Studies 1‒4) and the Swedish Cause of Death Registry (Study 4). Additional information was obtained through review of medical charts (Studies 2‒4). In Study 1, mortality, complications, and method of surgical intervention were compared in patients with AAAs detected by screening and in age-matched controls with AAAs that were not detected by screening. In Study 2 and Study 4, the outcome in patients with a ruptured abdominal aortic aneurysm (rAAA) who were misdiagnosed at the first assessment in the emergency department was compared to the outcome in patients who were correctly diagnosed initially. Study 2 included patients who reached surgery and Study 4 included all patients with rAAA, whether or not they reached surgery. In Study 3, mortality and complications in patients treated with a primary open abdomen after open repair for rAAA were compared to a propensity score-matched control group in which the majority of patients had the abdomen closed at the end of the procedure. Results Study 1: A higher proportion of the screening-detected patients were treated with open repair (56% vs. 45% in those with AAAs not detected by screening). The mortality 30 days, 90 days, and 1 year after open repair was similar in patients with screening detected and non screeningdetected aneurysms. Mortality at 30 days and 1 year after Endovascular Aortic Repair (EVAR) was similar in both groups. Mortality at 90 days after EVAR was lower in the screening-detected compared to the non screening-detected patients (0% vs. 3.1%; p = 0.04). The overall 30-day mortality (including patients treated with either open repair or EVAR) was 0.6% in screening-detected patients and 1.4% in non screeningdetected patients. (p = 0.45). The adjusted odds ratio for the primary endpoint (mortality or major complication at 30 days) was 1.64 (95% CI 0.82‒3.25) in non screening-detected patients. Studies 2 and 4: Misdiagnosis was common and occurred in more than one-third of the patients with rAAA. Overall, the mortality was 74.6% in misdiagnosed patients and 62.9% in correctly diagnosed patients (p = 0.01). The adjusted odds ratio for mortality in the whole cohort of misdiagnosed patients was 1.83 (1.13‒2.96). In patients who reached surgery, there was no significant difference in mortality between misdiagnosed patients and correctly diagnosed patients. Study 3: There were no significant differences in mortality or major complications between patients treated with a primary open abdomen with delayed closure and patients treated with primary closure of the abdomen. Conclusion The contemporary mortality after AAA surgery in Sweden was low irrespective of whether or not screening was used for detection. Patients with AAAs detected by screening had the same comorbidities and outcome as those with non screening-detected aneurysms, except for 90- day mortality after EVAR, which was lower in the screening group. Misdiagnosis is common in patients who seek care for a rAAA, and misdiagnosis is associated with a substantially higher risk of dying from the ruptured aneurysm. No survival advantage and no lower frequency of complications was observed in patients treated with a primary open abdomen and delayed closure after open repair for rAAA as compared to a propensity score-matched control group where the majority of patients were treated with primary closure of the abdomen.
Abdominoperineal excision for distal rectal carcinoma. Oncological outcome and aspects of self-assessed quality of life
(2016-09-15) Prytz, Mattias
Abstract: In recent years an adjusted method of performing an abdominoperineal excision (APE) - so called extralevator APE - has been developed and internationally spread. It has been proposed to decrease intraoperative perforations and non-radical surgery and therefor improve local cancer control and decrease rates of local recurrences as compared to standard APE. This thesis aims to investigate if the oncological outcome of ELAPE is superior to standard APE and to explore the association between patient reported intrusive thoughts and QoL as well as to type of surgery performed three years after surgery and to compare outcome to that found in a normative Swedish cohort. Data on all Swedish patients operated with any kind of APE in the years 2007-2009 were collected from the Swedish ColoRectal Cancer Registry and short-term oncological outcome was measured (i.e. perforations and non-radical surgery) as well as short-term complications and mortality. In order to be able to differ between APE and ELAPE, all patients’ operation notes were collected from the hospital charts where they had been operated, and analysed with regard to which operating technique had been used. When 3-years local recurrence data were available in the registry these data were also collected from the registry and analysed with regard to what operation had been performed. Furthermore, a special questionnaire was developed in order to be able to measure a number of health-related QoL parameters specific for this group of patients. The questionnaire was sent to all patients alive 3 years following surgery and data on QoL was compared to data from a Swedish normative population. Short-term oncological results were the same for both groups with regard to perforation and non-radical surgery. There were fewer intraoperative perforations for a subgroup of the most distal tumours in the ELAPE group but not for the entire group. There were more wound infections for the ELAPE-group. Local recurrences after 3 years were significantly more common in the ELAPE group as compared to standard APE but there was no difference between groups in overall survival. Intraoperative perforation was significantly associated with higher risk of local recurrence. A large proportion of survivors after abdominoperineal excision for rectal cancer have a quality of life comparable to a normative population, however many suffer from a symptom of stress, negative intrusive thoughts, which significantly decrease overall quality of life. Oncological outcome following ELAPE is not superior to standard APE. ELAPE is associated with more perineal wound complications. This method should be used in selected patients with high risk of intraoperative perforation.
Acetabular Revisions
(2015-09-15) Mohaddes, Maziar
Hip replacement is a successful intervention when treating patients with hip osteoarthritis. Approximately 10% of all patients undergoing primary hip replacement surgery require further surgical interventions (revisions) during their lifetime. Acetabular component (cup) failure is the most common reason for a revision. Cemented fixation in acetabular revision surgery was a common method until the mid-1980s. Low survival rates reported for cemented revision cups and encouraging results. There are, however, no studies comparing the results of revision surgery based on the method of fixation for the acetabular component. In 2006, a highly porous trabecular metal (TM) tantalum cup was introduced in the Swedish market and, in 2013, this cup was the most commonly used acetabular revision component in Sweden. The primary aim of this thesis was to compare cemented and uncemented fixation in acetabular revisions using radiostereometric analysis (RSA). Further, a comparative analysis of the TM cup and other cup designs frequently used in acetabular revisions was performed. Data from the SHAR, on 18,593 first-time revisions, were used in the first study to analyse differences relating to the risk of re-revision between cemented and uncemented cups. The overall risk of acetabular component failure did not differ between the two modes of fixation. In this analysis, cemented revision cups were re-revised more often due to aseptic loosening but less often due to dislocation. In Paper II, TM cups were compared with the other two cups most frequently used in first-time revisions recorded in the SHAR. The short-term re-revision rate of the TM design did not differ from that of the other two designs. The third paper addressed the influence of proximal migration on the risk of aseptic loosening. An analysis of 312 acetabular revisions followed with RSA for two to 20 years showed that proximal migration measured with RSA can be used a predictor of aseptic loosening of the acetabular component. In the fourth paper, 45 patients (47 hips) undergoing surgery with cemented or uncemented fixation were followed prospectively for 17 years. Radiostereometry was used to monitor the migration and rotation of acetabular components. Cups installed using cemented fixation showed a higher rate of early migration. In a randomised prospective study (Paper V), the RSA migration pattern of the TM cup was compared with that of a cemented cup in hips with large bone defects. The TM design showed less proximal migration compared with the cemented design, indicating a lower risk of aseptic loosening when the TM cup is used in hips with large bone defects. To summarise, there was no difference in the overall risk of re-revision based on the method of fixation, according to data from the SHAR. Proximal migration measured with RSA is a predictor of late aseptic loosening in acetabular revisions. The TM cup shows promising short-term results in the SHAR. The low early proximal migration of the TM design suggests that it has the potential to reduce the risk of late aseptic loosening in revision surgery, but this remains to be demonstrated in clinical studies with longer follow-up.
Achilles tendinopathy : evaluation and treatment
(2006) Grävare Silbernagel, Karin
Abstract. Background: Achilles tendinopathy is considered to be one of the most common overuse injuries in elite and recreational athletes. There are, however, only a few randomized studies of treatment and there is a need for standardized outcome measures for the patients’ symptoms and function. Purpose: The overall purpose of this thesis was to develop and evaluate outcome measures and treatment protocols for patients with Achilles tendinopathy. Material, Methods and Results: Initially, a method was developed to evaluate both symptoms and function in Studies I and II. The method was shown to have good reliability in 10 patients with acute Achilles tendon injuries and in 32 patients with chronic Achilles tendinopathy. We questioned, however, the validity of the methods since only small changes were detected while symptoms improved. At that time there was no standardized symptom questionnaire for the assessment of patients with Achilles tendinopathy. A questionnaire of this kind became available in 2001 in English. In Study III this questionnaire, the Victorian Institute of Sports Assessment – Achilles questionnaire (VISA-A), was cross-culturally adapted and evaluated for reliability, validity and structure on 15 healthy subjects and 51 patients. The Swedish version of the VISA-A questionnaire (VISA-A-S), which measured two factors, pain/symptoms and physical activity, was shown to have good reliability and to be a valid instrument, fully comparable to the original version. The VISA-A-S can be used in both research and clinical settings. A test battery for lower leg muscle/tendon function, including jump and strength tests, was developed and evaluated on 42 patients in Study IV. The purpose of the test battery was to evaluate, in more detail than had previously been possible, whether Achilles tendinopathy caused functional deficits on the injured side compared with the non-injured side. The test battery was found to be reliable and able to detect clinically relevant differences in lower leg function between the injured or “most symptomatic” and non-injured or “least symptomatic” sides in patients with Achilles tendinopathy. The test battery imposed more rigorous demands on patient function compared with each individual test. Treatment comprising iontophoresis using dexamethazone combined with exercise for patients with acute Achilles tendinopathy was evaluated on 25 patients in a randomized, double-blind design in Study II. Positive effects on symptoms were found from using iontophoresis with dexamethazone, compared with a control group in patients with acute Achilles tendon pain. Achilles tendon and calf muscle strengthening exercises (intensity modified with the use of a pain-monitoring model) as treatment for patients with chronic (symptoms for more than 2-3 months) Achilles tendinopathy was evaluated in 40 patients in Study I and in 38 patients in Study V. Furthermore, the effect of continued running and jumping on treatment outcome was evaluated in Study V. A treatment protocol which includes Achilles tendon and calf muscle exercises resulted in significant improvements in patients with chronic Achilles tendinopathy. When the pain-monitoring model was used, no negative effects could be demonstrated from continuing Achilles tendon loading activity (such as running and jumping) during treatment. Conclusion: The VISA-A-S questionnaire can be used to evaluate the clinical severity of patients with Achilles tendinopathy and it is useful in both research and clinical settings. Patients with Achilles tendinopathy reports not only pain, but also demonstrate deficits in lower leg function. In the acute phase, the use of iontophoresis with dexamethazone could potentially be beneficial. For patients with both acute and chronic Achilles tendinopathy, the performance of Achilles tendon and calf muscle strengthening exercises with the use of a pain-monitoring model for 6 months can be recommended. A training regimen of continued, pain monitored, Achilles tendon loading physical activity, such as running and jumping, might represent a valuable option for patients with Achilles tendinopathy.
Achilles tendon rupture: the evaluation and outcome of percutaneous and minimally invasive repair
(2017-11-17) Carmont, Michael R
Acute Achilles tendon rupture is common and has increasing incidence. This is thought to be due to increasing activity and sports participation in middle age. Sustaining an Achilles tendon rupture means a long rehabilitation period and many patients do not achieve full recovery of strength and function. One of the reasons for this reduced function is considered to be due to tendon elongation. The reasons for the lack of recovery has been discussed in earlier studies comparing operative and non-operative treatments. Operative treatment can be divided into open, minimally-invasive and percutaneous technique. Proponents for operative treatment consider open technique to prevent tendon elongation and reduce the re-rupture rate compared with non-operative treatment. Percutaneous repair is considered to lead to an increasing incidence of iatrogenic nerve damage and reduced repair strength compared with open repair but is considered to be advantageous because of lower risk of infections and wound problems. The purpose of this dissertation was to evaluate and optimise the results of percutaneous and minimally-invasive technique for an Achilles tendon rupture. Moreover, evaluation instruments were developed and an already existing validated questionnaire was culturally adapted in English to be used in the United Kingdom. Achilles Tendon Resting Angle (ATRA) is an indirect measure of tendon elongation. The method has been developed and validated in one of the studies in the dissertation. ATRA has subsequently been used to evaluate the clinical outcomes. The ATRA angle increases after an Achilles tendon rupture, then decreases after operative intervention to finally increase again during the first rehabilitation phase. The ATRA angle was shown to correlate with patient-reported symptoms and function as measured by heel rise height one year after injury. Thus, ATRA can provide an indication of function achieved after treatment of an Achilles tendon rupture. Achilles Tendon Total Rupture Score (ATRS) is a validated patient-reported questionnaire for evaluating limitations and physical activity after an Achilles tendon rupture. ATRS was originally developed for a Swedish population but has now been translated and culturally adapted to an English population in one of the studies. ATRS has also been used for evaluating patient-reported outcomes. Percutaneous and minimally-invasive operative techniques have been evaluated in 169 patients treated for an Achilles tendon rupture. Percutaneous technique was found to be more cost-effective in comparison to open procedure, with similar results regarding function and patient-reported symptoms. Minimally invasive repairs produced similar outcome to percutaneous repair but with a lower complication rate. Based on these results, minimally invasive repair is recommended for the operative treatment of an acute Achilles tendon rupture. In order to compare the strength of different suture materials after repair of the Achilles tendon, a cadaveric study was performed, in which the tendon was cyclically loaded. The result from this study shows that repair with non-absorbable suture has better strength in comparison to an absorbable one. However, there is still a lack of knowledge of why a patient suffering from an Achilles tendon rupture does not fully recover. Further studies involving how treatment and rehabilitation can be optimised is of value.
Achilles Tendon Ruptures Predictors; functional and economic impact
(2018-11-22) Westin, Olof
Acute Achilles tendon rupture is a common injury, which leads to significant morbidity in patients. Many patients never recover their full function even after long rehabilitation, whereas others make a good recovery. The factors behind this are unknown. The optimal treatment strategy, whether or not to treat surgically, is still controversial. This thesis consists of six studies with the overall aim of finding predictors of outcome, examining the long-term follow-up of re-ruptures and comparing the cost efficiency of two different management strategies. Study I is a cohort study of 45 patients who underwent acute ultrasonography within 72 hours of the index injury. They were randomly allocated to either surgical or non-surgical treatment. Three of four (75%) patients with a diastasis of more than 10 mm treated non-surgically sustained a re-rupture and these were the only re-ruptures in the study group. The patients with a diastasis of more than 5 mm displayed poorer heel-rise function and patient-re-ported outcome if treated non-surgically. Study II is a cross-sectional observational cohort study comprising 256 prospectively randomised patients. At two weeks post-operatively, patients underwent a micro-dialysis investiga-tion and six metabolites were collected. Patients were followed up at three, six and 12 months and the duration of surgery was examined. The results showed that glycerol and glutamate were higher with a longer duration of sur-gery. Interestingly, a longer duration of surgery was correlated with an improved clinical and functional outcome. Study III is a long-term follow-up of patients with an Achilles tendon re-rupture, where validated outcome meas-urements were used to assess lower extremity function and symptoms. Twenty patients with a mean (SD) follow-up of 50.9 (38.1) months were included. This cohort was compared with patients (n=87) treated for primary ruptures. The injured side was significantly worse compared with the healthy side in terms of heel-rise tests. The most inter-esting finding in this study was that patients treated for a re-rupture reported a poorer patient-reported outcome compared with those treated for primary ruptures. Study IV is a health-economic evaluation comparing the cost-effectiveness of surgical and non-surgical treatments. The data were collected prospectively from a randomised controlled trial comprising 100 patients. This study showed that the cost per quality-adjusted life year (QALY) gained is € 45,855 and that surgical treatment is 57% likely to be cost efficient at a willingness to pay per QALY of € 50,000. Study V is a mapping study that develops an algorithm, which converts the Achilles tendon total rupture score (ATRS) to the European Quality of Life-5 dimensions Questionnaire (EQ-5D), which enables detailed health-economic studies related to Achilles tendon injuries. It concludes that the algorithm has a high goodness of fit and can be used in future studies. Study VI comprised 391 patients from five different randomised controlled trials pre-dicting functional and patient-reported outcome one year after an acute Achilles tendon rupture. This study re-vealed that older age is a predictor of poorer outcome and that surgically treated patients have a tendency towards superior recovery in terms of heel-rise height. Taken together, this thesis shows that ultrasonography could be potentially useful in predicting the risk of re-rup-ture and outcome in acute Achilles tendon rupture. It also demonstrates that a longer duration of surgery leads to the upregulation of healing metabolites. Patients who have sustained a re-rupture have long-term deficits in terms of function and a poorer patient-reported outcome than those with primary ruptures. Moreover, it provides the first cost-effectiveness analysis in this field of research and develops an algorithm for future health-economic studies. Finally, it concludes that older age is a strong predictor of poorer heel-rise height at one year.
Acquired Epilepsy with a Focus on Stroke: Treatment and Prognosis
(2022-02-23) Larsson, David
The relationship between epilepsy and stroke is complicated. While stroke is a major cause of epilepsy after middle age, there is also evidence that the risk of stroke is increased in persons with epilepsy. The overall aim of this dissertation is to elaborate on the prognosis and treatment of epilepsy in older adults and its association to stroke. It is based on four studies which have been conducted using information from linked national registers, which offer unique opportunities to follow thousands of patients over a long period of time. The results from Papers I-II indicate that a significant proportion of all new-onset seizures after middle age will herald a subsequent stroke. Using incidence data and population statistics, we estimated the 10-year risk of stroke to be between 5-20%, depending on age group. In relative terms, the risk appears to be almost two-fold (odds ratio [OR] 1.77; 95% confidence interval [95%CI] 1.65-1.89) compared with age-matched controls from the general population – and highest during the first year after seizure onset (OR 2.21; 95 % CI 1.79–2.72). The studies described in Papers III-IV examined prognostic aspects of antiseizure medication (ASM) therapy in poststroke epilepsy. Paper III found the 5-year retention rate to be highest for lamotrigine (0.75, 95%CI 0.70–0.79) and levetiracetam (0.69, 95%CI 0.63–0.74), suggesting these drugs are well tolerated in this patient group. Paper IV used a similar methodology but investigated if mortality varied with different ASMs in monotherapy. Patients treated with lamotrigine had lower mortality (hazard ratio [HR] 0.72, 95%CI 0.60-0.86) than the reference group treated with carbamazepine, while patients treated with valproic acid had higher mortality (HR 1.40, 95%CI 1.23-1.59). Treatment with levetiracetam was associated with a reduced risk of cardiovascular death compared to carbamazepine (HR 0.77, 95%CI 0.60-0.99). In conclusion, this thesis supports a tailored management approach in adults with new-onset seizures late in life, particularly in those with a history of stroke. Persons with late-onset seizures have high vascular risk, potentially warranting screening and treatment for vascular risk factors. Moreover, the association between ASM selection and mortality raises concerns about clinically relevant drug-drug or drug-disease interactions that may modify vascular risk. Overall, lamotrigine and levetiracetam seem sensible initial treatment options in this patient group.
ACT for behaviour change in adults with poor oral health
(2021-05-19) Werner, Helene
The aim of this thesis is to contribute to the knowledge about psychological methods for behaviour change in adults with poor oral health. Study I is a systematic review of behavioural interventions for individuals ( 13 years of age) with poor oral health. Study II presents an adaptation of the modern behavioural intervention of Acceptance and Commitment Therapy (ACT) to young adults with poor oral health. Studies III and IV are based on a randomized controlled trial (RCT) including 135 caries-active 18-25-year-olds in public dental care and evaluate the effect of the intervention developed in Study II. The intervention included two individual ACT sessions provided by a licensed psychologist in addition to oral health information, whereas the control group only received oral health information. The outcomes were oral health-related behaviours +2w and +18w after baseline, health attitudes and psychological flexibility +18w after baseline. Results: Study I included eleven publications based on nine RCTs in the review. The meta-analyses found little to no effect of the psychological interventions on oral health, oral health-related behaviours and attitudes. The statistically significant findings found in favour of psychological interventions were on plaque index, oral hygiene behaviours and toothbrushing self-efficacy. Studies on adolescents and patients with dental caries were missing in the literature. Study II presents the treatment rationale and manual for a brief ACT intervention for young adults with poor oral health. Study III found the intervention group to have improved significantly with regard to more oral hygiene behaviours than the control group, immediately after the intervention. Study IV found the intervention group to have significantly improved in more oral health-related behaviours than the control group, after 18 weeks. However, there were no significant differences between the study groups in the measured outcomes after 18 weeks. Psychological interventions have the potential to be effective at changing behaviours, but new and current behavioural interventions need to be developed and tested further in adult individuals with poor oral health.
Actions of androgens and estrogens in experimental models of cardiovascular disease
(2010-10-31) Bourghardt, Johan
Men are at higher risk of developing both atherosclerotic cardiovascular disease and abdominal aortic aneurysm (AAA). Actions of sex steroids are hypothesized to underlie these gender differences. Testosterone, the major androgen, reduces atherosclerosis in male animal models but is suggested to promote AAA formation. However, the role of the androgen receptor (AR) in mediating these effects of androgens is unknown. Further, the physiological metabolic actions of androgens in females are unclear. Estradiol, the major estrogen in females, reduces atherosclerosis in female animal models and can be metabolized to 2-methoxyestradiol, a biologically active metabolite, in the vascular wall. This thesis aimed 1) to determine the role of the AR in the atheroprotection by testosterone in male mice, and 2) to investigate the physiological, AR-dependent actions of androgens in the development of atherosclerosis in female mice, and 3) to investigate the role of the AR in the development of AAA in male mice, and 4) to examine whether 2-methoxyestradiol affects the development of atherosclerosis in female mice. Male and female AR-deficient mice (AR- and AR-/-) on apolipoprotein E-deficient background were generated using Cre/loxP technology. Male AR- mice fed a high-fat diet displayed accelerated atherosclerosis and reduced atheroprotection by testosterone. Female AR-/- mice fed a high-fat diet displayed accelerated atherosclerosis associated with several features of the metabolic syndrome including obesity, insulin resistance and dyslipidemia. In an angiotensin II-induced model of AAA formation, male AR- mice were protected from the development of AAA while displaying increased atherosclerosis, and testosterone increased AAA formation in controls, but not in AR- mice. In addition, 2-methoxyestradiol treatment reduced atherosclerotic lesion formation in female apolipoprotein E-deficient mice. In conclusion, AR-mediated actions of androgens play important roles in both male and female mice. In males, AR-mediated actions of testosterone reduce atherosclerosis and promote AAA formation. In females, AR-mediated effects of androgens are important for metabolism and protects against atherosclerosis. Further, the estradiol metabolite 2-metoxyestradiol may hold promise as an atheroprotective drug.
Activation and immunoregulatory function of type II natural killer T lymphocytes
(2013-05-02) Rhost, Sara
Natural killer T (NKT) lymphocytes make up a potent immunomodulatory subset of innate-like lymphocytes. NKT cells are activated by self-lipids presented by the unconventional MHC class I-like molecule CD1d, resulting in the rapid production of a range of different cytokines, that modulate innate and adaptive immunity. NKT cells possess regulatory properties in several immune setting such as autoimmunity, infection and cancer. However, the activation of NKT cells is not fully understood. In this thesis, we have addressed the role of self-lipids for type II NKT cell activation and autoreactivity, and employed self-lipids to investigate the immunoregulatory function of type II NKT cells in murine disease models. The glycosphingolipid (GSL) sulfatide has previously been shown to be a stimulatory self-ligand for type II NKT cells. Sulfatide exists naturally as a mixture of different isoforms and is abundant in organs such as the central nervous system, gastrointestinal tract, kidneys and the pancreas where it has important functions. We demonstrate that naturally existing isoforms, including C24:1 sulfatide and lyso-sulfatide, activate type II NKT cells. Organ specific isoforms in particular, but not non-physiological isoforms, of sulfatide induced efficient activation of type II NKT cells. Despite the potent activation of NKT cells by natural sulfatide isoforms, the autoreactivity of the type II NKT cells to CD1d-expressing cells was not dependent on sulfatide production by the stimulatory cells, demonstrating that other self-lipids were causing autoreactivity. In a search for such lipids, isolated from stimulatory cells, we identified two novel NKT cell activating self-GSLs, glucosylceramide and galactosylceramide and defined their stimulatory isoforms. However, by using antigen presenting cells deficient in all GSLs we could demonstrate that the autoreactivity of the type II NKT cells did not require GSLs. In summary, we demonstrate that natural isoforms of sulfatide, glucosylceramide and galactosylceramide are ligands for type II NKT cells, suggesting that they may play a role to activate type II NKT cells upon increased exposure in autoimmunity or tumor immunity. We also find that the CD1d-dependent natural autoreactivity of the type II NKT cells depends on lipids other than GSLs. Sulfatide is present in pancreatic -cells that are targets for autoimmune destruction in type I diabetes (T1D). We demonstrate immune reactivity to sulfatide in non-obese diabetic mice that spontaneously develop TID. However, treatment of these mice with sulfatide, to activate immunomodulatory type II NKT cells, did not confer protection from TID. In contrast, we found that sulfatide treatment significantly improved the survival rate of mice with Staphylococcus aureus sepsis. The protective effects mediated by sulfatide required CD1d but not type I NKT cells, suggesting that activated type II NKT cells ameliorated sepsis development. Protection was associated with reduced serum levels of pro-inflammatory cytokines and improved platelet counts. In conclusion, our results provide novel information on the activation of type II NKT cells, and expands our understanding of their immunomodulatory capacity to improve disease outcome.

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