| 1. |
- Karlsson, Teresa, et al.
(författare)
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13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4 : a mechanism for its anti-androgenic effects in sebaceous glands?
- 2003
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - 0006-291X .- 1090-2104. ; 303:1, s. 273-278
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Tidskriftsartikel (refereegranskat)abstract
- Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione, which may stimulate sebum secretion. This oxidative 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity of RoDH-4 is competitively inhibited by retinol and 13-cis-retinol. Here, we further examine the substrate specificity of RoDH-4 and the inhibition of its 3 alpha-HSD activity by retinoids. Recombinant RoDH-4 oxidized 3,4-didehydroretinol-a major form of vitamin A in the skin-to its corresponding aldehyde. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, were potent competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4, i.e., reduced the formation of dihydrotestosterone and androstandione in vitro. Extrapolated to the in vivo situation, this effect might explain the unique sebosuppressive effect of isotretinoin when treating acne.
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| 2. |
- Nilsson, H-J., et al.
(författare)
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Profound inhibition of chronic itch induced by stimulation of thin cutaneous nerve fibres
- 2004
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Ingår i: Journal of the European Academy of Dermatology and Venereology. - : Elsevier. - 0926-9959 .- 1468-3083. ; 18:1, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite the fact that severe itch is common in many dermatological diseases, the therapeutic arsenal against itching is limited. From neurophysiological experiments, using a new technique termed cutaneous field stimulation, it is known that acute itch can be effectively relieved by stimulation of cutaneous nociceptors. METHODS: We tested the effects of cutaneous field stimulation (25 min, 16 electrodes, 4 Hz per electrode, up to 0.8 mA) on chronic itch due to atopic dermatitis. Transcutaneous electrical nerve stimulation (100 Hz, up to 26 mA) was used for comparison. In 27 patients, itch was measured just prior to, during and at regular intervals up to 12 h after either type of treatment. RESULTS: Both treatments augmented the itch sensation during ongoing stimulation, presumably reflecting an altered sensory processing in the somatosensory pathways of chronic itch patients. However, after cessation of cutaneous field stimulation, but not transcutaneous electrical nerve stimulation, the itch sensation was significantly depressed for up to 7 h. The peak inhibitory effect (about 25% of control) was reached between 1 and 5 h poststimulation. Neither treatment had any significant effect on alloknesis, as measured before and 10 min after stimulation. CONCLUSION: It is concluded that cutaneous field stimulation strongly depresses chronic itch, and is a potentially useful symptomatic treatment of itch.
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| 3. |
- Björklund, Martin, 1961-
(författare)
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Effects of repetitive work on proprioception and of stretching on sensory mechanisms : implications for work-related neuromuscular disorders
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the thesis were (i) to investigate the impact of repetitive low-intensity work exposure on proprioception and (ii) to examine effects of muscle stretching (especially sensory effects and effects on muscle nociception) and to relate its application to the prevention, alleviation and/or treatment of work-related neuromuscular disorders. The effects of low-intensity repetitive work on the shoulder proprioception were tested in healthy subjects. The effect of working time on the retention of subjective fatigue and their relation to changes in proprioception, and the immediate effect of stretching on shoulder proprioception were investigated. A new method to test the stretchability of the rectus femoris muscle was investigated for reliability and validity and used to assess the effects of a two-week stretching regimen on range of motion and on subjective stretch sensation. Finally, the interactions between innocuous muscle stretch and nociceptive chemical stimulation on discharge behavior of nociceptive dorsal horn neurons in the feline spinal cord were explored. The main findings were as follows: 1) The repetitive low-intensity work to fatigue diminished the shoulder proprioception; the working time as well as the retention of subjective fatigue were partly related to the extent of changed proprioception. 2) There was no effect of acute muscle stretching on the proprioception. 3) The new method for testing muscle stretchability proved valid and reliable. A two-week stretching regimen increased the tolerance to stretch torque, but the range of motion remained unchanged. 4) Half of the nociceptive dorsal horn neurons that responded to close arterial injections of bradykinin were modulated by muscle stretching applied directly after the injections. Altogether, the results give credence to the hypothesis of an involvement of sensory information distortion due to repetitive low-intensity work exposure in the development of work-related neuromuscular disorders. Increased tolerance to stretch torque may be an important mechanism in explaining improvements following stretch treatment. The spinal interactions between innocuous stretch and nociceptive muscle afferent inputs indicate a possible mechanism involved in stretching-induced pain alleviation.
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| 4. |
- Blomberg, Stina, 1966-
(författare)
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Autoantibodies and the Type I Interferon System in the Etiopathogenesis of Systemic Lupus Erythematosus
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
- Båve, Ullvi
(författare)
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Mechanisms of Interferon-α Induction in Systemic Lupus Erythematosus
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 6. |
- Dahmoun, Marju, 1954-
(författare)
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Apoptosis, proliferation, and sex steroid receptors in endometrium and endometrial carcinoma
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the involvement of apoptosis and proliferation in the mechanisms of menstruation and hormonal replacement therapy, HRT, as well as in the mechanisms of progesterone therapy in endometrial carcinoma. The aim of the first study was to investigate endometrium for 4 days before and for 2 days during menstruation. In the epithelium, rapid increase in the apoptotic index, decreasing expression of estrogen receptor α (ER) and progesterone receptor (PR), and minimal proliferation were observed prior to menstruation. In the stroma, an increase in the expression of ER and PR and proliferation was seen before the final decrease, and increased apoptosis was seen during menstruation. Thus, apoptosis is involved in the remodeling of the endometrium during menstruation. Postmenopausal endometrium showed unaffected homeostasis, i.e. unchanged ratio between apoptotic index and Ki-67 index during substitution therapy. ER expression was decreased both in the epithelium and stroma, while PR showed some increase in receptor expression. The unchanged homeostasis contributes to endometrial safety during combined continuous HRT. Unchanged apoptosis and increasing proliferation were observed with increasing tumor grade in 29 patients with endometrioid endometrial carcinoma, which may contribute to greater aggression as tumor grade increases. Decreased proliferation was observed after medroxy-progesterone at 20 mg per day particularly in the foci of maximal proliferation in G1 and G2 tumors. The expression of ER was unchanged, while PR was decreased in the foci of maximal expression for PR in G1 and G2 tumors. Since high proliferation and PR expression also coexisted in the same foci, evaluated in G1 and G2 tumors, the effect of progesterone could be facilitated in these tumor groups. High expression of sex steroid receptors was also a predicting factor for good response to progesterone (= decrease in proliferation), while the amount of stroma could not predict that effect.
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| 7. |
- Ingberg, Claes-Mårten, 1956-
(författare)
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Type 1 diabetes mellitus: Aspects of long-term complications and body composition
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Studies concerning social consequences, gastrointestinal and urinary tract symptoms were conducted in a population-based cohort comprising patients with long-standing type 1 diabetes and matched control persons. Three different questionnaires were sent by mail to diabetic patients and control persons. After a mean duration of 28.7±2.6 years, compared to the controls the diabetic patients showed an almost 10 times higher mortality, a lower employment rate and greater need for welfare benefits. These differences were mainly due to diabetic late complications. Education, housing conditions, life-style, civil state, alcohol and smoking habits were similar in the two groups. The prevalence of gastrointestinal symptoms was significantly higher in the diabetic patients than in the controls, and this was found to be attributable to the female diabetic patients. Female diabetic patients had been treated with antibiotics for urinary tract infections more often than controls, they experienced more social problems than controls in daily life because of urinary tract problems and used clamps to prevent wetting more often than did controls. Body composition and bone mineral density were evaluated in parts of the cohort with long-standing type 1 diabetes and control persons in another population-based cohort comprising diabetic females aged 16-19 years with type 1 diabetes since childhood and matched controls. Besides a tendency to reduced abdominal fat mass in diabetic males, no difference was observed in fat mass, muscle mass or bone mineral density between the patients with long-standing type 1 diabetes and controls. Significant correlations were found between insulin dosage and whole body fat mass in diabetic females and between serum cholesterol levels and abdominal fat mass in diabetic males. The female adolescents had a higher body mass index than the controls, and their overweight was shown to consist almost entirely of an increased fat mass. The distribution of fat, expressed as abdominal-to-leg ratio, correlated significantly to HbA1c and daily dosage of insulin. Bone mineral density did not differ between the groups. IGF I was significantly lower both in patients with long-standing type 1 diabetes and in the adolescent diabetic females compared with their matched controls.
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| 8. |
- Nordström, Anna, 1973-
(författare)
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Bone mass and physical activity
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Weak and osteoporotic bones in old age are an increasing cause of mortality and painful physical impairment of the elderly, especially in the western world. Bone mineral accrual during childhood and adolescence is thought to play a vital role in preventing osteoporosis. Identifying and optimizing the factors influencing peak bone mass is thus important for the prevention of osteoporosis and related fractures. A main aim of this thesis was to investigate the potential effects of various types of weight-bearing physical activity on bone accretion in young males just out of puberty. The results from our subgroups of athletes consisting of badminton, ice hockey, and soccer players suggest that weight-bearing physical activity gives rise to regional specific bone response that is determined by the degree of impact of the activity in areas subject to mechanical loading (papers I–IV). In summary, the bone is sensitive to loading after puberty in males, and important bone mass gains can be achieved by proper amount and type of exercise. Another aim of this thesis was to studythe effect of detraining on weight-bearing and non-weight-bearing bone in a cohort of adolescent males who participated in ice hockey and soccer training. Our results indicate that exercise-induced bone mineral density benefits decline, predominantly in weight-bearing bones, after retirement from an active sports career (papers II–IV). High bone density stemming from physical loading might be at least partly preserved even by reduced physical activity at nonweight-bearing sites after about three years of reduced activity (III, IV). A final aim was to follow prospectively the development of BMD during years of reduced activity in former male athletes, and evaluate whether exercise during adolescence could be associated with fewer fractures in old age. We found fewer fragility fractures in a cohort of 400 former athletes compared to in 800 age-matched controls. Thus, high bone density stemming from previous weight-bearing physical activity may reduce the risk of sustaining fragility fractures in the elderly. Key words: physical activity, peak bone mineral density, males.
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| 9. |
- Rehn, Börje, 1967-
(författare)
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Musculoskeletal disorders and whole-body vibration exposure among professional drivers of all-terrain vehicles
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Musculoskeletal disorders are common among professional driver groups. Ergonomic risk factors at work are often suggested as causative, aggravating or preserving. The general aim with this thesis is to investigate the association between musculoskeletal disorders and physical exposure with special with special focus on whole-body vibration (WBV), among professional drivers of all-terrain vehicles (ATVs). Drivers of ATVs are expsosed to high magnitudes of WBV and shock. This thesis included drivers of forest machines, snowgroomers and snowmobiles. A cross-sectional study revealed that ATV drivers had an increased risk of musculoskeletal symptoms in the neck-shoulder and thoracic regions, even after adjusting for age, smoking habits and psychosocial stress. Prevalence rates were in the range of 1.5-2.9 (CI:1.2-5.2) compared to an age-matched group from the general population. No group of ATV drivers had a significantly increased risk of low back pain. Trend analysis showed no association between symptoms and exposure time. A clinical investigation of a subgroup found that it was for ATV drivers with neck pain to have assymetrical and focal neuropathies, pure or in mix with a nociceptive disorder, in the neck and upper extremities (47-79%), which was in contrast to referents with neck pain who had more nociceptive disorders (27% prevalence of neuropathy). Two studies measured characteristics of seated WBV exposure in forest machines (forwarders), snowgroomers and snowmobiles. The magnitudes of WBV in ATVs, measured and analyzed according to ISO 2631-1, were between 0.5-3.5 m/s2 (frequency weighted vector sum), which was considered high compared to limits suggested by the international standard ISO 2631-1 and the physical agent directive from the Euoropean Union (0.5 m/s2, rms). Drivers of ATVs were exposed to horizontally directed WBV and shocks. Non-neutral neck postures are ergonomic risk factors that occured infrequently and with short duration. The magnitude of seated WBV in forwarder vehicles varied substantiálly depending on model, terrain condition and driver. This may result in different conclusions regarding health risk assessments. The main conclusion from this thesis is that musculoskeletal symptoms and disorders in the neck and upper extremities, among drivers of ATVs, may be a result of long-time exposure to shock-type and horisozontally oriented seated WBV.
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| 10. |
- Tenerz, Åke
(författare)
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Diabetes mellitus and related glucometabolic disturbances in acute myocardial infarction : Diagnosis, prevalence and prognostic implications
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In patients with diabetes mellitus (DM), acute myocardial infarction (AMI) is a major cause of death. We have studied two populations with respect to the relationship between DM or related glucometabolic disturbances and AMI.In the first population, the prevalence of DM and the importance of the glycaemic state for the long-term prognosis in non-diabetic patients were investigated in patients with AMI admitted to the Coronary Care Unite at Västerås Central Hospital.In the second population, the prevalence of impaired glucose tolerance (IGT), DM and other metabolic abnormalities was investigated in patients with AMI and without known DM admitted to the Coronary Care Units at Västerås and Karolinska Hospital, Stockholm.21% of the patients with AMI had previously known DM and 4% had newly detected DM if diagnosis is based upon fasting blood glucose (F-BG). The glycemic state, measured as HbA1c, at a 5.5 years follow-up was a risk factor for re-infarction and/or death in non-diabetic patients after AMI.If an oral glucose tolerance test (OGTT) is performed, 40-45% of all patients with AMI have DM and in addition about 30% have IGT. Both an OGTT and a single post-challenge blood glucose value after 60 minutes performed at hospital discharge, were independent predictors of IGT or DM at follow-up. Insulin resistance, measured by homeostatic model assessment (HOMA-IR), decreased during hospital stay, with no further decrease from hospital discharge to follow-up.In summary, the studies in this dissertation have revealed an unexpectedly high prevalence of abnormal glucose tolerance in patients with AMI. The glycaemic state, reflected by HbA1c, in non-diabetic patients after AMI has an impact on the long-term prognosis. Consequently, in all patients with AMI, HbA1c and casual blood glucose should be measured at admission and, at least, F-BG at hospital discharge.
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