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  • Ottosson, Filip, et al. (författare)
  • Connection between BMI-Related Plasma Metabolite Profile and Gut Microbiota
  • 2018
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - Oxford University Press. - 0021-972X. ; 103:4, s. 1491-1501
  • Tidskriftsartikel (refereegranskat)abstract
    • Context Emerging evidence has related the gut microbiome and circulating metabolites to human obesity. Gut microbiota is responsible for several metabolic functions, and altered plasma metabolome might reflect differences in the gut microbiome. Objective To identify a plasma metabolite profile associated with body mass index (BMI) in a general population and investigate whether such metabolite profile is associated with distinct composition of the gut microbiota. Design Targeted profiling of 48 plasma metabolites was performed in a population of 920 Swedish adults (mean age, 39 years; 53% women) from the ongoing Malmö Offspring Study using targeted liquid chromatography-mass spectrometry. Gut microbiota was analyzed by sequencing the 16S ribosomal RNA gene (V1-V3 region) in fecal samples of 674 study participants. Results BMI was associated with 19 metabolites (P < 0.001 for all), of which glutamate provided the strongest direct association (P = 5.2e-53). By orthogonal partial least squares regression, a metabolite principal component predictive of BMI was constructed (PC BMI). In addition to glutamate, PC BMI was dominated by branched-chain amino acids (BCAAs) and related metabolites. Four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) were associated with both BMI and PC BMI (P < 8.0e-4 for all). When simultaneously regressing PC BMI and metabolite-associated gut bacteria against BMI, only PC BMI remained statistically significant. Conclusions We discovered associations between four gut microbiota genera (Blautia, Dorea, Ruminococcus, and SHA-98) and BMI-predictive plasma metabolites, including glutamate and BCAAs. Thus, these metabolites could be mediators between gut microbiota and obesity, pointing to potential future opportunities for targeting the gut microbiota in prevention of obesity.
  • Ottosson, Filip, et al. (författare)
  • Postprandial Levels of Branch Chained and Aromatic Amino Acids Associate with Fasting Glycaemia
  • 2016
  • Ingår i: Amino Acids. - Springer. - 2090-0104. ; 2016
  • Tidskriftsartikel (refereegranskat)abstract
    • High fasting plasma concentrations of isoleucine, phenylalanine, and tyrosine have been associated with increased risk of hyperglycaemia and incidence of type 2 diabetes. Whether these associations are diet or metabolism driven is unknown. We examined how the dietary protein source affects the postprandial circulating profile of these three diabetes associated amino acids (DMAAs) and tested whether the postprandial DMAA profiles are associated with fasting glycaemia. We used a crossover design with twenty-one healthy individuals and four different isocaloric test meals, containing proteins from different dietary sources (dairy, fish, meat, and plants). Analysis of the postprandial DMAAs concentrations was performed using targeted mass spectrometry. A DMAA score was defined as the sum of all the three amino acid concentrations. The postprandial area under the curve (AUC) of all the three amino acids and the DMAA score was significantly greater after intake of the meal with dairy protein compared to intake of the three other meals. The postprandial AUC for the DMAA score and all the three amino acids strongly associated with fasting glucose level and insulin resistance. This indicates the importance of the postprandial kinetics and metabolism of DMAAs in understanding the overall association between DMAAs and glycaemia.
  • Ottosson, Jakob Ryd, et al. (författare)
  • A longitudinal study of antimicrobial resistant faecal bacteria in sediments collected from a hospital wastewater system
  • 2012
  • Ingår i: Infection ecology & epidemiology. - 2000-8686. ; 2, s. 7438
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>Objective:</strong></p><p>The objective with this study was to determine and follow antimicrobial resistance in faecal bacteria over time in hospital wastewater pipe sediment. A further aim was to determine bacterial growth rates of sensitive, intermediate and resistant intestinal enterococci in different ciprofloxacin concentrations as a measure of bacterial fitness.</p><p><strong>Methods:</strong></p><p>A system enabling the collection of settled particles over time was installed at Kalmar County Hospital. Samples were collected bi-monthly for a 14-month period. Coliform bacteria and enterococci were isolated from the sediment with standard methods and investigated for resistance to ciprofloxacin (CIP), imipenem (IMI), trimetroprim-sulfamethoxazole (TS), ampicillin (AMP) and vancomycin (VAN) by the disc diffusion method. Resistant isolates were further typed with the PhenePlateTM system. Growth assessments were performed with an automated spectrophotometer.</p><p><strong>Results:</strong></p><p>The rate of intestinal enterococci resistance was &lt; 0.6, 1.3, 1.9 and 13% to VAN, IMI, AMP and CIP respectively. Coliform resistance frequencies were 1.1, 2.2 and 2.2% to CIP, IMI and TS respectively. At two sampling occasions, significantly higher rates of ciprofloxacin resistant enterococci were found and the establishment of a resistant clone in the sewer was indicated by the PhP-analysis. Ciprofloxacin resistant intestinal enterococci had a significantly longer lag-phase time than sensitive isolates, but from 500 µg ml<sup>-1</sup> (half MIC) resistant isolates had a competitive advantage in terms of significantly faster generation time.</p><p><strong>Discussion:</strong></p><p>Despite high concentration of antimicrobials in the sediment, resistance frequencies were generally low. This can depend on limited growth possibilities for faecal bacteria. However, the establishment of a resistant clone shows that hospital sewers can serve as a reservoir for antibiotic resistant bacteria.</p>
  • Ottosson, Lars (författare)
  • Molecular characterization of the Ro52 autoantigen and its disease related epitopes
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The presence of high titers of autoantibodies in patient sera is characteristic for the autoimmune disorder Sjögren s syndrome. The major targets for these autoantibodies are three intracellular proteins Ro52, Ro60 and La. It is still unclear why these proteins become targets for the immune system, and how this autoreactivity is triggered. Antibodies to the Ro52 protein have also been shown to associate with the development of congenital heart block in fetuses of anti-Ro52 positive mothers. The focus of this thesis has been to characterize the Ro52 protein at the molecular level, and to analyze the role of anti-Ro52 antibodies in congenital heart block. By combining immunologic, biophysical and biochemical methods we have determined the protein domain composition of Ro52. The stable domains found in recombinant Ro52 correspond well with bioinformatic predictions. We have confirmed that the predicted RING-finger, B-box and coiled-coil domains are all functional in Ro52, based on secondary structure analysis and functional studies. The RING and B-box together form a single folding unit. Two Zn2+-binding sites with nanomolar affinities were found within the RING-finger, while the B-box contains one independent Zn2+-binding site with micromolar affinity. The region between RING and B-box appears crucial for Zn2+-dependent subdomain interactions within Ro52. Secondary structure analysis of the coiled-coil domain by circular dichroism confirmed that the domain has a predominant alpha-helical fold. This domain of Ro52 was determined to consist of two structurally stable coiled-coil formations, separated by a short stretch of exposed amino acid residues. The coiled-coil domain of Ro52 forms weak homodimers, which does not exclude possible heterodimerization with an unknown interaction partner. As a tool for studying congenital heart block, we identified and cloned two human monoclonal antibodies directed against the stretch of Ro52 recognized by antibodies associated with congenital heart block. The monoclonal antibodies were isolated from an antibody library from autoimmune patients by phage display technology. The specificities of these antibodies were fine mapped and one antibody clone was found to recognize a conformational epitope within the Ro52 coiled-coil domain. This antibody specificity was found in high frequency of sera from children affected by congenital heart block. In vitro studies with rat cardiomyocytes and in vivo studies in a rat model confirmed the importance of the certain antibody specificity in development of congenital heart block. The antibodies were found to interact with an antigen on the surface of cardiomyocytes, leading to disrupted Ca2+-homeostasis in response to antibody binding. After initial increase of calcium oscillation frequency, the cells were overloaded with Ca2+ and died via apoptosis. This mechanism is proposed as the initiating event in congenital heart block. In conclusion, this thesis work has revealed the presence and functionality of stable domains found in Ro52. We also suggest a mechanism for the induction of congenital heart block, and further characterized the role of specific anti-Ro52 autoantibodies in this process.
  • Ottosson, Lena, et al. (författare)
  • Vägen till ett aktivt och hälsosamt liv upplevelser och erfarenheter av vad som ger ett aktivt och hälsosamt åldrande bland personer i gruppen 60-74 år
  • 2015
  • Rapport (övrigt vetenskapligt)abstract
    • <p>Bakgrund: Den äldre befolkningen ökar i Sverige och i nästan alla delar av världen, därförär det viktigt med kunskap om hur vi kan skapa goda förutsättningar för att bevara hälsanför människor, även i hög ålder. Investeringar i hälsosamt åldrande ökar livskvalitet för denenskilde, skapar ett hållbart samhälle och bidrar till minskade samhällskostnader.Syfte: Syftet var att undersöka upplevelser och erfarenheter av vad som ger ett aktivt ochhälsosamt åldrande för personer i åldrarna 60 -74 år i Kristianstad kommun.Metod: En empirisk intervjustudie med datainsamling i två fokusgrupper, med sammanlagt15 deltagare och kvalitativ innehållsanalys.Resultat: Genomgående tema i resultatet var tillgänglighet till närsamhället. För bevaradhälsa var självständighet centralt och påverkades av var man bor, tillgänglig service, möjlighetatt ta sig fram samt goda möten med tid för samtal. För ett aktivt liv var känslan avdelaktighet, känna sig behövd och föreningsaktivitet av stor vikt. En trygg ekonomi, åtkomliginformation, mötas av respekt och att våga gå ut var förutsättningar för att vara aktivoch delta i samhället.Slutsats: För att möta den åldrande befolkningens behov behöver samhället arbeta preventivtför att ge seniorer en bra miljö att leva i. Det finns idag mycket forskning om hur viska leva hälsosamt och förebygga sjukdom. Den stora utmaningen är att forma ett samhällesom är hållbart för framtiden, där vi alla kan leva ett långt och hälsosamt liv, ävensom senior.</p>
  • Ottosson, Sandra, et al. (författare)
  • The experience of food, eating and meals following radiotherapy for head and neck cancer : a qualitative study
  • 2013
  • Ingår i: Journal of Clinical Nursing. - 0962-1067 .- 1365-2702. ; 22:7-8, s. 1034-1043
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Aims and objectives To describe the experience of food, eating and meals following radiotherapy in patients with head and neck cancer. Background Eating problems are common in patients with head and neck cancer and may remain for a long period of time after treatment. Design A qualitative study design using in-depth semi-structured interviews. Methods Interviews were conducted nine months after the termination of radiotherapy. A purposive sample of thirteen patients with head and neck cancer participated in the study. The interviews were tape-recorded, transcribed verbatim and analysed using content analysis. Results The experience of food, eating and meals up to nine months after radiotherapy was captured in six categories: A long journey taking small steps to an uncertain future', A new way of eating', Eating without satisfaction', Challenging meals outside the family', Support and information the key to a successful journey' and The creation and acceptance of a new normal'. Conclusion This study provides new information on the long-term aspects of food, eating and meals in patients with head and neck cancer. Head and neck cancer signifies a long journey with problems affecting physical, psychological and social aspects of food. Information and support and the use of strategies are important for patients with head and neck cancer to adapt to new possibilities for living after cancer treatment. Relevance to clinical practice All members of the multiprofessional team need to be aware of the struggles with food and eating experienced by patients with head and neck cancer during the convalescent period. It is therefore important that the follow-up focuses on all aspects of food, eating and meals as a part of a holistic approach.</p>
  • Ottosson, Sandra, et al. (författare)
  • Weight loss in patients with head and neck cancer during and after conventional and accelerated radiotherapy
  • 2013
  • Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 52:4, s. 711-718
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>BACKGROUND:</strong></p><p>Weight loss is common among patients with squamous cell carcinoma of the head and neck (SCCHN) and is mainly due to tumor and treatment related factors. The aim of the present study was to evaluate weight loss in patients with SCCHN undergoing two different radiotherapy (RT) schedules.</p><p><strong>MATERIAL AND METHODS:</strong></p><p>Nutritional data were analyzed from the ARTSCAN study, a controlled randomized prospective Swedish multicenter study conducted with the aim of comparing conventional fractionation (2.0 Gy per day, total 68 Gy during 7 weeks) and accelerated fractionation (1.1 + 2.0 Gy per day, total 68 Gy during 4.5 weeks). Seven hundred and fifty patients were randomized and 712 patients were followed from the start of RT in the present nutritional study.</p><p><strong>RESULTS:</strong></p><p>The patients had a weight loss of 11.3% (± 8.6%) during the acute phase (start of RT up to five months after the termination of RT). No difference in weight loss was seen between the two RT fractionation schedules (p = 0.839). Three factors were significantly predictive for weight loss during the acute phase, i.e. tumor site, overweight/obesity or lack of tube feeding at the start of RT. Moreover, the nadir point of weight loss occurred at five months after the termination of RT.</p><p><strong>CONCLUSION:</strong></p><p>The results of the present study showed no difference in weight loss between the two RT fractionation schedules and also highlight that weight loss in SCCHN is a multifactorial problem. Moreover, the nadir of weight loss occurred at five months after the termination of treatment which calls for more intense nutritional interventions during the period after treatment.</p>
  • Ottosson-Seeberger, Astrid (författare)
  • Cardiovascular and metabolic effects of endothelins in man : an experimental and clinical study
  • 1998
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Increased plasma concentrations of endothelin-1 (ET-1) and of its propeptide big endothelin-1 have been reported in diseases associated with endothelial dysfunction, cardiovascular remodelling and insulin resistance. In this thesis, we studied the hemodynamic effects of big ET-1 in healthy humans focusing on the mechanisms of the effects (study I-IV). We also investigated whether ET-1 and big ET-1 preserve their vasoactive potency in the presence of end-stage renal failure, since permanently increased plasma levels of ET, which are seen in this condition, do not necessarily imply an increased endothelin activity. In addition, we studied the way in which the hemodialysis procedure and ischemic heart disease affect plasma concentrations of ET-1 and big ET-1 in chronic hemodialysis patients (study V). Finally we studied the effects of ET-1 on insulin sensitivity and the vasoactive interactions between insulin and ET-1 in healthy humans (study VI). We made the following findings: II) Exogenous big ET-1 caused potent and long-lasting cardiovascular effects in healthy humans as demonstrated by an increase in mean arterial blood pressure and a decrease in heart rate, cardiac output and stroke volume and a fall in renal and splanchnic blood flow. Circulating big ET-1 was removed from the circulation in the renal and splanchnic vascular beds and probably also in the vasculature of forearm skeletal muscle with a plasma half-life that was longer than that previously shown for ET-1. The renal and splanchnic extraction of big ET-1 appeared to be accompanied by regional conversion of big ET-1. Big ET-1 itself was demonstrated to be without major intrinsic vasoactivity. The C-terminal big ET-1 (22-3 8) fragment, which is also formed during the conversion of big ET-1 to ET-1, had no intrinsic vasoactive potency or capacity to potentiate the cardiovascular effects of ET-1. II) Circulating ET-1 and big ET-1 preserved their vasoactive potency in end-stage renal failure. Thus, big ET-1 seems to be converted to ET-1 even in the presence of renal insufficiency. The plasma half-lives of both peptides were significantly prolonged compared with those of healthy subjects. Chronic hemodialysis patients with ischemic heart disease had higher plasma concentrations of ET-1 and big ET-1 than hemodialysis patients without this disorder. Hemodialysis lowered plasma levels of ET-1 and big ET-1 whereby high-flux membranes removed big ET-1 more efficiently than low-flux membranes. III) Exogenous ET-1 induced peripheral insulin resistance as demonstrated by a decrease in whole-body and leg glucose uptake without causing any changes in leg blood flow. Furthermore, ET-1 blocked not only the metabolic but also the vasoactive potency of insulin in healthy humans. In summary, we demonstrated that circulating ET-1 and big ET-1 give rise to symtoms commonly noted in cardiovascular diseases which are associated with increased plasma concentrations of ET-1 and big ET-1. Since exogenous ET-1 and big ET-1 were shown to preserve their vasoactive potency in the presence of permanently elevated plasma levels of endogenous ET-1 and big ET-1, we conclude that ET-1 and big ET-1 could conceivably contribute to the genesis of endothelial dysfunction, cardiovascular remodelling and insulin resistance in cardiovascular diseases.
  • Ottosson Wadlund, Astrid (författare)
  • Apoptosis signaling in leukemia and lymphoma: understanding mechanisms of chemoresistance
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Apoptosis (programmed cell death) is a basic physiological process, essential in the balance between life and death of cells of normal tissues in the body. Apoptosis can be considered as cellular “suicide” initiated by the cell itself when infected by a virus or transformed into a cancer cell. Cancer is a genetic disease and in cancer cells the molecules involved in initiation and execution of apoptosis are frequently lost or inactivated. Blockade of apoptosis is associated with resistance to conventional cancer drugs. The importance of intact apoptosis signaling pathways in leukemia and lymphoma was addressed in the current thesis. We found that apoptotic protease activating factor 1 (Apaf-1) is required for second mitochondria activator of caspases (Smac)- dependent potentiation of protein kinase inhibitor staurosporine- and proteasome inhibitor lactacystin-triggered apoptosis in chemoresistant Burkitt lymphoma cell lines Raji and DG-75. Furthermore, the importance of elevated levels of cellular inhibitor of apoptosis 2 (cIAP2), in these cells was examined in cellular extracts from Raji cells overexpressing cytosolic Apaf-1. Subsequently cytochrome c-dependent caspase activation in Raji cells immunodepleted for cIAP2 was assessed. We found immunodepletion of cIAP2 to potentiate caspase activation only in Raji cells stably transfected with cytosolic Apaf-1. To further study the importance of Apaf-1 in response to proteasome inhibitors we used a T cell acute lymphoblastic leukemia (T-ALL) cell line, Jurkat, stably transfected with shRNA against Apaf-1. The clinically relevant proteasome inhibitor bortezomib (Velcade®) failed to induce apoptosis in Jurkat cells without Apaf-1. The bortezomib-induced apoptosis was associated with induction of pro-apoptotic factor Noxa upstream of mitochondria. Moreover, we examined primary leukemic blasts from patients with TALL for Apaf-1 protein expression and responsiveness to bortezomib-induced apoptosis ex vivo. The Apaf-1 protein expression varied amongst the different patient samples and although the sample number was low we noted the lowest increase in bortezomib-induced apoptosis in the patient sample completely deficient for Apaf-1. In order to elucidate the importance of other mediators of apoptosis, anti-apoptotic HS-associated protein X-1 (HAX-1) was assessed at the protein and transcript level in malignant lymphomas. We thus determined the mRNA expression of HAX1 in two public transcriptomics databases. HAX-1 protein expression was assessed in a panel of 50 samples from patients with B lymphoma. We found that HAX-1 mRNA and protein was highly expressed in B lymphoma. Furthermore, we found a positive association with the proliferation marker Ki67 at the protein level in diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma samples, as well as an inverse correlation with Bcl-2 at the protein and transcript level in follicular lymphoma. Finally, the actions of the specific inhibitor of chymotrypsin-like serine proteases, TPCK and the NF-κB inhibitor Bay-11 7082 were elucidated in chemoresistant cell lines Raji and DG-75. Both compounds induced caspase-independent apoptosis as well as a decrease in constitutive NF-κB activity. Moreover, we found that TPCK and Bay-11 7082 reduced protein and mRNA expression of the NF-κB target HAX-1, which may contribute to the sensitization to apoptosis. In summary, these studies contribute to our understanding of the importance of intact apoptotic signaling pathways in sensitivity to apoptosis induced by anti-cancer substances. Studies of different pro- and anti-apoptotic molecules may lead to the identification of novel targets for therapy.
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