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  • 301.
    Westermark, Gunilla T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Krogvold, Lars
    Oslo Univ Hosp, Oslo, Norway;Univ Oslo, Norway.
    Dahl-Jorgensen, Knut
    Oslo Univ Hosp, Oslo, Norway;Univ Oslo, Oslo, Norway.
    Ludvigsson, Johnny
    Linköping Univ Hosp, Linköping, Sweden.
    Islet amyloid in recent-onset type 1 diabetes-the DiViD study2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 3, p. 201-203Article in journal (Refereed)
  • 302.
    Westermark, Gunilla T.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Oskarsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eighty years of research on islet amyloidosis in Uppsala2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 2, p. 117-123Article in journal (Refereed)
  • 303.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Amyloid in the islets of Langerhans: Thoughts and some historical aspects2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 2, p. 81-89Article, review/survey (Refereed)
    Abstract [en]

    Deposition of amyloid, derived from the polypeptide hormone islet amyloid polypeptide (IAPP; 'amylin') is the single most typical islet alteration in type 2 diabetes. Islet amyloid was described as hyalinization already in 1901, but not until 1986 was it understood that it is a polymerization product of a novel beta-cell regulatory product. The subject of this focused review deals with the pathogenesis and importance of the islet amyloid itself, not with the biological effect of the polypeptide. Similar to the situation in Alzheimer's disease, it has been argued that the amyloid may not be of importance since there is no strict correlation between the degree of islet amyloid infiltration and the disease. However, it is hardly discussable that the amyloid is important in subjects where islets have been destroyed by pronounced islet amyloid deposits. Even when there is less islet amyloid the deposits are widely spread, and beta-cells show ultrastructural signs of cell membrane destruction. It is suggested that type 2 diabetes is heterogeneous and that in one major subtype aggregation of IAPP into amyloid fibrils is determining the progressive loss of beta-cells. Interestingly, development of islet amyloid may be an important event in the loss of beta-cell function after islet transplantation into type 1 diabetic subjects.

  • 304.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lars Grimelius and his silver impregnation method-Commentaries on the paper in Upsala Journal of Medical Sciences with the highest number of citations2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 2, p. 113-116Article in journal (Refereed)
  • 305.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Localized AL amyloidosis: A suicidal neoplasm?2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 2, p. 244-250Article, review/survey (Refereed)
    Abstract [en]

    Although AL amyloidosis usually is a systemic disease, strictly localized AL deposits are not exceptionally rare. Such case reports form a considerable body of published articles. Although both AL amyloidosis types are formed from an N-terminal segment of a monoclonal immunoglobulin light chain, a typical localized AL amyloid differs from the systemic counterpart by the morphological appearance of the amyloid, and presence of clonal plasma cells and of giant cells. In this article it is pointed out that localized AL amyloidosis ('amyloidoma') represents a true plasma cell neoplasm and not a pseudotumor. The pathogenesis of localized AL amyloidosis may differ from that of the systemic type, a suggestion underlined by the fact that localized AL amyloidosis of kappa type is as common as that of lambda origin, in contrast to the systemic form where lambda chains constitute the overwhelming majority of cases. It is suggested that oligomeric assemblies of the produced immunoglobulin light chain are toxic to plasma cells, which in this way commit suicide.

  • 306.
    Westermark, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Suhr, Ole B.
    Berg, Svante
    Transthyretin-derived amyloidosis: Probably a common cause of lumbar spinal stenosis2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 3, p. 223-228Article in journal (Refereed)
    Abstract [en]

    Background. Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, which can lead to severe restrictive cardiomyopathy. SSA is, however, a systemic disease, and amyloid deposits may appear in many other tissues but are thought to be without clinical symptoms outside the heart. Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs. Results. We questioned whether lumbar spinal stenosis sometimes could be a manifestation of undiagnosed SSA. In this first report we have studied the presence of amyloid in material obtained at surgery for spinal stenosis in 26 patients. Amyloid was found in 25 subjects. Transthyretin was demonstrated immunohistochemically in 5 out of 15 studied resected tissues. Four of the positive materials were analyzed with Western blot revealing both full-length transthyretin (TTR) and C-terminal TTR fragments, typically seen in SSA. Conclusion. We conclude that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted.

  • 307.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A solid phase radioimmunoassay method for ferritin in serum using (125)I-labelled ferritin1977In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 82, no 1, p. 15-19Article in journal (Refereed)
    Abstract [en]

    A solid phase radioimmunoassay method for ferritin in serum was developed using ferritin conjugated with an (125)I-labelled ester. The method was based upon competitive inhibition utilizing the free antigen-binding sites of antibodies to ferritin bound to a ferritin which had been chemically coupled to insoluble polysaccharide particles. The method was evaluated with regard to specificity, sensitivity, precision and practicability and was found to be a robust method suitable for the assay of ferritin in human serum in clinical studies. There was a significant (P<0.001) difference between the ferritin levels in healthy men and women, mean values 100 and 66 arb U/l respectively. Male blood donors had significantly (P<0.002) lower ferritin levels in serum (mean 68.5 arb U/l) than other healthy men. Patients with iron overload or hepatic damage had high values, as expected, and the serum levels of ferritin reflected changes in iron deposits during phlebotomy and iron treatment in 3 healthy men.

  • 308.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Dynamic changes in glycosylation and glycan composition of serum FSH and LH during natural ovarian stimulation2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 3, p. 153-164Article in journal (Refereed)
    Abstract [en]

    Background. Glycosylation and glycan composition are of fundamental importance for the biological properties of FSH and LH. The aim of this study was to determine the glycosylation, sialylation, and sulfonation of serum FSH and LH throughout the normal menstrual cycle. Methods. Serum samples were collected from 79 healthy women with regular menstrual cycles. The mean numbers of anionic monosaccharide (AMS), sialic acid (SA), and sulfonated N-acetylgalactosamine (SU) residues per FSH and LH molecule were estimated for all sera with methods based on electrophoreses, neuraminidase treatments, and fluoroimmunoassays of the gonadotrophins. Results. Di-glycosylated glycoforms (FSHdi, LHdi) were detected in serum in addition to tetra-glycosylated FSH (FSHtetra) and tri-glycosylated LH (LHtri). FSHdi exhibited two peaks: one on day 5 to 7 and one, more pronounced, at midcycle. FSHtetra plateaued at a high concentration from day 5 to 15, without a midcycle peak. There were lower concentrations of LHdi than LHtri, except at midcycle when the opposite occurred. The mean numbers of SA and SU residues per molecule of FSH and LH in serum showed four different patterns during the cycle, all with highly significant (P < 0.0001) differences between levels at different phases of the cycle. The pattern of SA residues on FSH was 'M'-shaped, and that of SU on LH 'V'-shaped. Conclusion. Serum FSH and LH governing the natural ovarian stimulation process exhibited dynamic changes of glycosylation and glycan composition. This new information on the FSH and LH molecular structures may lead to more successful mono-ovulatory treatment regimens for ovulation induction in anovulatory women.

  • 309.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Low-glycosylated forms of both FSH and LH play major roles in the natural ovarian stimulation2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 2, p. 100-108Article in journal (Refereed)
    Abstract [en]

    Background: The natural ovarian stimulation is mediated by four gonadotrophin glycoforms: FSHtri with three, FSHtetra with four, LHdi with two, and LHtri with three N-glycans. The aim of the study was to determine the serum concentrations of the four glycoforms and their contents of anionic monosaccharides (AMS), i.e. sialic acid (SA) and sulfonated N-acetylgalactosamine (SU) residues throughout the menstrual cycle. Methods: Serum samples were collected from 78 healthy women with regular menstrual cycles. The serum glycoform molecules were identified by their distributions at electrophoreses. Analyses were also performed after removal of terminal SA. The hormones were measured with time-resolved sandwich fluoroimlooimm u noassays. Results: The concentration profiles of the four glycoforms were markedly different. FSHtri, which had a 3-fold higher biopotency than FSHtetra, had peak levels on cycle day 5 and at midcycle and nadirs on cycle days 9 and 21-23. FSHtetra had a raised level on cycle days 5-12, followed by a decrease. LHdi and LHtri had similar patterns, but the peak/nadir ratio was much more pronounced for LHdi than for LHtri, 18 versus 4. The numbers of SA residues per molecule were at a maximum around midcycle when the corresponding numbers of SU were at a minimum. The SU/SA ratio was at a minimum on cycle day 12. Conclusion: The results indicate that the LHdi and the FSHtri molecules play major roles in the natural ovarian stimulation. The SU/SA ratios per molecule favoured a prolonged circulatory half-life of all glycoforms at the midcycle phase. The observations may lead to more successful inductions of ovulation in anovulatory women.

  • 310.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Molecular size and charge as dimensions to identify and characterize circulating glycoforms of human FSH, LH and TSH2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 217-223Article in journal (Refereed)
    Abstract [en]

    Background: FSH, LH, and TSH are glycoprotein hormones secreted from the pituitary as fully and low-asparagine-glycosylated hormones. These glycoforms of the hormones exist as a large number of isoforms varying in their glycan contents of terminal anionic monosaccharides (AMS), i.e. sialic acid (SA) and sulfonated N-acetylgalactosamine (SU). Due to the immense heterogeneity and the low concentrations in serum it has been a challenge to develop reliable analytical methods to measure and characterize the circulating glycoforms of these hormones. Methods: The hormones were separated with respect to AMS content per molecule by calibrated 0.1% agarose suspension electrophoreses. Glycoforms in separated fractions were then analyzed with respect to size by 180 calibrated Sephadex G-100 gel filtrations. The hormones were measured with timeresolved sandwich fluoroimmunoassays. All separations and assays were performed in veronal buffer at pH 8.7. Sera and fractions were also analyzed after removal of terminal SA. Results: In addition to the fully glycosylated FSH, LH, and TSH, also tri-glycosylated FSH and di-glycosylated LH and TSH forms could be identified in serum samples. The low-and fully glycosylated hormones differed both with respect to size and to median number of AMS per molecule. Algorithms, based on the distributions by electrophoreses, were developed for each hormone to estimate percent low-glycosylated forms in serum. The median numbers of SA and SU per glycoform molecule were estimated using results obtained after desialylation. Conclusion: The methods can be used for identification and characterization of glycoforms of circulating FSH, LH, and TSH in physiological and clinical studies.

  • 311.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Effects of 17 beta-oestradiol and norethisterone acetate on sulfonation and sialylation of gonadotrophins in post-menopausal women2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 2, p. 97-106Article in journal (Refereed)
    Abstract [en]

    Background. The number of terminal sialic acid and sulfonated N-acetylgalactosamine (SO3-GalNAc) on gonadotrophins in serum varies during the menstrual cycle and changes at menopause, suggesting that gonadal steroids modify their oligosaccharide synthesis. Our objective was to determine the effects of 17 beta-oestradiol (E-2) and a progestogen, norethisterone acetate (NETA), on the sulfonation and sialylation of gonadotrophins in post-menopausal women. Methods. Serum samples were obtained from eight post-menopausal women treated with 20 mg E-2 implants every 6 months, from four women who in addition were treated daily with 5 mg NETA orally for a 2-week period, and from four women who got this NETA treatment during a 4-week period. Sera from 11 non-treated post-menopausal women served as a reference group. The gonadotrophin serum concentrations, the number of SO3-GalNAc and sialic acid residues per serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) molecule, and the distributions of molecules with 0-1-2-3-4 sulfonated residues were measured. Results. The E-2-treated post-menopausal women had considerably less (P < 0.001) sialic acid and slightly more (P < 0.01) SO3-GalNAc per serum LH and FSH molecule than the non-treated. Two weeks of NETA treatment increased the sulfonation of LH (P < 0.01) and FSH (P < 0.05) concomitantly with decreased (P < 0.05) sialylation of LH. Conclusion. The primary effect of E-2 treatment was a decrease in sialylation and, due to competition for the same substrate, a secondary and consequentially minor increase in sulfonation of LH and FSH. The primary effect of the NETA therapy was an increase in the sulfonation of LH and FSH concomitantly with secondary and consequentially decreases in sialylation of LH.

  • 312.
    Wiklund, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Johansson, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Martin H: son Holmdahl.2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 2Article in journal (Refereed)
  • 313.
    Willén, Roger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hultén, Leif
    Prophylactic surgery for patients with longstanding ulcerative colitis. Which option? Histopathological and clinical implications.2007In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 112, no 1, p. 49-60Article in journal (Refereed)
    Abstract [en]

    Patients with longstanding chronic ulcerative proctocolitis are at risk to develop colorectal cancer Conflicting views as regards surveillance, the indications for surgery and type of preventive procedure exist. For permanent prevention of cancer development complete removal of all potential malignant colorectal mucosa has to be done. Panprocto-

    colectomy with a conventional ileostomy or continent ileostomy removing all colorectal mucosa should therefore eliminate further risks of colorectal cancer.

    Colectomy and ileorectal anastomosis is a controversial issue. While many surgeons today are reluctant to use the technique, emphasising the persistent cancer risk, others consider the operation a viable alternative when used on a selective basis. The long-term risk of cancer in the rectal stump is the main strong argument.

    In restorative proctocolectomy, i.e. proctocolectomy with construction of an ileopouch anal anastomosis residual rectal mucosa is left behind irrespective of technique used and is therefore at risk for cancer development. Quite a few cancers have been reported to occur in these patients but controversy exists as regards the origin of these tumours but the risk for cancer development is very low.

    Biopsies from ileal pouches demonstrate various histopathological changes from nearly normal mucosa, to inflammation and atrophy, inflammatory cell changes, dysplasia as well as development of carcinoma. Grading of type and atypia is a challenge to reproduce and requires the participation of experienced gastrointestinal histopathologists.

  • 314.
    Wålinder, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Runeson, Roma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Arakelian, Erebouni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nordqvist, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Runeson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rask-Andersen, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    A supportive climate and low strain promote well-being and sustainable working life in the operation theatre.2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 3, p. 183-190Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Shortage of health-care workers e.g. in operating theatres is a global problem. A shortage of staff negatively affects patient outcomes, making it important to keep the employees from quitting. The aim of this survey was to study if well-being, zest for work, and thoughts about leaving work in an operating theatre can be related to the psychosocial work environment, as described by the job demand-control-support (JDCS) model.

    METHODS: A questionnaire was provided to personnel in operating theatres of seven Swedish hospitals (n = 1405, with a response rate of 68%) that included the JDCS model, personal factors, work ability, well-being, zest for work, and thoughts about leaving their position. Ordinal scale regression was used for analyses.

    RESULTS: A majority reported moderate to high zest for work (76%). A minority (30%) had sometimes thought during at least one month in the last year of leaving their position. Lower social support scores and high demands together with low control (high-strain) scores were related to lower well-being, lower zest for work, and more thoughts about leaving the position. Anaesthetists scored in the low-strain field, nurse anaesthetists and assistant nurses in the passive field, and operating nurses in the active field, in comparison to all personnel.

    CONCLUSION: According to the JDCS model, both lower social support and high strain were related to lower well-being and negative thoughts about the position. Social support scores were about the same for different occupational groups in the operating theatre, and no occupation scored on average in the high-strain field.

  • 315.
    Wånggren, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Prag, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Skoog Svanberg, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Attitudes towards embryo donation in Swedish women and men of reproductive age2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 3, p. 187-195Article in journal (Refereed)
    Abstract [en]

    Background

    When performing in-vitro fertilization (IVF), more embryos than needed are often derived. These embryos are usually frozen and stored, but as ruled by Swedish law they have to be discarded after 5 years. In other countries it is legal to donate the excess embryos to other infertile couples who for different reasons cannot undergo the procedure of IVF. The aim of the present study was to investigate public opinion in Sweden regarding different aspects of embryo donation.

    Methods

    A questionnaire regarding attitudes towards aspects of embryo donation was sent to a randomized sample of 1,000 Swedish women and men of reproductive age.

    Results

    A total of 34% responded to the questionnaires. A majority of the respondents (73%) were positive towards embryo donation. Seventy-five per cent agreed that it should be possible to donate embryos to infertile couples. Approximately half of the participants (49%) supported embryo donation to single women. A majority of the participants emphasized that demands should be imposed on the recipient's age (63%), alcohol addiction (79%), drug addiction (85%), and criminal record (67%). Forty-seven per cent of the respondents agreed that the recipient should be anonymous to the donor, and 38% thought that the donor should remain anonymous to the child.

    Conclusions

    The results of the present study indicate support for embryo donation among a subset of the Swedish population of reproductive age. If embryo donation were to be allowed in Sweden, strategies for treatment and counselling need to be developed.

  • 316.
    Zang, Guangxiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barbu, Andreea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Activated pancreatic stellate cells can impair pancreatic islet function in mice2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 169-180Article in journal (Refereed)
    Abstract [en]

    Background. Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets. Methods. Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets. Results. PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets cocultured with PSCs for 24-48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days. Conclusion. Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.

  • 317.
    Zethelius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The interaction between impaired acute insulin response and insulin resistance predict type 2 diabetes and impairment of fasting glucose: report from a 20-year follow-up in the Uppsala Longitudinal Study of Adult Men - ULSAM2008In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 113, no 2, p. 117-130Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Impaired acute insulin response (AIR) and insulin resistance (IR) are characteristics of Type 2 diabetes (T2DM). The aim was to develop risk models for T2DM and impaired fasting glucose (IFG), reflecting estimates both of AIR and IR, and of their interaction, as predictors over 20 years of follow-up. METHODS: We developed predictive models using hierarchic multiple regression analyses in a population-based cohort of 1227 men with normal fasting blood glucose at baseline (1970-73) and were reinvestigated after 10 and after 20 years. Using IVGTT-variables correlated either to AIR or to IR, separate models were developed. Combined models were also estimated from which prediction scores, representing individual risk, were calculated. RESULTS: In combined models, interaction between prediction scores reflecting AIR and IR predicted T2DM and IFG. Lowest tertile of AIR and the highest tertile of IR showed a relative risk (RR) of 15.3 (95%-CI=5.58-41.84) for T2DM compared to the contrast group (high AIR and low IR). Corresponding RR for IFG was 13.23 (95%-CI=6.53-26.78). C-statistic increased from 0.76 to 0.79 (p=0.018) for T2DM and from 0.77 to 0.80 for IFG (p=0.062) taking interaction into account. Main effects of lowest tertile of AIR and highest tertile of IR versus best were: RR for T2DM, 8.80 (95%-CI=4.25-18.21) and 6.31 (95%-CI=3.26-12.21); for IFG, 9.07, (95%-CI=5.38-15.29) and 4.49 (95%-CI=2.98-6-76). CONCLUSION: The interaction between low AIR and high IR revealed a high relative risk for T2DM or IFG reflecting the interplay between these factors over long time on worsening glucose tolerance and development of manifest disease.

  • 318.
    Zhang, X-Q
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundh, Ulla Beckman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zetterqvist, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 2, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Protein histidine phosphorylation accounts for about 6% of the total protein phosphorylation in eukaryotic cells; still details concerning histidine phosphorylation and dephosphorylation are limited. A mammalian 14-kDa phosphohistidine phosphatase, also denominated PHPT1, was found 6 years ago that provided a new tool in the study of phosphohistidine phosphorylation. The localization of PHPT1 mRNA by Northern blot analysis revealed high expression in heart and skeletal muscle. The main object of the present study was to determine the PHPT1 expression on protein level in mouse tissues in order to get further information on the physiological role of the enzyme. Tissue samples from adult mice and 14.5-day-old mouse embryos were processed for immunostaining using a PHPT1-specific polyclonal antibody. The same antibody was also provided to the Swedish human protein atlas project (HPR) (http://www.proteinatlas.org/index.php). The results from both studies were essentially consistent with the previously reported expression of mRNA of a few human tissues. In addition, several other tissues, including testis, displayed a high protein expression. A salient result of the present investigation was the ubiquitous expression of the PHPT1 protein and its high expression in continuously dividing epithelial cells.

  • 319.
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Overcoming scientific and structural bottlenecks in antibacterial discovery and development2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 170-175Article, review/survey (Refereed)
    Abstract [en]

    Antibiotic resistance is becoming an increasing threat, with too few novel antibiotics coming to market to replace those lost due to resistance development. Efforts by the pharmaceutical industry to screen for and design novel antibacterials have not been successful, with several companies minimizing or closing down their antibacterial research units, leading to a loss of skills and know-how. At the same time, antibiotic innovation in academia is not filling the void due to misaligned incentive structures and lack of vital knowledge of drug discovery. The scientific and structural difficulties in discovering new antibiotics have only begun to be appreciated in the latest years. Part of the problem has been a paradigm shift within both industry and academia to focus on 'rational' drug development with an emphasis on single targets and high-throughput screening of large chemical libraries, which may not be suited to target bacteria. The very particular aspects of 'targeting an organism inside another organism' have not been given enough attention. In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered.

  • 320.
    Åkerblom, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Latva-Rasku, Aino
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Dept Endocrinol, Turku, Finland.
    Johansson, Lars
    Antaros Med AB, Gothenburg, Sweden.
    Lisovskaja, Vera
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Cecilia
    AstraZeneca, Gothenburg, Sweden.
    Oscarsson, Jan
    AstraZeneca, Gothenburg, Sweden.
    Nuutila, Pirjo
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Dept Endocrinol, Turku, Finland.
    Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients - a description of the DAPACARD study2019In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 1, p. 59-64Article in journal (Refereed)
    Abstract [en]

    Background: Diabetes increases the risk for cardiovascular (CV) events. It has recently been shown that the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors leads to a reduction in CV outcomes in patients with type 2 diabetes mellitus (T2DM), including mortality and heart failure hospitalization. The exact mechanisms of how SGLT2 inhibitors lead to this CV risk reduction remain incompletely understood. The study of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency and myocardial contractile work in type 2 diabetes patients (DAPACARD) (NCT03387683) explores the possible effects of dapagliflozin, an SGLT2 inhibitor, on cardiac work, metabolism, and biomarker levels.

    Methods: DAPACARD is an international, randomized, double-blind trial that aims to examine the effects of dapagliflozin versus matching placebo in 52 patients with T2DM that are on stable metformin therapy prior to and during the 6 weeks of treatment. The primary efficacy endpoint is change in global longitudinal strain of the left ventricle (GLSLV) measured with magnetic resonance imaging (MRI) between baseline (pre-treatment) and end of study (on-treatment). The secondary endpoint is the corresponding change in myocardial efficiency measured as external left ventricular work divided by total left ventricular work, which is estimated using [11C]-acetate clearance using positron emission tomography (PET).

    Conclusion: The DAPACARD study is an extensive investigation of cardiac function and metabolism, by advanced imaging with PET and MRI, as well as biomarkers, performed in order to further explore how the SGLT2 inhibitor dapagliflozin could influence cardiovascular outcomes in patients with T2DM.

  • 321.
    Öhman, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Ingela
    Rosen, Christer
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Biochemical effects of consumption of eggs containing omega-3 polyunsaturated fatty acids2008In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 113, no 3, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Today, eggs with an increased content of -3 fatty acids are available but there are few publications on the effects of consumption of such eggs on the lipoproteins and acute phase markers in humans. The aim of the present study was to evaluate the effects of consumption of standard eggs and -3 enriched eggs on lipoproteins, glucose and inflammation markers. Nineteen healthy volunteers consumed one extra egg per day of either standard eggs or omega-3 enriched eggs in a double-blind, cross-over study. The duration of each period was 1 month. The effects of the different egg diets on apolipoprotein A1 and B (Apo A1 and B), lipoprotein (a), creatinine, cystatin C, C-reactive protein, serum amyloid protein A, interleukin 6, triglycerides, glucose, total-, high-density lipoprotein and low-density lipo-protein cholesterol concentrations were analyzed. Addition of one regular egg per day to the normal diet had no negative impact on blood lipids or inflammation markers. Consumption of omega-3 enriched eggs resulted in higher levels of ApoA1, lower ApoB/ApoA1 ratio and lower plasma glucose. These effects have been associated in previous studies with a reduced risk for cardiovascular mortality and diabetes.

  • 322.
    Östberg, Erland
    et al.
    Västerås & Koping Hosp, Dept Anaesthesia & Intens Care, Västerås, Sweden..
    Auner, Udo
    Vasteras Hosp, Dept Radiol, Västerås, Sweden..
    Enlund, Mats
    Clin Res Ctr, Västerås, Sweden..
    Zetterström, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Edmark, Lennart
    Västeras & Koping Hosp, Dept Anaesthesia & Intens Care, Västerås, Sweden..
    Minimizing atelectasis formation during general anaesthesia-oxygen washout is a non-essential supplement to PEEP2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 2, p. 92-98Article in journal (Refereed)
    Abstract [en]

    Background: Following preoxygenation and induction of anaesthesia, most patients develop atelectasis. We hypothesized that an immediate restoration to a low oxygen level in the alveoli would prevent atelectasis formation and improve oxygenation during the ensuing anaesthesia. Methods: We randomly assigned 24 patients to either a control group (n=12) or an intervention group (n=12) receiving an oxygen washout procedure directly after intubation. Both groups were, depending on body mass index, ventilated with a positive end-expiratory pressure (PEEP) of 6-8 cmH(2)O during surgery. The atelectasis area was studied by computed tomography before emergence. Oxygenation levels were evaluated by measuring blood gases and calculating estimated venous admixture (EVA). Results: The atelectasis areas expressed as percentages of the total lung area were 2.0 (1.5-2.7) (median [interquartile range]) and 1.8 (1.4-3.3) in the intervention and control groups, respectively. The difference was non-significant, and also oxygenation was similar between the two groups. Compared to oxygenation before the start of anaesthesia, oxygenation at the end of surgery was improved in the intervention group, mean (SD) EVA from 7.6% (6.6%) to 3.9% (2.9%) (P=.019) and preserved in the control group, mean (SD) EVA from 5.0% (5.3%) to 5.6% (7.1%) (P=.59). .Conclusion: Although the oxygen washout restored a low pulmonary oxygen level within minutes, it did not further reduce atelectasis size. Both study groups had small atelectasis and good oxygenation. These results suggest that a moderate PEEP alone is sufficient to minimize atelectasis and maintain oxygenation in healthy patients.

4567 301 - 322 of 322
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