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  • 1.
    Albinsson, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    A Palliative Approach to Dementia Care: Leadership and organisation, existential issues and family support2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main purpose of this thesis was to apply the WHO and NHS palliative care approach to dementia care.

    Thirty-one staff-members in mid-Sweden (studies I and II) and 20 next-of- kin (study IV) were interviewed. In study III, 316 staff-members from dementia care and 121 staff-members from palliative cancer care responded to a questionnaire about family support. The interviews were tape-recorded and analysed with a qualitative phenomenographic (I and II) and a hermeneutic approach (IV). The questionnaires (III) were analysed using qualitative and quantitative content analysis.

    The staff-members stated almost unanimously that daily leadership was lacking, and consequently clear goal formulations and care planning were rare (I). Proper teamwork between the doctor and the staff who worked on a daily basis with the patients was absent (I). With respect to existential issues, education and staff discussions were lacking (II). The staff were at a loss concerning how to deal with these issues. Nevertheless, these issues are central to family-members who have to deal with an existential crisis (IV). Important questions emerged about obligation and guilt, faithfulness, responsibility, and paying back what you once received. Existential isolation could be identified e.g. in the reversal of roles experienced as "being a parent to your parent" and in the burden of "visiting a living dead person".

    There were no routines for bereavement visits. The type of support suggested for dementia family members is partly similar to support in palliative cancer care, but it also differs in other respects such as feelings of guilt because the early signs of the disease are misunderstood, the need for respite because of the long trajectory of dementia diseases, and the occurrence of anticipatory grief because in the late phase family members can no longer make any contact at all with the patient (III).

    A palliative approach can improve the quality of life for the dementia patient and for the family. It can be used as a basis for a clear goal formulation. Some of the suggestions listed in this thesis for improving the quality of care are more a reflection of the need for a change in attitudes rather than the need for substantial budget increases.

  • 2. Andersen, Janice
    et al.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Sandberg, Sverre
    Illness Perception and Psychological Distress in Persons with Porphyria Cutanea Tarda2016In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 96, no 5, p. 674-678Article in journal (Refereed)
    Abstract [en]

    Porphyria cutanea tarda (PCT) requires long-term treatment and follow-up, although many patients experience life-long remission. The aim of this cross-sectional postal survey was to describe and investigate the association between illness perception, health complaints, self-reported symptoms and distress in persons with PCT. The participants perceived PCT as a chronic condition with high levels of personal and treatment control. Persons who reported active symptoms scored higher on perceived illness threat, total health complaints and psychological distress compared with those in remission or latent phases. However, a higher perception of illness threat and the total burden of health complaints were more closely associated with psychological distress than were perceived PCT symptoms activity. This has implications for clinical consultation; dermatologists should be attentive to symptoms activity, but also recognize that patients in remission with a high perceived illness threat and multiple health complaints might be especially vulnerable to psychological distress with regards to PCT.

  • 3.
    Aneblom, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    The Emergency Contraceptive Pill – a Second Chance: Knowledge, Attitudes and Experiences Among Users and Providers2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of this thesis was to study knowledge, attitudes and experience of emergency contraceptive pills among women and providers.

    Both quantitative and qualitative methods were used. Focus-group interviews were conducted with teenage-girls (I) and with women who had purchased ECP without prescription (IV). Self-administered waiting-room questionnaires were administered to women presenting for induced abortion in three large hospitals (II, III), and after the deregulation of ECP, a postal questionnaire was sent to pharmacy staff and nurse-midwives in three counties in mid-Sweden (V).

    Overall, women showed high basic awareness of ECP although specific knowledge such as the level of effectiveness, time-frames and how the method works was lacking. Approval of the method was high and most women were positive to use the method if they needed. Contradictory views as to whether ECP undermines contraceptive behavior were expressed. As many as 43% of women requesting induced abortion had a history of one or more previous abortions. Among the abortion applicants, one out of five, 22%, had previously used ECP and 3% had used it to prevent the current pregnancy. Media and friends were the two most common sources of information on ECP. Half of the women, 52%, were positive to having ECP prescription-free. Those women who had purchased ECP in a pharmacy without prescription, appreciated this possibility, and the major benefits expressed were time saving aspects. No severe side-effects were reported. The women's experiences of interaction with pharmacy staff were both positive and negative. The importance of up-to-date information about ECP and the OTC-availability from the health care providers was emphasized. Both pharmacy staff and nurse-midwives had positive attitudes towards ECP and the OTC availability. Of pharmacy staff, 38% reported that they referred women to nurse-midwives/gynecologists for further counseling and follow-ups. The need for increased communication and collaboration between pharmacies and local family planning clinics was reported by both study groups with suggestions of regular meetings for information and discussions.

    The results suggest that ECP is still underused and that more factual information is needed before the method is becoming a known, accepted and integrated back-up method to the existing family planning repertoire. Longitudinal research to assess the long-term effects of ECP is needed.

    List of papers
    1. Focus group interviews of Swedish teenage girls about the emergency contraceptive pill
    Open this publication in new window or tab >>Focus group interviews of Swedish teenage girls about the emergency contraceptive pill
    1999 (English)In: Scandinavian Journal of Sexology, ISSN 1398-2966, Vol. 2, no 4, p. 175-184Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90593 (URN)
    Available from: 2003-05-27 Created: 2003-05-27 Last updated: 2011-02-22Bibliographically approved
    2. Reasons for pregnancy termination, contraceptive habits and contraceptive failure among Swedish women requesting an early pregnancy termination
    Open this publication in new window or tab >>Reasons for pregnancy termination, contraceptive habits and contraceptive failure among Swedish women requesting an early pregnancy termination
    2002 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 81, no 1, p. 64-71Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: More than 30 000 legal abortions are performed every year in Sweden despite sexual education in schools, widespread youth-clinics and family planning services that are free of charge. The aim of this study was to investigate reasons for induced abortion, contraceptive habits and reasons for contraceptive failure among women presenting for induced abortion.

    METHODS: A questionnaire was administered to 591 Swedish-speaking women consecutively attending three different health care providers concerning an induced abortion during spring 2000.

    RESULTS: The response rate was 88% (n = 518). As many as 43%, among daily smokers 53%, had experienced one or more previous legal abortions. The majority of the women (97%) had discussed the decision about abortion with someone. The most cited reasons contributing to their decision were financial concerns, worries about the relationship and bad timing of the pregnancy. Though 85% had used contraception during the previous year, 36% of the women had not used any contraceptive method at the time of conception. The main reason given for not using contraception was the belief that they could not at that time become pregnant (35%). Ninety percent of the women planned to use contraception after the abortion.

    CONCLUSION: Women's decisions regarding induced abortion are multifactorial. One important reason was "poor economy". One out of three did not use any contraception, as they believed they could not become pregnant. Women presenting for induced abortion are a risk-group for further terminations. Counseling must include information about the fertile window, effective contraceptives and the emergency contraceptive pill.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91677 (URN)10.1046/j.0001-6349.2001.00169.x (DOI)000174398000012 ()11942890 (PubMedID)
    Available from: 2004-05-03 Created: 2004-05-03 Last updated: 2017-12-14Bibliographically approved
    3. Knowledge, use and attitueds towards emergency contraceptive pills among Swedish women presenting for induced abortion
    Open this publication in new window or tab >>Knowledge, use and attitueds towards emergency contraceptive pills among Swedish women presenting for induced abortion
    2002 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 109, no 2, p. 155-160Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To investigate the knowledge, experiences and attitudes towards emergency contraceptive pills (ECP) among women presenting for induced abortion. DESIGN: Survey by self-administered waiting room questionnaires. SETTING: Three large hospitals in the cities of Uppsala, Västerås and Orebro in Sweden. POPULATION: 591 Swedish-speaking women consecutively attending the clinics for an induced abortion during a four-month period in 2000. RESULTS: The response rate was 88% (n = 518). As many as 43% had a history of one or more previous abortions and 43% were daily smokers. Four out of five women, 83%, were aware of ECP, but only 15 women used it to prevent this pregnancy. Fewer, 38%, knew the recommended timeframes for use and 54% had knowledge of the mode of action. The two most common sources of information about ECP were media and friends. One out of five, 22%, had previously used the method, and at the time of conception, 55% would have taken ECP if it had been available at home, and 52% were positive to having ECP available over the counter. CONCLUSIONS: Emergency contraception is well known but is still underused. Lack of awareness of pregnancy risk may be one limiting factor for its use. Making ECP available over the counter may be an important measure towards better availability. Information strategies to the public are needed before ECP will be a widely used back-up method.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90595 (URN)10.1111/j.1471-0528.2002.01239.x (DOI)11888097 (PubMedID)
    Available from: 2003-05-27 Created: 2003-05-27 Last updated: 2017-12-14Bibliographically approved
    4. Women's voices about emergency contraceptive pills "over-the-counter": a Swedish perspective
    Open this publication in new window or tab >>Women's voices about emergency contraceptive pills "over-the-counter": a Swedish perspective
    2002 (English)In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 66, no 5, p. 339-343Article in journal (Refereed) Published
    Abstract [en]

    This study aimed to describe women’s experiences with the emergency contraceptive pill (ECP) as a prescription-free over-the-counter (OTC) product. Women (median age 24) who had bought ECP as an OTC product were interviewed in focus groups. Data were analyzed by content analysis. All participants appreciated the OTC availability. Timesaving aspects were seen as important benefits and pharmacies were seen as the right place to sell ECP. The media was the main source of information about OTC, probably due to the debates of the introduction of ECP as an OTC product in Sweden. All women discussed the mechanism of action. The women’s experiences of interacting with the pharmacists were both positive and negative. Inconsistencies in routines with regard to providing ECP and different attitudes toward use of ECP among the pharmacists, were identified. The women expected up-to-date information about ECP and the OTC availability from gynecologists and other health professionals.

    Keywords
    Attitudes, Emergency contraception, Focus group, Non-prescription, Sexual behavior
    National Category
    Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:uu:diva-90596 (URN)10.1016/S0010-7824(02)00367-0 (DOI)000179452600007 ()12443964 (PubMedID)
    Available from: 2003-05-27 Created: 2003-05-27 Last updated: 2017-12-14Bibliographically approved
    5. Emergency contraceptive pills over-the-counter: practices and attitudes of pharmacy and nurse-midwife providers
    Open this publication in new window or tab >>Emergency contraceptive pills over-the-counter: practices and attitudes of pharmacy and nurse-midwife providers
    Show others...
    2004 (English)In: Patient Education and Counseling, ISSN 0738-3991, E-ISSN 1873-5134, Vol. 55, no 1, p. 129-135Article in journal (Refereed) Published
    Abstract [en]

    Deregulation of emergency contraceptive pills (ECP) has led to pharmacy staff becoming a new provider group of ECP, together with nurse-midwives, who are already experienced in prescribing contraceptives. This postal questionnaire survey aimed to assess practices and attitudes towards ECP and the over-the-counter (OTC)-availability among pharmacy staff (n=237) and nurse-midwives (n=163). The overall response rate was 89%. Both study groups were positive to ECP and the OTC-availability and the vast majority agreed that sexually active women should be aware of ECP and that routine information about ECP should be included in contraceptive counseling. Verbal information on all aspects of ECP to clients was reported more often by nurse-midwives than by pharmacy staff. Both groups supported collaboration between providers. Our findings suggest that further collaboration between pharmacies and family planning clinics should be encouraged to ensure a competent and client-friendly provision of ECP.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90597 (URN)10.1016/j.pec.2003.08.008 (DOI)15477000 (PubMedID)
    Available from: 2003-05-27 Created: 2003-05-27 Last updated: 2017-12-14Bibliographically approved
  • 4.
    Arrelöv, Britt
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Towards Understanding of Determinants of Physicians’ Sick-listing Practice and their Interrelations: A Population-based Epidemiological Study2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Physicians are supposed to act as sick-listing experts and they possess a role as gate-keepers to the social insurance system. Earlier studies have demonstrated variation between physicians and physician categories regarding sick-listing practice. In addition to the patient's disease and its severity, a number of other factors may be expected to influence sick-listing practice. Most earlier studies have focused on the patient's disease and his or her work place as cause for sickness absence.

    The aims of this study were to analyse variation of sick-listing practice between physician categories and the influence of physician characteristics on sick-listing practice, the influence of structure, organisation and remuneration of health care on physician sick-listing practice, the influence of local structural factors in the community, and the influence of a legislative change on physician sick-listing practice.

    The study was conducted as a cross-sectional epidemiological study of 57563 doctors’ certificates for sickness absence, received by 28 local social insurance offices in eight Swedish counties, during four months in 1995 and two months in 1996.

    Patient age, sex, and diagnostic group, issuing physician category, presence of a hospital in the municipality, municipality population size and county were all significantly and independently correlated to number of net days of sick-listing. Physician characteristics, such as age, sex and degree of specialisation were all associated with number of net days of sick-listing. Physicians working in general practice issued significantly shorter periods of sick-listing than the other physician categories. Reimbursement of general practice and participation in financial co-operation with social insurance were significantly correlated to length of sickness episode issued by general practitioners. A legislative change performed during the study period was associated with small effects in sick-listing practice.

    In conclusion, a number of factors other than disease and disease severity and other patient and physician linked factors were found to influence the variation of sick-listing practice. It appears that the closer the influencing factor was to the place were the decision was taken, i.e., the patient-physician consultation, the higher the impact on the decision appeared to be.

    List of papers
    1. Do GPs sick-list patients to a lesser extent than other physician categories?: A population-based study
    Open this publication in new window or tab >>Do GPs sick-list patients to a lesser extent than other physician categories?: A population-based study
    2001 In: Family Practice, Vol. 18, no 4, p. 393-398Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90765 (URN)
    Available from: 2003-09-03 Created: 2003-09-03Bibliographically approved
    2. The influence of change of legislation concerning sickness absence on physicians' performance as certifiers.: A population-based study
    Open this publication in new window or tab >>The influence of change of legislation concerning sickness absence on physicians' performance as certifiers.: A population-based study
    2003 In: Helath Policy, Vol. 63, p. 259-268Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90766 (URN)
    Available from: 2003-09-03 Created: 2003-09-03Bibliographically approved
    3. Influence of local structural factors on physicians' sick-listing practice: a population-based study
    Open this publication in new window or tab >>Influence of local structural factors on physicians' sick-listing practice: a population-based study
    2005 (English)In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 15, no 5, p. 470-4Article in journal (Refereed) Published
    Abstract [en]

    Background: Physicians have a central role as gatekeepers to the social security system, includingsick-listing. Variation in physicians’ sick-listing practices has been demonstrated in several studies. Theobjective of this study was to determine whether local structural factors affect sick-listing practice.Methods: A total of 57 563 consecutive sick-listing certificates, issued during 4 months in 1995 and2 months in 1996, were collected from the local branches of the National Social Insurance Office ineight Swedish counties. County code, local community population size and presence of a hospital in thearea were used as indicators of local structural factors. Length of the sick-listing certificates and of thesick-listing episodes were used as outcome variables. Results: After ajustment for the influence of categoryof issuing physician, patients’ age, sex and diagnosis (‘case mix’), and type of certificate there was alarge variation of the length of the sick-listing certificates and of the sick-listing episodes betweencounties, between communities of various size and between communities with or without a hospitalin the area. All these factors were independently and significantly correlated to the length of thecertificate and of the sick-listing episode. Conclusions: The results support the hypothesis that physicians’sick-listing practice is influenced by local structural factors.

    Keywords
    epidemiology, sick-leave, sick-listing, sickness certification practice, structural factors, Sweden
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90767 (URN)10.1093/eurpub/cki029 (DOI)16126748 (PubMedID)
    Available from: 2003-09-03 Created: 2003-09-03 Last updated: 2017-12-14Bibliographically approved
    4. Influence of financial incentives on general practitioners' sick-listing practice.: A population-based study
    Open this publication in new window or tab >>Influence of financial incentives on general practitioners' sick-listing practice.: A population-based study
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90768 (URN)
    Available from: 2003-09-03 Created: 2003-09-03Bibliographically approved
  • 5. Aushev, M.
    et al.
    Mussolino, C.
    Cathomen, T.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Reichelt, J.
    Molecular surgery for epidermolysis bullosa simplex2014In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 170, no 4, p. E35-E35Article in journal (Other academic)
  • 6.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Associations Between Rheumatoid Arthritis and Malignant Lymphomas2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with rheumatoid arthritis (RA) are at increased risk of developing malignant lymphoma, although details about this association remain unclear. The aims of this thesis were to investigate risk factors for lymphoma in patients with RA and to characterize these lymphomas regarding subtype, presence of Epstein-Barr virus (EBV), clinical manifestations and prognosis.

    The Swedish hospital discharge register and the cancer register were used to identify RA patients with lymphoma. Two case-control studies were performed, one smaller including RA patients with lymphoma hospitalised in Uppsala health care region 1964-1983 (n=41) and one larger study of hospitalised RA patients with lymphoma in Sweden 1964-1995 (n=378). RA patients from the same cohorts, but without lymphoma, were matched as controls. Medical records for cases and controls were scrutinized for exposure information. The lymphoma tissues were reclassified according to the WHO classification, and presence of EBV was analysed by EBER in situ hybridisation.

    The most important risk factor for lymphoma development was high RA disease activity. No association was determined between treatment with traditional disease modifying drugs, non-steroidal anti-inflammatory drugs, aspirin, peroral and intra-articular corticosteroids and lymphoma risk. Diffuse large B-cell lymphoma (DLBCL) was more frequent in RA patients than in lymphoma patients in the general population and displayed stronger association with RA disease activity than other lymphoma subtypes. RA patients with DLBCL had increased extranodal involvement and more advanced lymphoma stage at presentation than DLBCL patients in general, and the prognosis was poor.

    A further subdivision of DLBCL into germinal centre (GC) and non-GC subtypes by the expression patterns of CD10, bcl-6 and IRF-4 showed a predominance of the non-GC subtype. This suggested peripheral activated B-cells as the cells of origin in these lymphomas.

    The presence of EBV was low in lymphomas in RA patients (12%).

    List of papers
    1. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study
    Open this publication in new window or tab >>Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study
    Show others...
    1998 (English)In: British Medical Journal, Vol. 317, p. 180-181Article in journal (Refereed) Published
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-93460 (URN)
    Available from: 2005-09-16 Created: 2005-09-16 Last updated: 2018-01-13
    2. Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma
    Open this publication in new window or tab >>Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma
    Show others...
    2003 (English)In: Arthritis & Rheumatism, Vol. 48, no 6, p. 1543-1550Article in journal (Refereed) Published
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-93461 (URN)
    Available from: 2005-09-16 Created: 2005-09-16 Last updated: 2018-01-13
    3. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis
    Open this publication in new window or tab >>Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis
    Show others...
    2006 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 3, p. 692-701Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.

    METHODS:

    We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.

    RESULTS:

    The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.

    CONCLUSION:

    Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.

    Keywords
    Adolescent, Adult, Aged, Aged; 80 and over, Antirheumatic Agents, Arthritis; Rheumatoid/*complications/drug therapy, Case-Control Studies, Chronic Disease, Female, Herpesvirus 4; Human/isolation & purification, Humans, Inflammation/*complications, Lymphoma/*etiology/virology, Male, Middle Aged, Research Support; Non-U.S. Gov't, Risk Factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102195 (URN)10.1002/art.21675 (DOI)16508929 (PubMedID)
    Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2017-12-13
    4. Diffuse large B-cell lymphomas in rheumatoid arthritis display a predominance of non-germinal center type
    Open this publication in new window or tab >>Diffuse large B-cell lymphomas in rheumatoid arthritis display a predominance of non-germinal center type
    Show others...
    (English)Manuscript (Other academic)
    Abstract
    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-93463 (URN)
    Available from: 2005-09-16 Created: 2005-09-16 Last updated: 2018-01-13
  • 7. Berntsson, Matilda
    et al.
    Broberg, Ann
    Lönngren, Vincent
    Lunds universitet.
    Svensson, Åke
    Två fall av pellagra: 4D-sjukdomen - bortglömd men dödlig sjukdom2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 5, p. 228-229Article in journal (Refereed)
    Abstract [en]

    Epidemics of pellagra, the dreaded “4D disease”, still occur in wars and disasters. It also remains endemic in parts of the world, even though prevention with nicotinic acid is known to be remarkably efficient. Elsewhere, there are sporadic cases. Timely diagnosis and treatment are essential to avoid permanent functional impairment and even death. Two cases are presented here.A 31-year-old autistic woman with a history of eating disorder suffered from gastrointestinal and neurological symtoms. Upon examination erythematous, weeping, thickened and desquamating skin lesions were found on sun-exposed areas. The patient’s diet consisted mostly of Greek salad. A 44-year-old woman suffered from disabling weakness of the lower limbs after a period of weight loss and high alcohol consumption. Cobalamine and folic acid supplementation was ineffective. Dermatological examination revealed pellagrous skin lesions on the back of her hands. Both patients responded rapidly to nicotinic acid replacement therapy.

  • 8.
    Björkegren, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Studies on Vitamin B12 and Folate Deficiency Markers in the Elderly: A Population-based Study2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aims of this study were to document the levels of cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) in serum and their relations to symptoms, clinical findings, and other factors in order to improve the possibilities of detecting early deficiency of vitamin B12 or folate, and to study the effects of cobalamin and folic acid treatment over a three-year period.

    The study population consisted of a 20% random sample of persons 70 years or older living in Älvkarleby in mid-Sweden. They were invited to a survey and 224 (88.4%) persons responded. Data were obtained by questionnaire, laboratory investigations and physical examination for the period 1993 – 1999.

    In a multivariate analysis performed at baseline, serum MMA and tHcy were significantly and independently correlated to age, serum cobalamin, and creatinine levels, and tHcy also to sex and serum folate. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin or mean red cell volume. Almost half of the study population had signs of low tissue levels of vitamin B12 or folate. Among those who took multivitamin preparations, the proportion was much lower, 25%.

    Among traditional symptoms and clinical findings that have been linked to vitamin B12 or folate tissue deficiency, only changes in the tongue mucosa and mouth angle stomatitis were significantly associated with abnormal serum folate and tHcy levels. Traditional symptoms of vitamin deficiency may appear later in the course.

    69 persons who had laboratory indications of early or overt tissue deficiency of vitamin B12 or folate and who had no ongoing vitamin treatment were given cobalamin for six months. Those whose MMA or tHcy levels did not normalise were given folic acid in addition to cobalamin. After further treatment for three months, all persons but one had normal levels. The laboratory effect still remained after three years of treatment. There was a tendency towards improvement of vibration sense, especially in the long nerve paths, and improvement of neurological symptoms and oral mucosa findings.

    Conclusion: A substantial proportion of elderly persons have laboratory signs of incipient tissue deficiency of vitamin B12 and folate. Treatment normalises lab parameters and some symptoms.

    List of papers
    1. Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes - a population-based study
    Open this publication in new window or tab >>Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes - a population-based study
    2001 In: J Int Med, Vol. 249, p. 423-432Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90216 (URN)
    Available from: 2003-04-11 Created: 2003-04-11Bibliographically approved
    2. Reported symptoms and clinical findings in relation to serum cobalamin, folate, methylmalonic acid and total homocysteine among elderly Swedes: A population-based study
    Open this publication in new window or tab >>Reported symptoms and clinical findings in relation to serum cobalamin, folate, methylmalonic acid and total homocysteine among elderly Swedes: A population-based study
    In: J Int MedArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90217 (URN)
    Available from: 2003-04-11 Created: 2003-04-11Bibliographically approved
    3. Elevated serum levels of methylmalonic acid and homocysteine in elderly people: A population-based intervention study
    Open this publication in new window or tab >>Elevated serum levels of methylmalonic acid and homocysteine in elderly people: A population-based intervention study
    1999 In: J Int Med, Vol. 246, p. 603-611Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90218 (URN)
    Available from: 2003-04-11 Created: 2003-04-11Bibliographically approved
    4. A population-based intervention study on elevated serum levels of methylmalonic acid and homocysteine in elderly people: Results after 36 months of follow-up
    Open this publication in new window or tab >>A population-based intervention study on elevated serum levels of methylmalonic acid and homocysteine in elderly people: Results after 36 months of follow-up
    In: J Int MedArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90219 (URN)
    Available from: 2003-04-11 Created: 2003-04-11Bibliographically approved
  • 9.
    Björklund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Early Risk Stratification, Treatment and Outcome in ST-elevation Myocardial Infarction2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    We evaluated, in patients with ST-elevation myocardial infarction (STEMI) treated with thrombolytics, admission Troponin T (tnT), ST-segment resolution and admission N-terminal pro-brain natriuretic peptide (NT-proBNP) for early risk stratification as well as time delays and outcome in real life patients according to prehospital or in-hospital thrombolytic treatment. Also, baseline characteristics, treatments and outcome in patients enrolled in the ASSENT-2 trial in Sweden and in patients not enrolled were evaluated.

    TnT (n=881) and NT-proBNP (n=782) on admission and ST-resolution at 60 minutes (n=516) in patients from the ASSENT-2 and ASSENT-PLUS trials were analysed. Elevated levels of NT-proBNP and tnT on admission were both independently related to one-year mortality. However, when adding information on ST-resolution (</≥50%) 60 minutes after initiation of thrombolytic treatment, tnT no longer contributed independently to mortality prediction. High and low risk patients were best identified by a combination of NT-proBNP and ST-resolution at 60 minutes.

    We investigated consecutive STEMI patients included in the RIKS-HIA registry between 2001 and 2004, if they were ambulance transported and had received prehospital (n=1690) or in-hospital (n=3685) thrombolytic treatment. Prehospital diagnosis and thrombolysis reduced the time to thrombolysis by almost one hour, were associated with better left ventricular function and fewer complications and reduced the adjusted one-year mortality by 30% compared with in-hospital thrombolysis.

    Prospective data from the RIKS-HIA registry on STEMI patients treated with thrombolytics were linked to data on trial participants in the ASSENT-2 trial of thrombolytic agents and used for direct comparisons. Patients treated with thrombolytics and not enrolled in a clinical trial at trial hospitals (n=2048) had higher risk characteristics, more early complications and twice as high adjusted one-year mortality compared to those enrolled (n=729). One major reason for the difference in outcome appeared to be the selection of less critically ill patients to the trial.

    List of papers
    1. Admission Troponin T and measurement of ST-segment resolution at 60 min improve early risk stratification in ST-elevation myocardial infarction
    Open this publication in new window or tab >>Admission Troponin T and measurement of ST-segment resolution at 60 min improve early risk stratification in ST-elevation myocardial infarction
    Show others...
    2004 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 25, no 2, p. 113-120Article in journal (Refereed) Published
    Abstract [en]

    AIMS: The prognostic value of admission troponin T (tnT) levels and the resolution of the ST-segment elevation in ST-elevation myocardial infarction (STEMI) is well established. However, the combination of these two early available markers for predicting risk has not been evaluated.

    METHODS AND RESULTS: We evaluated 516 patients with fibrinolytic treated STEMI from the ASSENT-2 and ASSENT-PLUS studies, which had both admission tnT and ST-monitoring available. We used a prospectively defined cut-off value of tnT of 0.1microg/l. For ST-segment resolution, a cut-off of 50% measured after 60min was used. Both a tnT >/=0.1microg/l (n=116) and ST-segment resolution <50% (n=301) were related to higher one-year mortality, 13% vs 4% (P<0.001) and 8.4% vs 2.8% (P=0.009), respectively. In a multivariate analysis ST-segment resolution was and tnT showed a strong trend to be independently related to mortality. The combination of both further improved risk stratification. The one-year mortality in the group with elevation of tnT and without ST-segment resolution compared to the group without tnT elevation and with ST-segment resolution was 18.2% vs 2.8% (P<0.001).

    CONCLUSIONS: Both tnT on admission and ST-segment resolution after 60min are strong predictors of one-year mortality. The combination of both gives additive early information about prognosis and further improves risk stratification.

    Keywords
    Acute myocardial infarction, Troponin T, Electrocardiography, Prognosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-93678 (URN)10.1016/j.ehj.2003.10.025 (DOI)14720527 (PubMedID)
    Available from: 2005-11-03 Created: 2005-11-03 Last updated: 2017-12-14Bibliographically approved
    2. Admission N-terminal pro-brain natriuretic peptide and its interaction with admission troponin T and ST segment resolution for early risk stratification in ST elevation myocardial infarction
    Open this publication in new window or tab >>Admission N-terminal pro-brain natriuretic peptide and its interaction with admission troponin T and ST segment resolution for early risk stratification in ST elevation myocardial infarction
    Show others...
    2006 (English)In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 92, no 6, p. 735-740Article in journal (Refereed) Published
    Abstract [en]

    Objective: To assess the long term prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) on admission and its prognostic interaction with both admission troponin T (TnT) concentrations and resolution of ST segment elevation in fibrinolytic treated ST elevation myocardial infarction (STEMI).

    Design and setting: Substudy of the ASSENT (assessment of the safety and efficacy of a new thrombolytic) -2 and ASSENT-PLUS trials.

    Patients: NT-proBNP and TnT concentrations were determined on admission in 782 patients. According to NT-proBNP concentrations, patients were divided into three groups: normal concentration (for patients ≤ 65 years, ≤ 184 ng/l and ≤ 268 ng/l and for those > 65 years, ≤ 269 ng/l and ≤ 391 ng/l in men and women, respectively); higher than normal but less than the median concentration (742 ng/l); and above the median concentration. For TnT, a cut off of 0.1 μg/l was used. Of the 782 patients, 456 had ST segment resolution (< 50% or ≥ 50%) at 60 minutes calculated from ST monitoring.

    Main outcome measures: All cause one year mortality.

    Results: One year mortality increased stepwise according to increasing concentrations of NT-proBNP (3.4%, 6.5%, and 23.5%, respectively, p < 0.001). In receiver operating characteristic analysis, NT-proBNP strongly trended to be associated more with mortality than TnT and time to 50% ST resolution (area under the curve 0.81, 95% confidence interval (CI) 0.72 to 0.9, 0.67, 95% CI 0.56 to 0.79, and 0.66, 95% CI 0.56 to 0.77, respectively). In a multivariable analysis adjusted for baseline risk factors and TnT, both raised NT-proBNP and ST resolution < 50% were independently associated with higher one year mortality, whereas raised TnT contributed independently only before information on ST resolution was added to the model.

    Conclusion: Admission NT-proBNP is a strong independent predictor of mortality and gives, together with 50% ST resolution at 60 minutes, important prognostic information even after adjustment for TnT and baseline characteristics in STEMI.

    Place, publisher, year, edition, pages
    BMJ Publishing Group, 2006
    Keywords
    Aged, Female, Humans, Male, Middle Aged, Myocardial Infarction/*blood/mortality, Natriuretic Peptide; Brain/*blood, Patient Admission, Peptide Fragments/*blood, Prognosis, Regression Analysis, Risk Assessment, Sensitivity and Specificity, Survival Analysis, Troponin T/*blood
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-23949 (URN)10.1136/hrt.2005.072975 (DOI)16251228 (PubMedID)
    Available from: 2007-02-15 Created: 2007-02-15 Last updated: 2017-12-07Bibliographically approved
    3. Prehospital diagnosis and start of treatment reduce time delay and mortality in real life patients with ST-elevation myocardial infarction
    Open this publication in new window or tab >>Prehospital diagnosis and start of treatment reduce time delay and mortality in real life patients with ST-elevation myocardial infarction
    Show others...
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-93680 (URN)
    Available from: 2005-11-03 Created: 2005-11-03Bibliographically approved
    4. Outcome of ST-elevation myocardial infarction treated with thrombolysis in the unselected population is vastly different from samples of eligible patients in a large-scale clinical trial
    Open this publication in new window or tab >>Outcome of ST-elevation myocardial infarction treated with thrombolysis in the unselected population is vastly different from samples of eligible patients in a large-scale clinical trial
    Show others...
    2004 In: American Heart Journal, ISSN 0002-8703, Vol. 148, no 4, p. 566-573Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93681 (URN)
    Available from: 2005-11-03 Created: 2005-11-03Bibliographically approved
  • 10.
    Blomberg, Stina
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Autoantibodies and the Type I Interferon System in the Etiopathogenesis of Systemic Lupus Erythematosus2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In sera remitted for anti-nuclear antibody (ANA) analysis, the supplement of a sensitive anti-SSA/Ro ELISA to the conventional ANA screening by immunofluorescence (IF) revealed that one fourth of the individuals with IF-ANA negative, but SSA/Ro ELISA positive sera, had systemic lupus erythematosus (SLE) or cutaneous LE. Consequently, adding a sensitive anti-SSA/Ro ELISA to the ANA screening is valuable for the serological detection of ANA negative SLE/LE patients.

    SLE patients often have measurable interferon-alpha (IFN-α) levels in serum, and IFN-α treatment of patients with non-autoimmune diseases can induce SLE. Thus, the type I IFN system seems to be important in SLE and was therefore investigated. Initially, a decreased IFN-α producing capacity, due to a 70-fold reduction in the number of circulating natural IFN-α producing cells (NIPC), was noted in peripheral blood mononuclear cells (PBMC) from SLE patients. SLE-sera contained an endogenous IFN-α inducing factor (SLE-IIF), consisting of IgG and DNA in the form of small immune complexes (300-1000 kD). The SLE-IIF selectively activated NIPC and was more common in sera from patients with active disease compared to individuals with inactive disease. IFN-α producing cells could be detected by immunohistochemistry in both lesional and unaffected skin from SLE patients, and IFN-α gene transcription could be verified by in situ hybridisation in some of the skin biopsies. A reduced number of NIPC, detected by expression of the blood dendritic cell antigen (BDCA)-2, was noted among SLE-PBMC. The IFN-α production triggered by SLE-IIF in SLE-PBMC was inhibited by monoclonal antibodies (mAbs) to BDCA-2 and markedly decreased by anti-BDCA-4 mAbs.

    The observations in the present thesis may explain the ongoing IFN-α production in SLE patients, indicate an important role for the activated type I IFN system in the pathogenesis, and suggest that direct targeting of SLE-NIPC may constitute a new therapeutic principle in SLE.

  • 11. Broesby-Olsen, Sigurd
    et al.
    Dybedal, Ingunn
    Gülen, Theo
    Kielsgaard Kristensen, Thomas
    Boe Møller, Michael
    Ackermann, Leena
    Sääf, Maria
    Karlsson, Maria A
    Agertoft, Lone
    Brixen, Kim
    Hermann, Pernille
    Stylianou, Eva
    Mortz, Charlotte G
    Torfing, Trine
    Havelund, Troels
    Sander, Birgitta
    Bergström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Bendix, Marie
    Garvey, Lene H
    Weis Bjerrum, Ole
    Valent, Peter
    Bindslev-Jensen, Carsten
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Vestergaard, Hanne
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Multidisciplinary Management of Mastocytosis: Nordic Expert Group Consensus2016In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 96, no 5Article in journal (Refereed)
    Abstract [en]

    Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.

  • 12.
    Buraczewska, Izabela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skin barrier responses to moisturizers2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Moisturizers are used in various types of dry skin disorders, but also by people with healthy skin. It is not unusual that use of moisturizers is continued for weeks, months, or even years. A number of moisturizers have been shown to improve the skin barrier function, while others to deteriorate it, but the reason for observed effects remains unknown. Further understanding of the mechanism by which long-term treatment with moisturizers influences the skin barrier would have clinical implications, as barrier-deteriorating creams may enhance penetration of allergens or irritants and predispose to dry skin and eczema, while barrier-improving ones could reduce many problems.

    The present research combined non-invasive techniques with analyses of skin biopsies, allowing studies of the epidermis at molecular and cellular level. Test moisturizers were examined on healthy human volunteers for their effect on the skin barrier, with regard to such factors as pH, lipid type, and presence of a humectant, as well as complexity of the product. After a 7-week treatment with the moisturizers, changes in transepidermal water loss, skin capacitance, and susceptibility to an irritant indicated a modified skin barrier function. Moreover, the mRNA expression of several genes involved in the assembly, differentiation and desquamation of the stratum corneum, as well as lipid metabolism, was altered in the skin treated with one of the moisturizers, while the other moisturizer induced fewer changes.

    In conclusion, long-term use of moisturizers may strengthen the barrier function of the skin, but also deteriorate it and induce skin dryness. Moisturizers have also a significant impact on the skin biochemistry, detectable at molecular level. Since the type of influence is determined by the composition of a moisturizer, more careful selection of ingredients could help to design moisturizers generating a desired clinical effect, and to avoid ingredients with a negative impact on the skin.

    List of papers
    1. Treatment of surfactant-damaged skin in humans with creams of different pH values
    Open this publication in new window or tab >>Treatment of surfactant-damaged skin in humans with creams of different pH values
    2005 In: Pharmacology, ISSN 0031-7012, Vol. 73, no 1, p. 1-7Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97589 (URN)
    Available from: 2008-10-01 Created: 2008-10-01Bibliographically approved
    2.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    3.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    4. Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids
    Open this publication in new window or tab >>Moisturizers change the mRNA expression of enzymes synthesizing skin barrier lipids
    Show others...
    2009 (English)In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 301, no 8, p. 587-594Article in journal (Refereed) Published
    Abstract [en]

    In a previous study, 7-week treatment of normal human skin with two test moisturizers, Complex cream and Hydrocarbon cream, was shown to affect mRNA expression of certain genes involved in keratinocyte differentiation. Moreover, the treatment altered transepidermal water loss (TEWL) in opposite directions. In the present study, the mRNA expression of genes important for formation of barrier lipids, i.e., cholesterol, free fatty acids and ceramides, was examined. Treatment with Hydrocarbon cream, which increased TEWL, also elevated the gene expression of GBA, SPTLC2, SMPD1, ALOX12B, ALOXE3, and HMGCS1. In addition, the expression of PPARG was decreased. On the other hand, Complex cream, which decreased TEWL, induced only the expression of PPARG, although not confirmed at the protein level. Furthermore, in the untreated skin, a correlation between the mRNA expression of PPARG and ACACB, and TEWL was found, suggesting that these genes are important for the skin barrier homeostasis. The observed changes further demonstrate that long-term treatment with certain moisturizers may induce dysfunctional skin barrier, and as a consequence several signaling pathways are altered.

    Keywords
    Long-term treatment, Moisturizers, Skin barrier function, Gene expression, Arachidonate lipoxygenases, PPAR
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-97592 (URN)10.1007/s00403-009-0958-2 (DOI)000269055000005 ()
    Available from: 2008-10-01 Created: 2008-10-01 Last updated: 2017-12-14Bibliographically approved
  • 13.
    Buraczewska, Izabela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Lindberg, Magnus
    Lodén, Marie
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Long-term treatment with moisturizers affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation2009In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 301, no 2, p. 175-181Article in journal (Refereed)
    Abstract [en]

    In a recent study, we showed that long-term treatment with two different moisturizers affected TEWL in opposite directions. Therefore, we decided to examine the effect of these moisturizers on the cellular and molecular level. In a randomized controlled study on 20 volunteers, epidermal mRNA expression of genes essential for keratinocyte differentiation and desquamation after a 7-week treatment with two moisturizers was analyzed. Treatment with one test moisturizer increased gene expression of involucrin, transglutaminase 1, kallikrein 5, and kallikrein 7, while the other moisturizer affected only expression of cyclin-dependent kinase inhibitor 1A. Thus, moisturizers are able to modify the skin barrier function and change the mRNA expression of certain epidermal genes. Since the type of influence depends on the composition of the moisturizer, these should be tailored in accordance with the requirement of the barrier of each individual patient, which merits further investigations.

  • 14.
    Bäckman, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Treatment of Experimental Neuroblastoma with Angiogenic Inhibitors2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neuroblastoma is a childhood cancer that originates from neuroblasts in the peripheral nervous system. Neuroblastoma show considerable heterogeneity with respect to location, responsiveness to treatment and prognosis. Since current therapy involves drugs with risk of serious side effects in the growing child, there is a clinical need for more effective and less toxic treatment strategies.

    Angiogenesis, the formation of new blood vessels, is critical for tumor progression. Specific inhibition of tumor-induced angiogenesis should restrict growth of most solid tumors and thereby provide a new treatment strategy. The aim of this study was to investigate the effects of angiogenic inhibition in experimental neuroblastoma in mice.

    We found that experimental neuroblastomas expressed the perhaps most potent angiogenic growth factor, VEGF-A, and that plasma VEGF-A levels correlated with tumor size. SU5416, a novel antagonist of VEGFR-1 and 2, reduced angiogenesis and tumor growth in our model. We also investigated the properties of SU11657, a new, orally available, synthetic small molecule multi-targeted tyrosine kinase inhibitor. SU11657, at a well-tolerated dose, was more potent than SU5416 in reducing tumor growth rate and angiogenesis, even in MYCN-amplified tumors. Chemotherapeutics can also inhibit angiogenesis, when administrated daily in a non-toxic dose. CHS 828, a new chemotherapeutic, given orally, alone induced complete neuroblastoma regression in 44 % of the animals. Furthermore, the bisphosphonate zoledronic acid, developed to reduce bone resorption, showed anti-tumor activity in our model. Zoledronic acid was more potent than the angiogenic inhibitor TNP-470. Thus bisphosphonates may have other beneficial properties in patients with cancer apart from preventing bone resorption.

    In conclusion, SU5416, SU11657, CHS 828, and zoledronic acid represent new drugs with potent anti-tumor effects. Angiogenic inhibition as single therapy or in combination with chemotherapeutics may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood such as neuroblastoma.

    List of papers
    1. Importance of Vascular Endothelial Growth Factor A in the Progression of Experimental Neuroblastoma
    Open this publication in new window or tab >>Importance of Vascular Endothelial Growth Factor A in the Progression of Experimental Neuroblastoma
    2002 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 5, no 4, p. 267-274Article in journal (Refereed) Published
    Abstract [en]

    Vascular endothelial growth factor A (VEGF-A) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis. SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase. We have developed a reproducible murine model for neuroblastoma, a childhood cancer, based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells. We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels, that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml, and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals. Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity. SU5416 treatment also suppressed tumor angiogenesis, despite an increase in plasma VEGF-A levels per ml tumor volume during therapy. Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma.

    Keywords
    Angiogenesis Inhibitors/pharmacology, Animals, Cell Division/drug effects, Endothelial Growth Factors/blood/*physiology, Female, Humans, Indoles/pharmacology, Male, Mice, Mice; Nude, Neoplasms; Experimental/drug therapy/etiology/metabolism, Neuroblastoma/drug therapy/*etiology/metabolism, Protein-Tyrosine Kinase/antagonists & inhibitors, Pyrroles/pharmacology, Research Support; Non-U.S. Gov't, Transplantation; Heterologous, Tumor Cells; Cultured, Vascular Endothelial Growth Factor A
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90512 (URN)10.1023/A:1024564817563 (DOI)12906318 (PubMedID)
    Available from: 2003-05-14 Created: 2003-05-14 Last updated: 2017-12-14Bibliographically approved
    2. The Selective Class III/V Receptor Tyrosine Kinase Inhibitor SU11657 Inhibits Tumor Growth and Angiogenesis in Experimental Neuroblastoma
    Open this publication in new window or tab >>The Selective Class III/V Receptor Tyrosine Kinase Inhibitor SU11657 Inhibits Tumor Growth and Angiogenesis in Experimental Neuroblastoma
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90708 (URN)
    Available from: 2003-09-05 Created: 2003-09-05Bibliographically approved
    3. CHS 828 Inhibits Neuroblastoma Growth in Mice Alone and in Combination with Antiangiogenic Drugs
    Open this publication in new window or tab >>CHS 828 Inhibits Neuroblastoma Growth in Mice Alone and in Combination with Antiangiogenic Drugs
    Show others...
    2002 In: Pediatric Research, Vol. 51, no 5, p. 607-611Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90709 (URN)
    Available from: 2003-09-05 Created: 2003-09-05Bibliographically approved
    4. The Bisphosphonate Zoledronic Acid Reduces Experimental Neuroblastoma Growth by Interference with Tumor Angiogenesis
    Open this publication in new window or tab >>The Bisphosphonate Zoledronic Acid Reduces Experimental Neuroblastoma Growth by Interference with Tumor Angiogenesis
    2008 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, no 3A, p. 1551-1557Article in journal (Refereed) Published
    Abstract [en]

    Background: Zoledronic acid is a new member of the bisphosphonate (BP) class of compounds, a family of closely related synthetic molecules originally derived from the naturally occurring pyrophosphate. These compounds that are potent inhibitors of bone resorption, have been shown to reduce the growth of several cancer cell lines in vitro, and can act as inhibitors of angiogenesis. The angiogenesis inhibitor TNP-470, a synthetic analogue of the fungal antibiotic fumagillin, has been shown to inhibit the growth of multiple tumors in vivo, and is currently in Phase H clinical trials for cancer. Materials and Methods: The effects of daily subcutaneous (s.c.) administration of zoledronic acid (0.1 mg/kg) were compared with those of TNP-470 (15 mg/kg/day and 30 mg/kg every other day, s.c.) in a nude mouse xenograft model for the childhood cancer, neuroblastoma (NB). Results: Zoledronic acid reduced the tumor growth by 33% whereas TNP-470 was less effective and reduced the tumor growth by 26% and 11% for animals treated with 15 mg/kg/day and 30 mg/kg every other day, respectively. Analysis of angiogenesis showed a significant reduction of the number of vessels per grid and in vessel length in all the treatment groups. Conclusion: Zoledronic acid shows tumoristatic and angiostatic properties that might be beneficial in the treatment of solid tumors such as neuroblastoma.

    Keywords
    angiogenesis, zoledronic acid, TNP-470, neuroblastoma, SH-SY5Y
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90710 (URN)000256940300014 ()18630510 (PubMedID)
    Available from: 2003-09-05 Created: 2003-09-05 Last updated: 2017-12-14Bibliographically approved
  • 15.
    Båve, Ullvi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Mechanisms of Interferon-α Induction in Systemic Lupus Erythematosus2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity.

    In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA.

    Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa.

    To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes.

    The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.

    List of papers
    1. The Combination of Apoptotic U937 Cells and Lupus IgG Is a Potent IFN-α Inducer
    Open this publication in new window or tab >>The Combination of Apoptotic U937 Cells and Lupus IgG Is a Potent IFN-α Inducer
    2000 In: The Journal of Immunology, Vol. 165, p. 3519-3526Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90440 (URN)
    Available from: 2003-05-08 Created: 2003-05-08Bibliographically approved
    2. Activation of Natural Interferon-α Producing Cells by Apoptotic U937 Cells Combined with Lupus IgG and its Regulation by Cytokines
    Open this publication in new window or tab >>Activation of Natural Interferon-α Producing Cells by Apoptotic U937 Cells Combined with Lupus IgG and its Regulation by Cytokines
    2001 In: Journal of Autoimmunity, Vol. 17, p. 71-80Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90441 (URN)
    Available from: 2003-05-08 Created: 2003-05-08Bibliographically approved
    3. FcγRIIa is Expressed on Natural IFN-α Producing Cells (Plasmacytoid Dendritic Cells) and is Required for the IFN-α Production Induced by Apoptotic Cells Combined with Lupus IgG
    Open this publication in new window or tab >>FcγRIIa is Expressed on Natural IFN-α Producing Cells (Plasmacytoid Dendritic Cells) and is Required for the IFN-α Production Induced by Apoptotic Cells Combined with Lupus IgG
    Show others...
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90442 (URN)
    Available from: 2003-05-08 Created: 2003-05-08Bibliographically approved
    4. Anti-SSA, -SSB and -RNP autoantibodies in Sjögren´s Syndrome and Systemic Lupus Erythematosus in Combination with Apoptotic or Necrotic Cell Material are Potent IFN-α Inducers
    Open this publication in new window or tab >>Anti-SSA, -SSB and -RNP autoantibodies in Sjögren´s Syndrome and Systemic Lupus Erythematosus in Combination with Apoptotic or Necrotic Cell Material are Potent IFN-α Inducers
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90443 (URN)
    Available from: 2003-05-08 Created: 2003-05-08 Last updated: 2010-01-13Bibliographically approved
  • 16. Cedervall, Jessica
    et al.
    Jamil, Seema
    Prasmickaite, Lina
    Cheng, YenFu
    Eskandarpour, Malihe
    Hansson, Johan
    Maelandsmo, Gunhild M.
    Ringborg, Ulrik
    Gulyas, Miklos
    Department of pathology and cytology, central hospital, Gävle, Sweden.
    Zhen, He Suo
    Kanter, Lena
    Ahrlund-Richter, Lars
    Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 9, p. 3746-3754Article in journal (Refereed)
    Abstract [en]

    For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.

  • 17.
    Chamcheu, Jean Christopher
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Disease-causing Keratin Mutations and Cytoskeletal Dysfunction in Human Skin: In vitro Models and new Pharmacologic Strategies for Treating Epidermolytic Genodermatoses2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) and epidermolytic ichthyosis (EI) are rare skin fragility diseases characterized by intra-epidermal blistering due to autosomal dominant-negative mutations in basal (KRT5 or KRT14) and suprabasal (KRT1 or KRT10) keratin genes,  respectively. Despite vast knowledge in the disease pathogenesis, the pathomechanisms are not fully understood, and no effective remedies exist. The purpose of this work was to search for keratin gene mutations in EBS patients, to develop in vitro models for studying EBS and EI, and to investigate novel pharmacological approaches for both diseases.

    We identified both novel and recurrent KRT5 mutations in all studied EBS patients but one which did not show any pathogenic keratin mutations. Using cultured primary keratinocytes from EBS patients, we reproduced a correlation between clinical severity and cytoskeletal instability in vitro. Immortalized keratinocyte cell lines were established from three EBS and three EI patients with different phenotypes using HPV16-E6E7. Only cell lines derived from severely affected patients exhibited spontaneous keratin aggregates under normal culture conditions. However, heat stress significantly induced keratin aggregates in all patient cell lines. This effect was more dramatic in cells from patients with a severe phenotype. In organotypic cultures, the immortalized cells were able to differentiate and form a multilayered epidermis reminiscent of those observed in vivo. Addition of two molecular chaperones, trimethylamine N-oxide dihydrate (TMAO) and sodium 4-phenylbutyrate (4-PBA), reduced the keratin aggregates in both stressed and unstressed EBS and EI keratinocytes, respectively. The mechanism of action of TMAO and 4-PBA was shown to involve the endogenous chaperone system (Heat shock proteins e.g. Hsp70). Besides, MAPK signaling pathways also seemed to be incriminated in the pathogenesis of EBS. Furthermore, depending on which type of keratin is mutated, 4-PBA up-regulated Hsp70 and KRT4 (possibly compensating for mutated KRT1/5), and down-regulated KRT1 and KRT10, which could further assist in protecting EBS and EI cells against stress.

    In conclusion, novel and recurrent pathogenic keratin mutations have been identified in EBS. Immortalized EBS and EI cell lines that functionally reflect the disease phenotype were established. Two pharmacologic agents, TMAO and 4-PBA, were shown to be promising candidates as novel treatment of heritable keratinopathies in this in vitro model.

    List of papers
    1. Epidermolysis bullosa simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes
    Open this publication in new window or tab >>Epidermolysis bullosa simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective effects of trimethylamine N-oxide in cultured primary keratinocytes
    Show others...
    2010 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 162, no 5, p. 980-989Article in journal (Refereed) Published
    Abstract [en]

    Summary Background Epidermolysis bullosa simplex (EBS) is a mechanobullous skin fragility disease characterized by cytolysis of basal keratinocytes and intraepidermal blistering often caused by mutations in keratin genes (KRT5 or KRT14). No remedies exist for these disorders presenting a need for development of novel therapies. Objectives To identify new genotype-phenotype relationships in vivo and in cultured primary EBS keratinocytes in vitro, and to study the cytoskeletal stabilizing effects of trimethylamine N-oxide (TMAO) in heat-stressed EBS cells. Methods Genomic DNA and cDNA samples from three Swedish patients with EBS were analysed for keratin mutations. Primary EBS keratinocyte cultures were established, heat stressed with and without added TMAO, followed by evaluation of cellular fragility. Results In addition to the previously reported KRT5 mutation (V186L) in one patient, two patients were found to have a novel I183M and recurrent E475G replacements in KRT5. Cultured EBS keratinocytes did not exhibit keratin aggregates or cell loss, except in the patient with the p.I183M mutation who showed 3% aggregates and 2% cell loss. Upon transient heat stress the number of aggregate-containing cells increased to 21%, 27% and 13%, respectively, in the p.I183M, p.E475G and p.V186L mutant cells. Interestingly, pretreatment with TMAO prior to heat stress, dose dependently reduced the number of aggregate-containing cells and cell loss. Conclusion These results revealed a genotype-phenotype correlation in EBS keratinocytes upon heat stress and suggest protein stabilization as a new therapeutic strategy.

    Place, publisher, year, edition, pages
    Wiley InterScience, 2010
    Keywords
    chemical chaperones, heat stress, keratin filament aggregates, keratin mutation, keratinocytes, protein stability
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-114415 (URN)10.1111/j.1365-2133.2009.09615.x (DOI)000276853600006 ()20128788 (PubMedID)
    Available from: 2010-05-03 Created: 2010-02-15 Last updated: 2017-12-12Bibliographically approved
    2. Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition
    Open this publication in new window or tab >>Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines: trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition
    Show others...
    2009 (English)In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 53, no 3, p. 198-206Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Epidermolysis bullosa simplex (EBS) is an autosomal inherited mechano-bullous disease, characterized by intraepidermal blistering and skin fragility caused by mutations in the keratin (KRT) 5 or 14 genes. Despite a vast knowledge about the intermediate filament pathology in this disease, the progress in therapy has been slow. Animal models and well-characterized continuous cell culture models of EBS are needed prior to clinical testing.

    OBJECTIVES: Our aim was to generate immortalized cell lines as an in vitro model for the study of EBS and test a chemical chaperone, trimethylamine N-oxide (TMAO), as a putative novel therapy.

    METHODS: We generated four immortalized cell lines, two each from an EBS patient with a KRT5-mutation (V186L) and a healthy control, using human papillomavirus 16 (HPV16) E6E7 as transducer. Cell lines were established in serum-free and serum-containing medium and assessed for growth characteristics, keratin expression profiles, ability to differentiate in organotypic cultures, and response to heat stress with and without the presence of TMAO.

    RESULTS: All cell lines have been expanded >160 population doublings and their cellular characteristics are similar. However, the formation of cytoplasmic keratin filament aggregates in response to heat-shock treatment differed between EBS and normal cell lines. Notably, serum-free established EBS-cell line was most vulnerable to heat shock but both cell lines exhibited significant reduction in the number of keratin aggregates containing cells by TMAO.

    CONCLUSION: The immortalized cell lines represent a suitable model for studying novel therapies for EBS. TMAO is a promising new agent for future development as a novel EBS therapy.

    Place, publisher, year, edition, pages
    Elsevier, 2009
    Keywords
    Chemical chaperone, Cytoprotection, EBS-cell lines, Genetic skin disorder, Human papilloma virus 16 E6/E7, Heat stress, Keratin, Organotypic epidermis, TMAO
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-88245 (URN)10.1016/j.jdermsci.2008.11.003 (DOI)000263766300005 ()19157792 (PubMedID)
    Available from: 2010-05-03 Created: 2009-01-27 Last updated: 2017-12-14Bibliographically approved
    3. Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation::  Involvement of heat shock proteins and MAP kinases
    Open this publication in new window or tab >>Chemical chaperones protect epidermolysis bullosa simplex keratinocytes from heat stress-induced keratin aggregation::  Involvement of heat shock proteins and MAP kinases
    Show others...
    (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747Article in journal (Refereed) Submitted
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) is an inherited epithelial tissue fragility disorder due to mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In some protein folding disorders such as cystic fibrosis and Alzheimer’s disease, chaperones and the ubiquitin-proteasome system modify disease severity, suggesting a novel therapeutic approach even for EBS. In this study, the effects of two chemical chaperones (trimethylamine-N oxide (TMAO) and 4-phenylbutyrate (4-PBA)) on heat stress-induced keratin aggregation responses were examined in newly and previously established immortalized control and EBS patient-derived keratinocyte cell lines. Heat-induced keratin-positive aggregates were observed in all EBS cells, which were most prominent in severe keratin-defective cell lines and less so in normal cells. The proportion of cells containing aggregates were dramatically reduced by TMAO and 4-PBA pretreatment. Furthermore, heat stress greatly induced MAP kinase activation (p38 and JNK) and increased Hsp70/Hsc70 expression, and TMAO was able to transiently modulate these effects. The results suggest that TMAO rescue may involve components of the endogenous chaperone and MAPK machineries, which may represent novel targets for the development of more effective treatments for EBS and other keratin-related genetic disorders.

    Keywords
    EBS, keratinocytes, keratin, MAPK, immunostaining, Hsp, TMAO, 4-PBA
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-123064 (URN)
    Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2017-12-12Bibliographically approved
    4. Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype: A useful in vitro model for testing new treatments
    Open this publication in new window or tab >>Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype: A useful in vitro model for testing new treatments
    Show others...
    2011 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 164, no 2, p. 263-272Article in journal (Refereed) Published
    Abstract [en]

    Background: Epidermolytic ichthyosis (EI) is a skin fragility disorder caused by mutations in genes encoding suprabasal keratins 1 and 10. While the aetiology of EI is known, model systems are needed for pathophysiological studies and development of novel therapies. Objectives To generate immortalized keratinocyte lines from patients with EI for studies of EI cell pathology and the effects of chemical chaperones as putative therapies. Methods We derived keratinocytes from three patients with EI and one healthy control and established immortalized keratinocytes using human papillomavirus 16-E6/E7. Growth and differentiation characteristics, ability to regenerate organotypic epidermis, keratin expression, formation of cytoskeletal aggregates, and responses to heat shock and chemical chaperones were assessed. Results The cell lines EH11 (K1-p.Val176-Lys197del), EH21 (K10-p.156Arg>Gly), EH31 (K10-p.Leu161-Asp162del) and NKc21 (wild-type) currently exceed 160 population doublings and differentiate when exposed to calcium. At resting state, keratin aggregates were detected in 9% of calcium-differentiated EH31 cells, but not in any other cell line. Heat stress further increased this proportion to 30% and also induced aggregates in 3% of EH11 cultures. Treatment with trimethylamine N-oxide and 4-phenylbutyrate (4-PBA) reduced the fraction of aggregate-containing cells and affected the mRNA expression of keratins 1 and 10 while 4-PBA also modified heat shock protein 70 (HSP70) expression. Furthermore, in situ proximity ligation assay suggested a colocalization between HSP70 and keratins 1 and 10. Reconstituted epidermis from EI cells cornified but EH21 and EH31 cells produced suprabasal cytolysis, closely resembling the in vivo phenotype. Conclusions These immortalized cell lines represent a useful model for studying EI biology and novel therapies.

     

    Place, publisher, year, edition, pages
    British Association of Dermatologists, 2011
    National Category
    Medical and Health Sciences
    Research subject
    Dermatology and Venerology
    Identifiers
    urn:nbn:se:uu:diva-123067 (URN)10.1111/j.1365-2133.2010.10092.x (DOI)000286668300009 ()20977447 (PubMedID)
    Available from: 2010-04-23 Created: 2010-04-23 Last updated: 2017-12-12Bibliographically approved
  • 18.
    Chamcheu, Jean Christopher
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Navsaria, Harshad
    Pihl-Lundin, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Liovic, Mirjana
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Chemical Chaperones Protect Epidermolysis Bullosa Simplex Keratinocytes from Heat Stress-Induced Keratin Aggregation: Involvement of Heat Shock Proteins and MAP Kinases2011In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 131, no 8, p. 1684-1691Article in journal (Refereed)
    Abstract [en]

    Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused by mutations in keratin genes (KRT5 or KRT14), with no existing therapies. Aggregates of misfolded mutant keratins are seen in cultured keratinocytes from severe EBS patients. In other protein-folding disorders, involvement of molecular chaperones and the ubiquitin-proteasome system may modify disease severity. In this study, the effects of heat stress on keratin aggregation in immortalized cells from two patients with EBS (KRT5) and a healthy control were examined with and without addition of various test compounds. Heat-induced (43 °C, 30 minutes) aggregates were observed in all cell lines, the amount of which correlated with the donor phenotype. In EBS cells pre-exposed to proteasome inhibitor, MG132, and p38-mitogen-activated protein kinase (MAPK) inhibitor, SB203580, the proportion of aggregate-positive cells increased, suggesting a role of proteasomes and phosphorylation in removing mutated keratin. In contrast, aggregates were reduced by pretreatment with two chemical chaperones, trimethylamine N-oxide (TMAO) and 4-phenylbutyrate (4-PBA). TMAO also modulated stress-induced p38/c-jun N-terminal kinase (JNK) activation and expression of heat shock protein (HSPA1A), the latter of which colocalized with phosphorylated keratin 5 in EBS cells. Taken together, our findings suggest therapeutic targets for EBS and other keratinopathies.

  • 19.
    Chen, Hongjiang
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Studies on Cell Injury Induced by Hypoxia-Reoxygenation and Oxidized Low Density Lipoprotein: With Special Reference to the Protectiove Effect of Mixed Tocopherols, Omega-3 Fatty Acids and Transforming Growth Factor-beta12003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hypoxia-reoxygenation (H-R) injury is an important clinical phenomenon in patients with coronary artery disease (CAD). Endothelial injury is a critical step in the initiation and progression of atherosclerosis. Therefore, endothelial and cardiomyocyte protection has been considered an effective step in prevention and treatment of CAD.

    To investigate the cardioprotective effect of tocopherols, omega-3 fatty acid [eicosapentaenoic acid (EPA)] and transforming growth factor-β1 (TGF-β1) during H-R, calcium tolerant myocytes isolated from adult rats were cultured and subjected to hypoxia for 24 hrs followed by reoxygenation of 3 hrs. All strategies, including tocopherol preparations, EPA and TGF-β1, showed attenuation of H-R-induced myocyte injury indicated by reduction of lactate dehydrogenase (LDH) release. Both a-tocopherol and a mixed- tocopherols (α-, γ-, and δ-) decreased the effects of H-R on iNOS expression and SOD activity in cultured myocytes. The mixed-tocopherols was more potent than a-tocopherol alone. EPA inhibited H-R-induced lipid peroxidation, MMP-1 expression and p38MAPK phosphorylation. TGF-β1 blocked the increase in iNOS and PKB phosphorylation as well as the decrease in eNOS expression in cultured myocytes exposed to H-R.

    To further investigate the protective effect of omega-3 fatty acids [docosahexaenoic acid (DHA) and EPA] and TGF-β1, the cultured endothelial cells were exposed to oxidant injury mediated by oxidized low-density lipoprotein (ox-LDL). Ox-LDL markedly reduced TGF-β1 release, increased the expression of TGF-β1 receptors, upregulated the expression of adhesion molecules, P-selectin and ICAM-1, enhanced the adhesion of monocytes to endothelial cells, and decreased protein kinase B (PKB) activation. Both DHA and EPA blocked these effects of ox-LDL on endothelial cells. Exogenous recombinant TGF-β1 also ameliorated ox-LDL-induced expression of adhesion molecules and monocytes adhesion, which were blocked by antibodies to the TGF-β1 type 2, but not to the type 3 receptor.

    These observations provide mechanistic insights into H-R and oxidant injury and tissue protection by three different strategies.

  • 20.
    Christiansen, Mats
    et al.
    Diakonhjemmets Sykehus.
    Löwhagen, G B
    Sexually transmitted diseases and sexual behavior in men attending an outpatients' clinic for gay men in Gothenburg, Sweden.2000In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 80, no 2, p. 136-9Article in journal (Refereed)
    Abstract [en]

    The prevalence of sexually transmitted diseases (STDs) diagnosed in men attending an outpatients' clinic for gay men from 1983 to 1997 and the results from a questionnaire survey concerning sexual behaviour conducted in 1994-96 are reported. The prevalence of gonorrhoea and chlamydia has decreased during the period, although in 1997 there was a micro-epidemic of gonorrhoea in gay men in Gothenburg. The results indicate that the reservoir of syphilis and hepatitis B in the gay population was eradicated during the early 1980s. Of altogether 1,808 HIV tests performed, 3.0% (n=55) were positive. In the questionnaire, the majority claimed they had sufficient knowledge on how HIV is transmitted, while 11.3% stated that they lacked that knowledge. Half of the patients stated that they had a steady sexual partner. Starting a new relationship was the most common reason (69%) for HIV screening. The use of condoms in anal and oral sex was 88% and 31%, respectively. Of those practising anal sex, 4% stated that they never used a condom. The prevalence of STDs has decreased in this period of time and safer sex is fairly well accepted, but the results also tell us that there is still a need for dedicated clinics like ours.

  • 21.
    Craiglow, Brittany G.
    et al.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA.
    Boyden, Lynn M.
    Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
    Hu, Ronghua
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA.
    Virtanen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Su, John
    Univ Melbourne, Murdoch Childrens Res Inst, Dept Pediat, Melbourne, Vic, Australia;Monash Univ, Eastern Hlth, Dept Dermatol, Melbourne, Vic, Australia.
    Rodriguez, Gabriela
    Univ Costa Rica, Dept Dermatol, San Jose, Costa Rica.
    McCarthy, Catherine
    Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA.
    Luna, Paula
    Ramos Mejia Hosp, Dept Pediat Dermatol, Buenos Aires, DF, Argentina.
    Larralde, Margarita
    Ramos Mejia Hosp, Dept Pediat Dermatol, Buenos Aires, DF, Argentina.
    Humphrey, Stephen
    Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA.
    Holland, Kristen E.
    Med Coll Wisconsin, Dept Dermatol, Milwaukee, WI 53226 USA.
    Hogeling, Marcia
    Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, Los Angeles, CA 90095 USA.
    Hidalgo-Matlock, Benjamin
    Univ Costa Rica, Dept Dermatol, San Jose, Costa Rica.
    Ferrari, Bruno
    Ramos Mejia Hosp, Dept Pediat Dermatol, Buenos Aires, DF, Argentina.
    Fernandez-Faith, Esteban
    Ohio State Univ, Med Ctr, Dept Pediat & Dermatol, Columbus, OH 43210 USA;Nationwide Childrens Hosp, Dept Pediat & Dermatol, Columbus, OH USA.
    Drolet, Beth
    Nationwide Childrens Hosp, Dept Pediat & Dermatol, Columbus, OH USA.
    Cordoro, Kelly M.
    Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA;Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA.
    Bowcock, Anne M.
    Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Genet & Genome Sci, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA.
    Antaya, Richard J.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA;Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA.
    Ashack, Kurt
    Univ Illinois, Coll Med, Dept Dermatol, Chicago, IL 60680 USA.
    Ashack, Richard J.
    Dermatol Associates West Michigan, Grand Rapids, MI USA.
    Lifton, Richard P.
    Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
    Milstone, Leonard M.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA.
    Paller, Amy S.
    Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA;Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA.
    Choate, Keith A.
    Yale Univ, Sch Med, Dept Dermatol, POB 208059, New Haven, CT 06520 USA;Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA;Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA.
    CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris2018In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 79, no 3, p. 487-494Article in journal (Refereed)
    Abstract [en]

    Background: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-alpha inhibitors. Objective: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14. Methods: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed. Results: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab. Limitations: Relatively small sample size. Conclusions: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.

  • 22. Cui, Chang-Yi
    et al.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Georgii-Heming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fröjmark, Anne-Sophie
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Baig, Shahid M.
    Schlessinger, David
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frizzled6 Deficiency Disrupts the Differentiation Process of Nail Development2013In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 133, no 8, p. 1990-1997Article in journal (Refereed)
    Abstract [en]

    Nails protect the soft tissue of the tips of digits. The molecular mechanism of nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 (Fzd6), that is mutated in a human autosomal-recessive nail dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6(-/-) mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6(-/-) mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of nail/claw formation.

  • 23.
    Dahlin, Jakob
    et al.
    Skane Univ Hosp, Dept Occupat & Environm Dermatol, SE-20502 Malmo, Sweden..
    Berne, Berit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Med Prod Agcy, Dept Cosmet, S-75103 Uppsala, Sweden..
    Duner, Kari
    Blekinge Hosp, Dept Dermatol, S-37185 Karlskrona, Sweden..
    Hosseiny, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Matura, Mihaly
    SLSO, Unit Occupat & Environm Dermatol, Ctr Occupat & Environm Med, S-11365 Stockholm, Sweden..
    Nyman, Gunnar
    Hudlakarmottagningen Telegrafen, S-50330 Boras, Sweden..
    Tammela, Monica
    Med Prod Agcy, Dept Cosmet, S-75103 Uppsala, Sweden..
    Isaksson, Marlene
    Skane Univ Hosp, Dept Occupat & Environm Dermatol, SE-20502 Malmo, Sweden..
    Several cases of undesirable effects caused by methacrylate ultraviolet-curing nail polish for non-professional use2016In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 75, no 3, p. 151-156Article in journal (Refereed)
    Abstract [en]

    BackgroundUltraviolet (UV)-curing nail polishes based on acrylates or methacrylates are currently also available for non-professional use. The Swedish Medical Products Agency recently prohibited one brand of UV-curing polish, because several consumers reported undesirable effects after using it. ObjectivesTo investigate whether consumers with undesirable effects after using the UV-curing nail polish that was later prohibited were contact allergic to the polish and its individual ingredients. Materials/MethodsEight patients who had reported severe skin reactions after the use of the UV-curing polish were patch tested with two coatings of the nail polish and its ingredients at five dermatology departments in Sweden. ResultsAll patients tested except one showed contact allergic reactions to one or several of the acrylate-based or methacrylate-based ingredients in the nail polish. ConclusionsThe non-professional use of UV-curing nail polishes poses a risk of sensitization from acrylates and methacrylates.

  • 24.
    Dancila, Dragos
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Augustine, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Töpfer, Fritzi
    KTH Royal Inst Technol, Stockholm, Sweden.
    Dudorov, Sergey
    KTH Royal Inst Technol, Stockholm, Sweden.
    Hu, Xin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Emtestam, Lennart
    Karolinska Inst, Div Dermatol & Venereol, Stockholm, Sweden.
    Tenerz, Lars
    Optiga AB, Uppsala, Sweden.
    Oberhammer, Jachim
    KTH Royal Inst Technol, Stockholm, Sweden.
    Rydberg, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics.
    Millimeter wave silicon micromachined waveguide probe as an aid for skin diagnosis - results of measurements on phantom material with varied water content2014In: Skin research and technology, ISSN 0909-752X, E-ISSN 1600-0846, Vol. 20, no 1, p. 116-123Article in journal (Refereed)
    Abstract [en]

    Background

    More than 2 million cases of skin cancer are diagnosed annually in the United States, which makes it the most common form of cancer in that country. Early detection of cancer usually results in less extensive treatment and better outcome for the patient. Millimeter wave silicon micromachined waveguide probe is foreseen as an aid for skin diagnosis, which is currently based on visual inspection followed by biopsy, in cases where the macroscopical picture raises suspicion of malignancy.

    Aims

    Demonstration of the discrimination potential of tissues of different water content using a novel micromachined silicon waveguide probe. Secondarily, the silicon probe miniaturization till an inspection area of 600 x 200 m2, representing a drastic reduction by 96.3% of the probing area, in comparison with a conventional WR-10 waveguide. The high planar resolution is required for histology and early-state skin-cancer detection.

    Material and methods

    To evaluate the probe three phantoms with different water contents, i.e. 50%, 75% and 95%, mimicking dielectric properties of human skin were characterized in the frequency range of 95-105GHz. The complex permittivity values of the skin are obtained from the variation in frequency and amplitude of the reflection coefficient (S11), measured with a Vector Network Analyzer (VNA), by comparison with finite elements simulations of the measurement set-up, using the commercially available software, HFSS. The expected frequency variation is calculated with HFSS and is based on extrapolated complex permittivities, using one relaxation Debye model from permittivity measurements obtained using the Agilent probe.

    Results

    Millimeter wave reflection measurements were performed using the probe in the frequency range of 95-105GHz with three phantoms materials and air. Intermediate measurement results are in good agreement with HFSS simulations, based on the extrapolated complex permittivity. The resonance frequency lowers, from the idle situation when it is probing air, respectively by 0.7, 1.2 and 4.26GHz when a phantom material of 50%, 75% and 95% water content is measured.

    Discussion

    The results of the measurements in our laboratory set-up with three different phantoms indicate that the probe may be able to discriminate between normal and pathological skin tissue, improving the spatial resolution in histology and on skin measurements, due to the highly reduced area of probing.

    Conclusion

    The probe has the potential to discriminate between normal and pathological skin tissue. Further, improved information, compared to the optical histological inspection can be obtained, i.e. the complex permittivity characterization is obtained with a high resolution, due to the highly reduced measurement area of the probe tip.

  • 25. den Hollander, Lianne
    et al.
    Han, HongMei
    de Winter, Matthijs
    Svensson, Lennart
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Masich, Sergej
    Daneholt, Bertil
    Norlén, Lars
    Skin lamellar bodies are not discrete vesicles but part of a tubuloreticular network2016In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 96, no 3, p. 303-309Article in journal (Refereed)
  • 26.
    Domeika, Marius
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Zhurauskaya, L.
    Savicheva, A.
    Frigo, N.
    Sokolovskiy, E.
    Hallén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Unemo, M.
    Ballard, R. C.
    Guidelines for the laboratory diagnosis of trichomoniasis in East European countries2010In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 24, no 10, p. 1125-1134Article, review/survey (Refereed)
    Abstract [en]

    The laboratory diagnosis of sexually transmitted infections in many Eastern European countries remains suboptimal. The main objective of the present evidence-based guidelines is to provide comprehensive information regarding the laboratory diagnosis of infections caused by Trichomonas vaginalis in East European countries. In particular, the present guidelines recommend: (i) to encourage examination of the wet mounts of vaginal exudates, instead of stained smears, at all clinical settings; (ii) nucleic acid amplification tests (NAATs) or culture could be employed if no trichomonads are detected on microscopic examination of the wet preparation and there is a strong indication of infection and (iii) the use of NAATs is encouraged in screening, using non-invasive specimens, or high volume testing situations. In the absence of internationally recognized commercial NAAT systems, tests developed in-house should be validated using obtainable international standards and quality assured strictly. Individual East European countries may be required to make minor national adjustments to these guidelines as a result of lack of accessibility to some reagents or equipment, or laws in a specific country.

  • 27.
    Dunder, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Clinical Manifestations of Coronary Heart Disease and the Metabolic Syndrome: A Population-based Study in Middle-aged Men in Uppsala2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    During the past decades the knowledge concerning risk factors and pathophysiology of coronary heart disease (CHD) has substantially increased. However, despite identification of important risk factors CHD remains the leading cause of death in the western world.

    The metabolic syndrome is a cluster of metabolic disorders such as hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance associated with an increased risk of cardiovascular morbidity and mortality.

    The studies in this thesis are epidemiological in their character, and examine the relationships between different aspects of CHD and the metabolic syndrome in a population-based study of middle-aged men (ULSAM).

    The findings indicated that serum lipids were important risk factors for the development of both angina pectoris demanding revascularisation and acute myocardial infarction (MI). Proinsulin and blood pressure were independent predictors of MI only, suggesting these factors to be involved in thrombosis and plaque rupture.

    It was also found that antihypertensive treatment with beta-blockers and thiazide diuretics resulted in increased fasting blood glucose concentrations in subjects with an insulin resistant state with elevated proinsulin concentrations. Both proinsulin concentrations and increase in fasting blood glucose were associated with increased risk of developing future MI.

    The finding of a new Q/QS-pattern on the resting ECG, regardless of history of MI, was associated with impaired insulin secretion and was an independent predictor of total and cardiovascular mortality.

    A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was predictive for future fatal and nonfatal MI, and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.

    In summary these studies provide further knowledge about the associations between CHD and the metabolic syndrome and the possible importance of new markers of cardiovascular risk such as proinsulin and the apolipoproteins.

    List of papers
    1. Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study
    Open this publication in new window or tab >>Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study
    Show others...
    2003 In: BMJ, Vol. 326, no 7391, p. 681-3Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91823 (URN)
    Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
    2. Cardiovascular risk factors for stable angina pectoris versus unheralded myocardial infarction
    Open this publication in new window or tab >>Cardiovascular risk factors for stable angina pectoris versus unheralded myocardial infarction
    Show others...
    2004 In: Am Heart J., Vol. 147, no 3, p. 502-8Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91824 (URN)
    Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
    3. A new Q/QS pattern on the resting electrocardiogram is associated with impaired insulin secretion and a poor prognosis in elderly men independently of history of myocardial infarction
    Open this publication in new window or tab >>A new Q/QS pattern on the resting electrocardiogram is associated with impaired insulin secretion and a poor prognosis in elderly men independently of history of myocardial infarction
    2004 In: J Intern Med, Vol. 255, no 2, p. 221-8Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91825 (URN)
    Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved
    4. Evaluation of a scoring scheme, including proinsulin and the apolipoprotein B/apolipoprotein A1 ratio, for the risk of acute coronary events in middle-aged men: Uppsala Longitudinal Study of Adult Men (ULSAM)
    Open this publication in new window or tab >>Evaluation of a scoring scheme, including proinsulin and the apolipoprotein B/apolipoprotein A1 ratio, for the risk of acute coronary events in middle-aged men: Uppsala Longitudinal Study of Adult Men (ULSAM)
    Show others...
    2004 (English)In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 148, no 4, p. 596-601Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: In recent years, the importance of circulating levels of proinsulin and apolipoproteins as risk factors for myocardial infarction (MI) has been highlighted. The aims of the current study were to investigate whether introduction of these new markers of coronary risk could improve the performance of a risk prediction score and to compare this new score with traditional scoring schemes, such as the Framingham Study and the Prospective Cardiovascular Munster (PROCAM) Study schemes.

    METHODS: From 1970 to 1973 all 50-year-old men in Uppsala, Sweden, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease (the Uppsala Longitudinal Study of Adult Men [ULSAM] cohort). The current study investigated metabolic characteristics at baseline and the incidence of fatal and nonfatal MI (n = 251) during 28.7 years of follow-up in 1108 men who were free of coronary heart disease at baseline.

    RESULTS: The risk prediction score was derived from one half of the population sample from the ULSAM cohort and included systolic blood pressure, smoking, family history of MI, serum proinsulin, and the ratio between apolipoprotein B and apolipoprotein A1. The score was highly predictive for future MI (hazard ratio, 1.77 for a 1 SD increase; 95% CI, 1.49 to 2.10, P <.0001) in the other half of the population that was not used for generating the score. The ULSAM score performed slightly better than the Framingham and PROCAM scores (evaluated as areas under the receiver operating curves; Framingham, 61%; PROCAM, 63%; ULSAM, 66%; P =.08).

    CONCLUSIONS: A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was highly predictive for future fatal and nonfatal MI and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-91826 (URN)10.1016/j.ahj.2004.03.021 (DOI)15459588 (PubMedID)
    Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2017-12-14Bibliographically approved
  • 28.
    Emtestam, L.
    et al.
    Karolinska Univ Hosp, Dept Dermatol, Stockholm, Sweden.
    Al-Bayatti, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Popovic-Silwerfeldt, K.
    Karolinska Inst, Div Dermatol, Dept Clin Sci, Danderyd Hosp, Stockholm, Sweden.
    Weyler, L.
    AbbVie Ab, Stockholm, Sweden.
    Post marketing observational study to assess quality of life changes in Swedish Patients with moderate or severe Hidradenitis Suppurativa on Adalimumab Treatment (HOPE study), interim analysis2018In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 27, no Supplement: 1, p. 16-17Article in journal (Other academic)
  • 29. Engström, Katarina
    et al.
    Bergh, Peter
    Cederlund, Claes-Göran
    Hultborn, Ragnar
    Willen, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Aman, Pierre
    Kindblom, Lars-Gunnar
    Meis-Kindblom, Jeanne M.
    Irradiation of myxoid/round cell liposarcoma induces volume reduction and lipoma-like morphology2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 6, p. 838-845Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the clinical and morphological effects of radiotherapy in the treatment of myxoid/round cell liposarcoma (MLS/RCLS). Thirty-three primary and metastatic MLS/RCLS tumours in 15 patients were treated with radiation therapy. Twenty-seven of the 33 tumours were surgically removed after preoperative radiation (34-46 Gy) while six tumours were treated with radiotherapy alone (44-60 Gy). The pretreatment diagnosis was established in all 15 patients based on fine needle aspirates or histological findings. Tumour size was measured by CT or MRI before and after radiotherapy in 30 tumours. Thirteen tumours from 11 patients were genetically characterised before and/or after radiation therapy. Twenty-three of 30 irradiated tumours showed a median reduction in tumour volume of 52% and seven lesions a median progression of 36%. All 27 surgically removed tumours revealed histological features of radiation response. The most striking morphological changes were lipoma-like appearance, paucicellularity and hyalinisation. Twelve of 13 tumours analysed before and/or after radiation therapy showed the FUS-DDIT3 translocation. Radiation therapy of MLS/RCLS induces histopathologic accumulation of mature lipoma-like areas and tumour volume reduction that may facilitate resectability.

  • 30.
    Engvall, Karin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    A Sociological Approach to Indoor Environment in Dwellings: Risk factors for Sick Building Syndrome (SBS) and Discomfort2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The principal aim was to study selected aspects of indoor environment in dwellings and their association with symptoms compatible with the sick building syndrome (SBS). A validated questionnaire was developed specifically for residential indoor investigations, using sociological principles and test procedures. The questionnaire was mailed to 14,243 multi-family dwellings in Stockholm, selected by stratified random sampling. Females, subjects with a history of atopy, those above 65 y, and those in new buildings reported more symptoms. Subjects owning their own dwelling had less symptoms. A multiple regression model was developed, to identify residential buildings with a higher than expected occurrence of SBS. In total, 28.5% reported at least one sign of building dampness in their home (condensation on windows, humidity in the bathroom, mouldy odour, water leakage). All indicators of dampness were related to symptoms, even when adjusting for demographic data, and other building characteristics (OR=2.9-6.0). Associations between symptoms and other building data was evaluated in older houses, built before 1961. Subjects in older buildings with a mechanical ventilation system had fewer symptoms. Heating by electric radiators, and wood heating was associated with an increase of most types of symptoms (OR=1.2-5.0). Multiple sealing measures (OR=1.3), and major reconstruction (OR=1.1-1.9), was associated with an increase of symptoms. The effect of seasonal adapted ventilation (SAV) was studied in a small experimental study. A 20% reduction of ventilation flow from 0.5-0.8 ac/h to 0.4-0.5 ACH during the heating season increased the perception of poor indoor air quality in the dwelling in general, and in the bedroom. In conclusion, low building age, and building dampness in the dwelling are associated with SBS. In older houses, mechanical ventilation is beneficial. The thesis did not support the view that energy saving measures in general is an important risk factor for SBS, but major reconstruction and multiple sealing measures can be risk factor for symptoms. Reducing the outdoor ventilation flow below the current Swedish ventilation standard (0.5 ACH) may increase the perception of impaired air quality.

    List of papers
    1. The Stockholm Indoor Environment Questionnaire (SIEQ): A sociological based tool for assessment of indoor environment and health in dwellings
    Open this publication in new window or tab >>The Stockholm Indoor Environment Questionnaire (SIEQ): A sociological based tool for assessment of indoor environment and health in dwellings
    2004 (English)In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 14, no 1, p. 24-33Article in journal (Refereed) Published
    Abstract [en]

    The aim was to develop and validate a standardized questionnaire - the Stockholm Indoor Environment Questionnaire (SIEQ). The validation procedure was based on sociological principles and test procedures for validation. The indicators of indoor environment are air quality, thermal climate, noise, and illumination. The indicators of health are symptoms comprised in the sick building syndrome (SBS). The questionnaire also contains questions about the apartment, individual behavior, and personal factors. The everyday language describing the building and its function was first obtained by qualitative personal interviews, then by standardized questions. The interview questionnaire was transformed into a postal self-administered questionnaire. The reduction of the questionnaire was based on correlation analysis. It was found that to obtain a good validity, general questions are not sufficient, but specific question on perceptions and observations are needed. Good test-retest agreement was found both on an area level, building level, and individually. For each indicator, a set of questions are constructed and validated. SIEQ has been used in several studies, and the results are presented in graphic problem profiles. Reference data has been calculated for the Stockholm area.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90622 (URN)10.1111/j.1600-0668.2004.00204.x (DOI)14756843 (PubMedID)
    Available from: 2003-06-05 Created: 2003-06-05 Last updated: 2017-12-14Bibliographically approved
    2. Development of a multiple regression model to identify multi-family residential buildings with high prevalence of sick building syndrome (SBS).
    Open this publication in new window or tab >>Development of a multiple regression model to identify multi-family residential buildings with high prevalence of sick building syndrome (SBS).
    Show others...
    2000 In: Indoor Air, ISSN 0905-6947, Vol. 10, no 2, p. 101-110Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90623 (URN)
    Available from: 2003-06-05 Created: 2003-06-05Bibliographically approved
    3. Sick building syndrome (SBS) in relation to building dampness in multi-family residential buildings in Stockholm.
    Open this publication in new window or tab >>Sick building syndrome (SBS) in relation to building dampness in multi-family residential buildings in Stockholm.
    2001 In: International Archives of Occupational and Environmental Health, ISSN 0340-0131, Vol. 74, no 4, p. 270-278Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90624 (URN)
    Available from: 2003-06-05 Created: 2003-06-05Bibliographically approved
    4. Ocular, nasal, dermal and respiratory symptoms in relation to heating, ventilation, energy conservation and reconstruction of older multi-family houses
    Open this publication in new window or tab >>Ocular, nasal, dermal and respiratory symptoms in relation to heating, ventilation, energy conservation and reconstruction of older multi-family houses
    2003 (English)In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 13, no 3, p. 206-211Article in journal (Refereed) Published
    Abstract [en]

    The aim was to study relationships between symptoms compatible with the sick building syndrome, type of heating and ventilation system, energy saving, and reconstruction in older dwellings. In Stockholm, 4815 inhabitants in 231 multi-family buildings built before 1961 were randomly selected, of whom 3241 participated (77%). Symptoms and personal factors were assessed by a postal questionnaire. Independent information on building characteristics, and energy saving measures was gathered from the building owners. Multiple logistic regression analysis was applied to calculate odds ratios (OR) adjusting for age, gender, hay fever, current smoking, population density, type of ventilation, type of heating system, and ownership of the building. Subjects in buildings with a mechanical ventilation system had less ocular and nasal symptoms (OR = 0.29-0.85). Heating by electric radiators, and wood heating was associated with an increase of most symptoms (OR = 1.18-1.74). In total, 48% lived in buildings that had gone through at least one type of reconstruction or energy saving remedies during the latest 10 years, including exchange of heating or ventilation system, and sealing measures (exchange of windows, sealing of window frames, roof/attic insulation, and phasade insulation). Energy saving was associated with both a decrease and increase of different symptoms. Major reconstruction of the interior of the building was associated with an increase of most symptoms (OR = 1.09-1.90), and buildings with more than one sealing measure had an increase of ocular, nasal symptoms, headache and tiredness (OR = 1.22-2.49). In conclusion, major reconstruction of the interior, direct heated electric radiators, wood heating, and multiple sealing of buildings were associated with an increase of some symptoms. The study supports the view that mechanical ventilation in dwellings is beneficial from a health point of view.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90625 (URN)10.1034/j.1600-0668.2003.00174.x (DOI)12950582 (PubMedID)
    Available from: 2003-06-05 Created: 2003-06-05 Last updated: 2017-12-14Bibliographically approved
    5. Sick building syndrome (SBS) and percived indoor environment in relation to energy saving by reduced ventilation rate during the heating season: a one year intervention study in dwellings.
    Open this publication in new window or tab >>Sick building syndrome (SBS) and percived indoor environment in relation to energy saving by reduced ventilation rate during the heating season: a one year intervention study in dwellings.
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90626 (URN)
    Available from: 2003-06-05 Created: 2003-06-05Bibliographically approved
  • 31.
    Eriksson Mirkovic, Sandra
    et al.
    Hidrosis Clin, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
    Rystedt, Alma
    Hidrosis Clin, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
    Balling, Mie
    Hidrosis Clin, Warfvinges Vag 35, SE-11251 Stockholm, Sweden..
    Swartling, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Hidrosis Clin, Warfvinges Vag 35, SE-11251 Stockholm, Sweden.
    Hyperhidrosis Substantially Reduces Quality of Life in Children: A Retrospective Study Describing Symptoms, Consequences and Treatment with Botulinum Toxin2018In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 98, no 1, p. 103-107Article in journal (Refereed)
    Abstract [en]

    Studies on children with hyperhidrosis are sparse. This retrospective study presents clinical data and quality of life, along with treatment effect and safety of botulinum toxin (BTX). Case reports from 366 children were included to capture the medical history of hyperhidrosis. The total median score of the Dermatology Life Quality Index before treatment was 11 for children aged 16-17 years and 12 for children younger than 16 years. The children described physical, psychosocial and consequence-related symptoms. More than 70% had multifocal hyperhidrosis. BTX-A and/or BTX-B were given to 323 children, 193 of whom received repeated treatments. The highest score in a 5-grade scale concerning treatment effect was reported by 176/193 children, i.e. their "sweating disappeared completely". No severe adverse events occurred. Focal and multifocal hyperhidrosis in children reduces quality of life considerably. Treatment with BTX-A and/or BTX-B has been performed with success.

  • 32.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neural Stem Cell Differentiation and Migration2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neural stem cells are the precursors of neurons, astrocytes and oligodendrocytes. During neural development, the division of stem cells takes place close to the lumen of the neural tube, after which they migrate to their final positions within the central nervous system (CNS). Soluble factors, including growth factors, regulate neural stem cell proliferation, survival, migration and differentiation towards specific cell lineages.

    This thesis describes the function of platelet-derived growth factor (PDGF) and stem cell factor (SCF) in neural stem cell regulation. PDGF was previously suggested to stimulate neuronal differentiation, but the mechanisms were not defined. This study shows that PDGF is a mitogen and a survival factor that expands a pool of immature cells from neural stem cells. The PDGF-treated cells can be stained by neuronal markers, but need further stimuli to continue their maturation. They can become either neurons or glia depending on the secondary instructive cues. Moreover, neural stem cells produce PDGF. Inhibition of this endogenous PDGF negatively affects the cell number in stem cell cultures. We find that SCF stimulates migration and supports the survival of neural stem cells, but that it has no effect on their proliferation or differentiation into neurons and glia. Intracellular signaling downstream from the receptors for PDGF and SCF includes activation of extracellular signal-regulated kinase (ERK). This investigation shows that active ERK is not needed for the differentiation of stem cells into neurons, at least not during early stages.

    Neural stem cells have a future potential in the treatment of CNS disorders. To be able to use neural stem cells clinically we need to understand how their proliferation, differentiation, survival and migration are controlled. The results presented in this thesis increase our knowledge of how neural stem cells are regulated by growth factors.

    List of papers
    1. Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor
    Open this publication in new window or tab >>Immature neurons from CNS stem cells proliferate in response toplatelet-derived growth factor
    2001 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 21, no 10, p. 3483-3491Article in journal (Refereed) Published
    Abstract [en]

    Identifying external signals involved in the regulation of neural stem cell proliferation and differentiation is fundamental to the understanding of CNS development. In this study we show that platelet-derived growth factor (PDGF) can act as a mitogen for neural precursor cells. Multipotent stem cells from developing CNS can be maintained in a proliferative state under serum-free conditions in the presence of fibroblast growth factor-2 (FGF2) and induced to differentiate into neurons, astrocytes, and oligodendrocytes on withdrawal of the mitogen. PDGF has been suggested to play a role during the differentiation into neurons. We have investigated the effect of PDGF on cultured stem cells from embryonic rat cortex. The PDGF alpha-receptor is constantly expressed during differentiation of neural stem cells but is phosphorylated only after PDGF-AA treatment. In contrast, the PDGF beta-receptor is hardly detectable in uncommitted cells, but its expression increases during differentiation. We show that PDGF stimulation leads to c-fos induction, 5'-bromo-2'deoxyuridine incorporation, and an increase in the number of immature cells stained with antibodies to neuronal markers. Our findings suggest that PDGF acts as a mitogen in the early phase of stem cell differentiation to expand the pool of immature neurons.

    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-51636 (URN)11331377 (PubMedID)
    Available from: 2008-10-17 Created: 2008-10-17 Last updated: 2018-01-11Bibliographically approved
    2. Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons
    Open this publication in new window or tab >>Extracellular signal-regulated protein kinase signaling is uncoupled from initial differentiation of central nervous system stem cells to neurons
    2002 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 1, no 2, p. 147-154Article in journal (Refereed) Published
    Abstract [en]

    Knowledge about signaling pathways in response to external signals is needed to understand the regulation of stem cell proliferation and differentiation toward particular cell fates. The Ras/extracellular signal-regulated kinase (ERK) pathway has been suggested to play an essential role in neuronal differentiation. We have examined ERK signaling in the transition from multipotent stem cell to post-mitotic progeny using primary stem cells from the rat embryonic cortex. Fibroblast growth factor-2 (FGF-2) is a stem cell mitogen, whereas platelet-derived growth factor AA (PDGF-AA) expands a pool of committed neuronal precursors from stem cells. When comparing ERK activation by these growth factors, we found that FGF-2 stimulates high and PDGF-AA lower levels of ERK phosphorylation in stem cells. Differentiation was monitored as down-regulation of the bHLH transcription factor mammalian achaete-scute homologue-1 (MASH1). Even in the absence of active ERK, MASH1 became down-regulated and microtubule-associated protein 2-positive cells could form. Thus, ERK activation seems dispensable for the earliest steps of CNS stem cell differentiation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90758 (URN)000181772500007 ()12496361 (PubMedID)
    Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2017-12-14Bibliographically approved
    3. Regulation of neural stem cells by exogenous and endogenous PDGF.
    Open this publication in new window or tab >>Regulation of neural stem cells by exogenous and endogenous PDGF.
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90759 (URN)
    Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2010-01-13Bibliographically approved
    4. Stem cell factor is a chemoattractant and a survival factor for CNS stem cells
    Open this publication in new window or tab >>Stem cell factor is a chemoattractant and a survival factor for CNS stem cells
    2004 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 301, no 2, p. 201-210Article in journal (Refereed) Published
    Abstract [en]

    Migration of neural cells to their final positions is crucial for the correct formation of the central nervous system. Several extrinsic factors are known to be involved in the regulation of neural migration. We asked if stem cell factor (SCF), well known as a chemoattractant and survival factor in the hematopoietic lineage, could elicit similar responses in neural stem cells. For that purpose, a microchemotaxis assay was used to study the effect of SCF on migration of neural stem cells from the embryonic rat cortex. Our results show that SCF-induced chemotaxis and that specific antibodies to SCF or tyrosine kinase inhibitors abolished the migratory response. The SCF-receptor, Kit, was expressed in neural stem cells and in their differentiated progeny. We also show that SCF is a survival factor, but not a mitogen or a differentiation factor for neural stem cells. These data suggest a role for SCF in cell migration and survival in the developing cortex.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90760 (URN)10.1016/j.yexcr.2004.08.009 (DOI)15530856 (PubMedID)
    Available from: 2003-09-11 Created: 2003-09-11 Last updated: 2017-12-14Bibliographically approved
  • 33.
    Forsberg, Sofi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Human Epidermal Growth Factor Receptors and Biological Effects of HER-directed Molecules on Skin Epithelialization2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human skin forms a biologically active barrier and maintains vital protective functions through continuous regeneration of cells within its outermost layer, the epidermis. In healthy skin, renewal of epithelial cells is a tightly regulated process in which the epidermal growth factor receptor (EGFR or HER1) and its various ligands are involved. The biological role of other EGFR family members (HER2–4) in normal and diseased human skin has gained less interest. The purpose of this work was to investigate the expression and contribution of different HERs in cultured epidermis and psoriatic skin.

    Epidermal regeneration was studied by fluorescence imaging of a skin explant model exposed to anti-psoriatic drugs, HER ligands or HER-blocking molecules. EGFR, HER2 and HER3 were all markedly expressed with an in vivo-like immunostaining pattern in cultured neoepidermis, whereas only low amounts of HER4 were detected at protein and mRNA levels. Re-epithelialization was associated with receptor activation. Application of HER-selective tyrosine kinase inhibitors and monoclonal antibodies reduced the proliferative activity, receptor phosphorylation and radial outgrowth from normal skin explants. Similar anti-dynamic effects were obtained with HER kinase inhibition of neoepidermis generated from psoriatic skin. Among the HER receptors, EGFR seemed to be the dominant subtype during epithelialization in vitro although HER2 and HER3 were also involved. HER2 probably functioned as a co-receptor for the kinase-deficient HER3 in neoepidermis. In vivo, expression of HER4 mRNA was detected in normal and uninvolved psoriatic skin but was virtually absent in lesional skin, a potentially important finding for HER signalling in psoriasis.

    This thesis demonstrates the utility of combined dynamic and biochemical analyses of re-epithelialization and highlights the role of EGFR and other HERs for epidermal growth. It also underscores the potential of HER-directed inhibition to control hyperproliferative states of the epidermis.

    List of papers
    1. Comparison of growth-inhibitory agents by fluorescence imaging of human skin re-epithelialization in vitro
    Open this publication in new window or tab >>Comparison of growth-inhibitory agents by fluorescence imaging of human skin re-epithelialization in vitro
    2006 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 86, no 4, p. 292-299Article in journal (Refereed) Published
    Abstract [en]

    Drug screening procedures should preferably utilize experimental settings mimicking the in vivo situation. The aim of this study was to evaluate a skin explant model as a tool to identify topical agents with anti-proliferative properties in human epidermis. Re-epithelialization was initiated from a skin punch biopsy explanted onto de-epidermized dermis and cultured at the air-liquid interface in the presence of the epidermal growth factor receptor kinase inhibitor PKI166, tacrolimus or established topical anti-psoriatic drugs: betamethasone, calcipotriol, dithranol and tazarotene. Neo-epidermal extension was traced by fluorescence microscopy prior to histomorphometric analysis. PKI166 at 1 mu M decreased the mean radial outgrowth rate (-19%), frequency of BrdU-positive (-37%) and laminin 5-positive (-45%) cells, indicating reduced proliferation and migration of neo-epidermal keratinocytes. However, the papillomatosis index and epithelial thickness were not significantly affected. Calcipotriol at 1 mu M had a similar effect on the outgrowth rate (-15%) and fraction of laminin 5-stained keratinocytes (-40%). Furthermore, calcipotriol significantly reduced mean neo-epidermal thickness. Equimolar concentrations of the other test compounds had no apparent effect on histology or outgrowth parameters. This study exemplifies the versatility of combined dynamic and morphological analysis and emphasizes the potential of epidermal growth factor receptor-directed inhibition in hyperproliferative disorders of the epidermis.

    Keywords
    epidermal growth factor, tyrosine kinase inhibitors, proliferation, epidermis, fluorescent tracer
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89155 (URN)10.2340/00015555-0089 (DOI)000239602200001 ()16874412 (PubMedID)
    Available from: 2004-01-01 Created: 2004-01-01 Last updated: 2017-12-14Bibliographically approved
    2. Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase
    Open this publication in new window or tab >>Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase
    2008 (English)In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 300, no 9, p. 505-516Article in journal (Refereed) Published
    Abstract [en]

    The family of human epidermal growth factor receptors (EGFR, HER2-4) exerts key functions in normal and malignant epithelial cells. Both EGFR and HER2 are valuable targets for anti-cancer drugs by interfering with ligand binding, receptor dimerization, or tyrosine kinase activity. A similar therapeutic strategy has been advocated for chronic psoriasis since plaque lesions overexpress EGFR and its ligands. Our aim was to characterize EGFR/HER2 protein expression in skin cultures and to evaluate the effects of tyrosine kinase inhibitors on epidermal outgrowth, morphology, and EGFR activation. Human skin explants were established on cell-free dermis and cultured at the air-liquid interface. The impact of small-molecule HER inhibitors on outgrowth was assayed by fluorescence-based image analysis and histometry. Effects of a dual EGFR/HER2 kinase inhibitor, PKI166, on neoepidermis were studied by immunohistochemistry and Western blot. Receptor immunostaining showed in vivo-like distributions with highest EGFR intensity in the proliferative layers whereas HER2 was mainly expressed by suprabasal keratinocytes. Reepithelialization was associated with EGFR autophosphorylation irrespective of exogenous ligand stimulation. PKI166 inhibited neoepidermal EGFR activation, keratinocyte proliferation, and outgrowth from normal and psoriatic skin explants. The rate of epidermalization in presence of other HER inhibitors varied suggesting that drug specificity, potency, and reversibility determine the dynamic outcome. Overall, agents predominantly targeting EGFR kinase were more efficient inhibitors of epidermal regeneration than an HER2-selective drug. The study illustrates the usefulness of a dynamic skin model and emphasizes the potential of HER-directed approaches to control epidermal growth in hyperproliferative skin disorders.

    National Category
    Dermatology and Venereal Diseases
    Identifiers
    urn:nbn:se:uu:diva-89156 (URN)10.1007/s00403-008-0853-2 (DOI)000259455600005 ()
    Available from: 2004-01-01 Created: 2004-01-01 Last updated: 2017-12-14Bibliographically approved
    3. Neoepidermalization from human skin explant cultures is promoted by ligand-activated HER3 receptor
    Open this publication in new window or tab >>Neoepidermalization from human skin explant cultures is promoted by ligand-activated HER3 receptor
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-89157 (URN)
    Available from: 2004-01-01 Created: 2004-01-01Bibliographically approved
    4. Expression of HER receptor and ligand transcripts in psoriatic skin
    Open this publication in new window or tab >>Expression of HER receptor and ligand transcripts in psoriatic skin
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-89158 (URN)
    Available from: 2004-01-01 Created: 2004-01-01Bibliographically approved
  • 34.
    Forsberg, Sofi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Re-epithelialization from human skin explant cultures is promoted by ligand-activated HER3 receptor2010In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 59, no 1, p. 7-15Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Ligand-stimulated epidermal growth factor receptor (EGFR/HER1) plays a fundamental role in skin biology as potent transducer of mitotic and anti-apoptotic stimuli in keratinocytes. In human epidermis, at least two additional EGFR family members--HER2 and HER3--are expressed but their biological functions in normal and diseased human skin remain obscure. OBJECTIVE: Here, we studied the expression and biological impact of HER3 in regenerating human epidermis formed from skin explants adhered to acellular dermis. METHODS: Neoepidermal HER3 expression was examined by quantitative real-time reverse transcriptase polymerase chain reaction, immunohistochemistry and Western blot analysis. The dynamic effect of HER3 receptor stimulation by recombinant heregulin (HRG)-beta1 was assessed by fluorescence imaging of re-epithelialization. RESULTS: In the neoepidermis, HER3 mRNA and protein were detected with activated receptors being immunolocalized at basal and low suprabasal levels. Exogenous HRG-beta1 at 10-20 ng/ml increased the outgrowth rate corresponding to approximately 30% the response of exogenous EGF. The growth-promoting effect of HRG-beta1 was associated with enhanced HER3 phosphorylation, keratinocyte proliferation and thickening of viable neoepidermis whereas blockade of ligand-binding to HER3 delayed the outgrowth process and inhibited both constitutive and ligand-induced HER3 phosphorylation. HER2 antagonism using an anti-dimerization antibody, pertuzumab, impeded the re-epithelialization rate. In addition, a selective HER2 kinase inhibitor, CP654577, downregulated phospho-HER3 expression suggesting that transactivation of kinase-deficient HER3 was accomplished through dimerization with HER2. CONCLUSION: The study emphasizes the central role of EGFR in epidermal renewal and demonstrates that HRG-activated HER3 contributes to the outgrowth process of epidermis in vitro.

  • 35.
    Forsberg, Sofi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Östman, Arne
    Rollman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase2008In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 300, no 9, p. 505-516Article in journal (Refereed)
    Abstract [en]

    The family of human epidermal growth factor receptors (EGFR, HER2-4) exerts key functions in normal and malignant epithelial cells. Both EGFR and HER2 are valuable targets for anti-cancer drugs by interfering with ligand binding, receptor dimerization, or tyrosine kinase activity. A similar therapeutic strategy has been advocated for chronic psoriasis since plaque lesions overexpress EGFR and its ligands. Our aim was to characterize EGFR/HER2 protein expression in skin cultures and to evaluate the effects of tyrosine kinase inhibitors on epidermal outgrowth, morphology, and EGFR activation. Human skin explants were established on cell-free dermis and cultured at the air-liquid interface. The impact of small-molecule HER inhibitors on outgrowth was assayed by fluorescence-based image analysis and histometry. Effects of a dual EGFR/HER2 kinase inhibitor, PKI166, on neoepidermis were studied by immunohistochemistry and Western blot. Receptor immunostaining showed in vivo-like distributions with highest EGFR intensity in the proliferative layers whereas HER2 was mainly expressed by suprabasal keratinocytes. Reepithelialization was associated with EGFR autophosphorylation irrespective of exogenous ligand stimulation. PKI166 inhibited neoepidermal EGFR activation, keratinocyte proliferation, and outgrowth from normal and psoriatic skin explants. The rate of epidermalization in presence of other HER inhibitors varied suggesting that drug specificity, potency, and reversibility determine the dynamic outcome. Overall, agents predominantly targeting EGFR kinase were more efficient inhibitors of epidermal regeneration than an HER2-selective drug. The study illustrates the usefulness of a dynamic skin model and emphasizes the potential of HER-directed approaches to control epidermal growth in hyperproliferative skin disorders.

  • 36. Forssgren, Alexandra
    et al.
    Nelzén, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    A Repeat Validated Population Questionnaire of a Defined Swedish Population Verifies Reduction in Leg Ulcer Prevalence Over Time2015In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 95, no 6, p. 725-729Article in journal (Refereed)
    Abstract [en]

    This study was performed to measure if the introduced interventions in leg ulcer care in a selected Swedish county yield a detectable reduction in leg ulcer prevalence in the population. A validated postal questionnaire sent to 10,000 (9,868) randomly selected 30-89-year-olds in the Skaraborg county (255,042 inhabitants). All positive responders were telephone-interviewed and verified ulcer patients were clinically examined including assessment of arterial/venous circulation with hand-held Doppler and, where indicated, duplex ultrasound scanning. All results were compared with numbers from 1990 (initial study). The response rate was 82% (8,070/9,868), 200 active ulcers and 290 previous ulcers. The calculated prevalence was 0.75% for 30-89 years and 1.05% for 50-89 years (2.1% in 1990). The leg ulcer prevalence was reduced by 32% (0.52% compared to 0.77% in 1990), and the relative risk was reduced by 50% (95% CI 0.36-0.69). The study shows a true reduction in leg ulcer prevalence detectable in the population supporting a successful care of leg ulcer patients.

  • 37.
    Fransen, Jian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Huss, Fredrik R. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery. Univ Uppsala Hosp, Dept Plast & Maxillofacial Surg, Uppsala, Sweden..
    Nilsson, Lennart E.
    Linkoping Univ, Dept Clin & Expt Med, Clin Microbiol, Linkoping, Sweden..
    Rydell, Ulf
    Linkoping Univ, Inst Clin & Expt Med, Infect Dis, Linkoping, Sweden..
    Sjöberg, Folke
    Linkoping Univ, Inst Clin & Expt Med, Linkoping, Sweden..
    Hanberger, Håkan
    Linkoping Univ, Inst Clin & Expt Med, Infect Dis, Linkoping, Sweden..
    Surveillance of antibiotic susceptibility in a Swedish Burn Center 1994-20122016In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 42, no 6, p. 1295-1303Article in journal (Refereed)
    Abstract [en]

    Patients with burn trauma are at risk for infections caused by antibiotic resistant bacteria (ABR) with subsequent increase in morbidity and mortality. As part of the Swedish strategic program against antibiotic resistance in intensive care (ICU-Strama), we have surveyed the distribution of species and ABR in isolates from patients admitted to a Swedish burn center at Linkoping University Hospital from 1994 through 2012. In an international comparison Strama has been successful in reducing the antibiotic consumption among animals and humans in primary care. The aim of this study was to investigate the antibiotic consumption pressure and resistance rates in a Swedish burn unit. Methods: Microbiology data, total body surface area (TBSA), patient days, and mortality were collected from a hospital database for all patients admitted to the Burn Center at the University Hospital of Linkoping from April 1994 through December 2012. Results: A total of 1570 patients were admitted with a mean annual admission rate of 83 patients (range: 57-152). 15,006 microbiology cultures (approximately 10 per patient) were collected during the study period and of these 4531 were positive (approximately 3 per patient). The annual mean total body surface area (TBSA) was 13.4% (range 9.5-18.5) with an annual mortality rate of 5.4% (range 1-8%). The MRSA incidence was 1.7% (15/866) which corresponds to an MRSA incidence of 0.34/1000 admission days (TAD). Corresponding figures were for Escherichia coli resistant to 3rd generation cephalosporins (ESBL phenotype) 8% (13/170) and 0.3/TAD, Klebsiella spp. ESBL phenotype 5% (6/134) and 0.14/TAD, carbapenem resistant Pseudomonas aeruginosa 26% (56/209) and 1.28/TAD, and carbapenem resistant Acinetobacter spp. 3% (2/64) and 0.04/TAD. Conclusions: Our results show a sustained low risk for MRSA and high, although not increasing, risk for carbapenem resistant P. aeruginosa.

  • 38.
    Fukuhara, Mari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Agnarsdottir, Margret
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Coter, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    SATB2 is expressed in Merkel cell carcinoma2016In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 308, no 6, p. 449-454Article in journal (Refereed)
    Abstract [en]

    Merkel cell carcinoma (MCC) is a rare aggressive skin cancer with neuroendocrine differentiation. With immunohistochemistry, the tumor cells stain for both neuroendocrine (i.e., synaptophysin and chromogranin A) and epithelial markers. The epithelial marker cytokeratin 20 (CK20) stains positive with immunohistochemistry in a vast majority of MCCs. The expression of the special AT-rich sequence-binding protein (SATB2) was analyzed in MCC (n = 20) together with other forms of skin cancer and neuroendocrine tumors (n = 51) using immunohistochemistry. The results were compared to the expression of CK20, synaptophysin, and chromogranin A. The majority of the MCCs stained positive for synaptophysin and chromogranin A (95 vs 80 % respectively), and 75 % of the MCCs showed cytoplasmic positivity for CK20 and nuclear positivity for SATB2, with two discordant cases lacking expression of one of these markers. We conclude that immunohistochemistry for SATB2 can be used as an additional marker with similar sensitivity and specificity as CK20 for the diagnosis of Merkel cell carcinoma, suggesting a clinical utility in difficult cases where MCC is suspected.

  • 39.
    Garbani, M.
    et al.
    Swiss Inst Allergy Fdn, Davos, Switzerland..
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engkvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Scheynius, A.
    Karolinska Inst, Stockholm, Sweden..
    Malissen, B.
    Ctr Immunol Marseille Luminy, Marseille, France..
    Maurer, M.
    Charite, Berlin, Germany..
    Crameri, R.
    Swiss Inst Allergy Fdn, Davos, Switzerland..
    Terhorst, D.
    Charite, Berlin, Germany..
    Allergen-loaded strontium-doped hydroxyapatite spheres improve allergen-specific immunotherapy in mice2016In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 136, no 9, p. S225-S225Article in journal (Refereed)
  • 40.
    Garbani, M.
    et al.
    Univ Zurich, Swiss Inst Allergy & Asthma Res, Davos, Switzerland..
    Xia, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Rhyner, C.
    Univ Zurich, Swiss Inst Allergy & Asthma Res, Davos, Switzerland..
    Prati, M.
    Univ Zurich, Swiss Inst Allergy & Asthma Res, Davos, Switzerland..
    Scheynius, A.
    Karolinska Inst, Stockholm, Sweden.;Univ Hosp, Dept Med Solna, Translat Immunol Unit, Stockholm, Sweden..
    Malissen, B.
    Ctr Immunol Marseille Luminy, Marseille, France..
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Maurer, M.
    Charite, D-13353 Berlin, Germany..
    Crameri, R.
    Univ Zurich, Swiss Inst Allergy & Asthma Res, Davos, Switzerland..
    Terhorst, D.
    Ctr Immunol Marseille Luminy, Marseille, France.;Charite, D-13353 Berlin, Germany..
    Novel microparticles create a slow releasing depot for long-term immunostimulation in allergen-specific immunotherapy2016In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 25, no 3, p. E20-E21Article in journal (Refereed)
  • 41.
    Gauffin, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Öster, Caisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Gerdin, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Prevalence and prediction of prolonged pruritus after severe burns2015In: Journal of Burn Care & Research, ISSN 1559-047X, E-ISSN 1559-0488, Vol. 36, no 3, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Years after injury, pruritus is a common and severe problem for many burn patients. However, its characteristics and consequences are often only partially described. The authors therefore performed a prospective detailed examination of burn- and individual-related factors and considered those in relation to pruritus severity. Sixty-seven consecutive burn patients were assessed during acute care, and at 3 and 12 months postburn regarding preburn psychiatric disorders, health-related quality of life, post traumatic stress disorder, and personality traits. Postburn pruritus was subsequently assessed 2 to 7 years postburn using the Questionnaire for Pruritus Assessment. Fifty-one individuals, 76% of the participants, reported burn pruritus any time after the burn. Thirty-three individuals, 49% of the participants, reported ongoing pruritus the last 2 months. Information on the characteristics of pruritus was obtained from 32 of these individuals. Most perceived pruritus as bothersome or annoying and as present every day, 16 (50 %) were considered to have severe pruritus, and 11 (34 %) scratched themselves to the point of bleeding. In logistic regressions, this was independently related to TBSA full-thickness burn and health-related quality of life at 3 months, and to TBSA full thickness burn and the personality trait impulsiveness, respectively. About half of the previous burn patients experienced ongoing pruritus on an average of 4.5 years after injury, and half of them had severe pruritus. Scratching oneself to the point of bleeding is linked both to a certain personality and to pruritus. It is suspected that many patients are left without access to the best available treatment.

  • 42.
    Gillbro, J. M.
    et al.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    Merinville, E.
    Oriflame R&D Ltd, Bray, Co Wicklow, Ireland..
    Cattley, K.
    Oriflame R&D Ltd, Bray, Co Wicklow, Ireland..
    Al-Bader, T.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    Hagforsen, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Nilsson, M.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    Mavon, A.
    Oriflame Skin Res Inst, S-11121 Stockholm, Sweden..
    In vivo topical application of acetyl aspartic acid increases fibrillin-1 and collagen IV deposition leading to a significant improvement of skin firmness2015In: International Journal of Cosmetic Science, ISSN 0142-5463, E-ISSN 1468-2494, Vol. 37, p. 41-46Article in journal (Refereed)
    Abstract [en]

    Synopsis ObjectiveAcetyl aspartic acid (A-A-A) was discovered through gene array analysis with corresponding Cmap analysis. We found that A-A-A increased keratinocyte regeneration, inhibited dermal matrix metalloprotease (MMP) expression and relieved fibroblast stiffness through reduction of the fibroblast stiffness marker F-actin. Dermal absorption studies showed successful delivery to both the epidermal and dermal regions, and in-use trial demonstrated that 1% A-A-A was well tolerated. In this study, the aim was to investigate whether A-A-A could stimulate the synthesis of extracellular matrix supporting proteins invivo and thereby improving the viscoelastic properties of human skin by conducting a dual histological and biophysical clinical study. MethodTwo separate double-blind vehicle-controlled invivo studies were conducted using a 1% A-A-A containing oil-in-water (o/w) emulsion. In the histological study, 16 female volunteers (>55years of age) exhibiting photodamaged skin on their forearm were included, investigating the effect of a 12-day treatment of A-A-A on collagen IV (COLIV) and fibrillin-1. In a subsequent pilot study, 0.1% retinol was used for comparison to A-A-A (1%). The biomechanical properties of the skin were assessed in a panel of 16 women (>45years of age) using the standard Cutometer MPA580 after topical application of the test products for 28days. The use of multiple suction enabled the assessment of F4, an area parameter specifically representing skin firmness. ResultsTwelve-day topical application of 1% A-A-A significantly increased COLIV and fibrillin with 13% and 6%, respectively, compared to vehicle. 1% A-A-A and 0.1% retinol were found to significantly reduce F4 after 28days of treatment by 15.8% and 14.7%, respectively, in the pilot Cutometer study. No significant difference was found between retinol and A-A-A. However, only A-A-A exhibited a significant effect vs. vehicle on skin firmness which indicated the incremental benefit of A-A-A as a skin-firming active ingredient. ConclusionIn this study, we showed the invivo efficacy of 1% A-A-A both on a protein level (fibrillin and collagen IV) and on a clinical end point, specifically skin firmness, providing proof that, acetyl aspartic acid has a strong potential as an anti-ageing cosmeceutical' ingredient answering the needs of our key consumer base. Resume ObjectifL'acide aspartique acetyle (A-A-A) a ete identifie en utilisant la technologie de puces a ADN combine a une analyse en connectivity mapping' (Cmap), pour ces potentielles proprietes anti-age. A-A-A a la capacite d'augmenter la regeneration cellulaire et d'inhiber l'expression des MMP, ainsi que reduire la rigidite des fibroblastes en depolymerisant le reseau d'actine. Les etudes d'absorption cutanee ont montre une tres bonne biodisponibilite tant dans l'epiderme que le derme et les etudes de securite on confirme une tres bonne tolerance cutanee de A-A-A. Dans cette etude, nous avons cherche a demontrer que A-A-A pouvait stimuler la synthese des proteines de la matrice extra-cellulaire ainsi qu'ameliorer les proprietes viscoelastiques de la peau humaine en procedant a une double etude clinique, par immunohistochimie et biophysique sur volontaires. MethodesLes deux etudes on ete realisees en double aveugle contre placebo avec une emulsion H/E contenant 1% A-A-A. L'etude histologique a ete realisee sur 16 femmes volontaires (>55ans) presentant des signes de photoveillissement sur l'avant-bras durant une periode de 12 jours sur l'expression du collagene IV (COLIV) et de la fibrilline-1. Dans la seconde etude, les proprietes biomecaniques de la peau ont ete evaluees dans un panel de 16 femmes (>45ans) utilisant le Cutometre MPA580 et en mesurant le parametre F4, valeur representant specifiquement la fermete de la peau, apres l'application topique de produits durant pour 28 jours. Pour cette etude A-A-A (1%) a ete compare, en plus du placebo, a une formulation contenant 0.1% de retinol. ResultatsApres 12 jours d'application topique de 1% A-A-A, nous avons pu demontre une augmentation significative de l'expression de COLIV et de la fibrilline respectivement 13% et 6% par rapport au placebo. L'application de 1% A-A-A et 0,1% de retinol ont permis de pour reduire significativement F4 apres 28 jours de traitement respectivement de 15.8% et 14.7%. Aucune difference significative n'a ete trouvee entre le retinol et A-A-A. Cependant, seul A-A-A presentait une ameloration significative sur la fermete de la peau, ce qui confime le benefice apporte par A-A-A comme actif stimulant le raffermissement de la peau. ConclusionDans cette etude, nous avons montre l'efficacite de 1% A-A-A a la fois invivo sur l'expression des proteines (fibrilline et collagene IV) et sur un parametre clinique specifiquement lie a la fermete de la peau. Ces deux etudes confirment que l'acide acetyl-aspartique a un fort potentiel en tant qu' agent anti-age pouvant aussi etre considere comme un ingredient cosmeceutique' repondant aux besoins des consommateurs en demande de produits cosmetiques a efficacite prouvee.

  • 43.
    Gottvall, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tydén, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Höglund, Anna T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Larsson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Knowledge of human papillomavirus among high school students can be increased by an educational intervention2010In: International Journal of STD and AIDS (London), ISSN 0956-4624, E-ISSN 1758-1052, Vol. 21, no 8, p. 558-562Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate the effect of an educational intervention concerning human papillomavirus (HPV) directed at Swedish first year high school students. The intervention consisted of a class room lesson, a website and a folder. Outcome variables were knowledge of HPV and attitudes to preventive methods such as HPV vaccination, condom use and Pap smear testing. An intervention group (n = 92) was matched with two comparison groups (n = 184). At baseline, the median score for HPV knowledge was one out of 10 in both groups. At follow-up, the median knowledge score had increased to six in the intervention group, but was still one in the comparison group (P < 0.001). Attitudes to HPV vaccination, condom use and Pap smear testing remained the same (P > 0.05). In conclusion, a short school-based intervention can greatly increase the students' knowledge about HPV, but attitudes and behaviours are less easy to influence.

  • 44.
    Gunningberg, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Mårtensson, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care. Högskolan Gävle.
    Mamhidir, Anna-Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Högskolan Gävle.
    Florin, Jan
    Högskolan Dalarna.
    Muntlin Athlin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Bååth, Carina
    Karlstad universitet.