| 1. |
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| 2. |
- Bill-Axelson, Anna, et al.
(författare)
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Experiences of randomization : Interviews with patients and clinicians in the SPCG-IV trial
- 2008
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 42:4, s. 358-363
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Recruitment of both patients and clinicians to randomized trials is difficult. Low participation carries the risk of terminating studies early and making them invalid owing to insufficient statistical power. This study investigated patients' and clinicians' experiences of randomization with the aim of facilitating trial participation in the future. Material and methods. This was a qualitative study using content analysis. Patients offered to participate in a randomized trial and randomizing clinicians were interviewed. Five participants, four non-participants and five randomizing clinicians were interviewed, 2-8 years from randomization. Results. Clinicians used strategies in interaction with the patients to facilitate decision making. Patients' attitudes differed and experiences of relatives or friends were often stated as reasons for treatment preferences. Patients described that letting chance decide treatment was a difficult barrier to overcome for randomization. The clinicians used a number of different strategies perceived to make randomization more acceptable to their patients. The clinicians' own motivation for randomizing patients for trials depended on the medical relevance of the study question and the clinicians' major obstacle was to maintain equipoise over time. Regular meetings with the study group helped to maintain equipoise and motivation. Conclusions. To establish a good platform for randomization the clinician needs to know about the patient's treatment preferences and the patient's attitude concerning the role of the clinician to facilitate decision making. The strategies used by the clinicians were perceived as helpful and could be tested in an intervention study.
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| 3. |
- Bill-Axelson, Anna, 1965-
(författare)
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Localized Prostate Cancer : Results From a Randomized Clinical Trial
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the thesis were to• explore whether radical prostatectomy is beneficial compared with watchful waiting in survival and disease progression• find possible effect modifiers• evaluate a protocol of multiple biopsies and investigate if men with previous benign prostate biopsies are a group at risk for later prostate cancer• inquire into patients’ and clinicians’ experiences of randomization in order to find out what made this study possible to conduct, and thereby contribute to improve randomization in the futureThe background material was a large randomized clinical trial, the Scandinavian Prostatic Cancer Group Study Number 4, or SPCG-4, which was open for inclusion from February 1989 through December 1999. It comprised 695 men in Sweden, Finland and Iceland who had localized prostate cancer and were randomized to either radical prostatectomy or watchful waiting. After a mean follow-up time of 6.2 years the first analyses, according to intention-to-treat, showed that radical prostatectomy reduced disease specific mortality, risk of metastases and risk of local progression but did not statistically significantly reduce overall mortality. The second analyses confirmed our earlier findings and furthermore, at ten years, radical prostatectomy also statistically significantly reduced overall mortality. Age appeared as an independent effect modifier that will be further investigated.A total of 547 men, with a suspicion of prostate cancer that had undergone multiple biopsies, and whose biopsies had benign histology were later compared with the background population to evaluate whether they were a group at risk of developing prostate cancer. Within six years of follow-up, there was no increased risk of prostate cancer.Patients as well as clinicians used individual strategies to cope with the situation. The randomizing clinician has to understand the patient’s strategy and his expectations in order to individualize the information accordingly.
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| 4. |
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| 5. |
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| 6. |
- Bill-Axelson, Anna, et al.
(författare)
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No increased prostate cancer incidence after negative transrectal ultrasound guided multiple biopsies in men with increased prostate specific antigen and/or abnormal digital rectal examination.
- 2003
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 170:4 Pt 1, s. 1180-3
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We investigated the incidence of prostate cancer after negative transrectal ultrasound (TRUS) guided multiple biopsies. Our secondary aim was to calculate the sensitivity of the extended protocol used.MATERIALS AND METHODS: A cohort of 547 men with elevated prostate specific antigen and/or abnormal digital rectal examination but with results negative for prostate cancer on a mean of 9 TRUS guided biopsies was followed through record linkage to the national cancer Registry. The observed number of prostate cancers was compared with the expected number during the same calendar period in an age matched male population to determine the standardized incidence ratio. The sensitivity of TRUS with multiple biopsies after 5 years of followup was calculated. Relative survival was estimated if there was an excess death rate due to undiagnosed prostate cancer.RESULTS: We found 11 men diagnosed with prostate cancer. The expected number in the age standardized male population was 15, resulting in a standardized incidence ratio of 0.8 (95% CI 0.4 to 1.2). Five-year sensitivity of the extended protocol of TRUS guided biopsies was 95.2% (95% CI 93.5 to 96.4) and relative survival was more than 100%, indicating a selection of men deemed candidates for curative treatment.CONCLUSIONS: Men with clinical suspicion of prostate cancer who are examined by an extended protocol of TRUS guided biopsies negative for cancer do not have an increased incidence of prostate cancer within 6 years compared with an age matched male population. Five-year sensitivity of this protocol was high.
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| 7. |
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| 8. |
- Bill-Axelson, Anna, et al.
(författare)
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Radical prostatectomy versus watchful waiting in early prostate cancer
- 2005
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 352:19, s. 1977-1944
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results.METHODS:From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression.RESULTS:During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test).CONCLUSIONS:Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.
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| 9. |
- Bill-Axelson, Anna, et al.
(författare)
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Radical prostatectomy versus watchful waiting in localized prostate cancer : the Scandinavian prostate cancer group-4 randomized trial
- 2008
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:16, s. 1144-1154
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
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| 10. |
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| 11. |
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Drömbyggen
- 2009
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Samlingsverk (redaktörskap) (populärvet., debatt m.m.)
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| 12. |
- Holmberg, Lars, et al.
(författare)
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A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer
- 2002
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 347:11, s. 781-789
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. METHODS: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. RESULTS: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50; 95 percent confidence interval, 0.27 to 0.91; P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63; 95 percent confidence interval, 0.41 to 0.96). CONCLUSIONS: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival.
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| 13. |
- Holmberg, Lars, et al.
(författare)
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Prognostic markers under watchful waiting and radical prostatectomy
- 2006
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Ingår i: Hematology/Oncology Clinics of North America. - : Elsevier. - 0889-8588 .- 1558-1977. ; 20:4, s. 845-855
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Tidskriftsartikel (refereegranskat)abstract
- A suitable setting to analyze factors that determine prognosis or treatment response in prostate cancer is an unbiased comparison of radical prostatectomy and watchful waiting as in the Scandinavian Prostate Cancer Group Trial number 4. In our previous presentation of 10-year results, we studied Gleason score, serum prostate-specific antigen (PSA) at diagnosis, and age at diagnosis as modifiers of the effect of radical prostatectomy on survival. Because overall prognostic information obtained by these parameters or by tumor stage was not provided in our publication, we now present these data in the two study arms separately.
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| 14. |
- Landegren, Nils, et al.
(författare)
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A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:51
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Tidskriftsartikel (refereegranskat)abstract
- Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.
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| 15. |
- Lundborg, Magnus, et al.
(författare)
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Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
- 2018
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Ingår i: Journal of Structural Biology. - : Academic Press. - 1047-8477 .- 1095-8657. ; 203:2, s. 149-161
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Tidskriftsartikel (refereegranskat)abstract
- In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.
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| 16. |
- Lundborg, Magnus, et al.
(författare)
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Predicting drug permeability through skin using molecular dynamics simulation
- 2018
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 283, s. 269-279
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Tidskriftsartikel (refereegranskat)abstract
- Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.
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| 17. |
- Lundborg, Magnus, et al.
(författare)
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Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates
- 2022
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Ingår i: Biophysical Journal. - : Biophysical Society. - 0006-3495 .- 1542-0086. ; 121:20, s. 3837-3849
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Tidskriftsartikel (refereegranskat)abstract
- A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin’s barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calc mean square difference was 0.9 cm2 h−2.
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| 18. |
- Narangifard, Ali, et al.
(författare)
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Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 141:5, s. 1243-1253
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Tidskriftsartikel (refereegranskat)abstract
- In vertebrates, skin upholds homeostasis by preventing body water loss. The skin's permeability barrier is located intercellularly in the stratum corneum and consists of stacked lipid lamellae composed of ceramides, cholesterol, and free fatty acids. We have combined cryo-electron microscopy with molecular dynamics modeling and electron microscopy simulation in our analysis of the lamellae's formation, a maturation process beginning in stratum granulosum and ending in stratum corneum. Previously, we have revealed the lipid lamellae's initial- and end-stage molecular organizations. In this study, we reveal two cryo-electron microscopy patterns representing intermediate stages in the lamellae's maturation process: a single-band pattern with 2.0-2.5 nm periodicity and a two-band pattern with 5.5-6.0 nm periodicity, which may be derived from lamellar lipid structures with 4.0-5.0 nm and 5.5-6.0 nm periodicity, respectively. On the basis of the analysis of the data now available on the four maturation stages identified, we can present a tentative molecular model for the complete skin barrier formation process.
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| 19. |
- Norlén, Filip, et al.
(författare)
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Occupational exposure to inorganic particles during pregnancy and birth outcomes : A nationwide cohort study in Sweden
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The aim of this study was to investigate if occupational exposure to inorganic particles or welding fumes during pregnancy is associated with negative birth outcomes. Design A prospective national cohort study. Setting All single births from 1994 to 2012 in Sweden. Information on birth weight, preterm birth, small for gestational age, smoking habits, nationality, age, occupation, absence from work and education was obtained from nationwide registers. Exposure to inorganic particles (mg/m 3) was assessed from a job exposure matrix. Participants This study included all single births by occupationally active mothers (995 843). Outcome measures Associations between occupational exposures and negative birth outcomes in the form of low birth weight, preterm birth and small for gestational age. Results Mothers who had high exposure to inorganic particles and had less than 50 days (median) of absence from work during pregnancy showed an increased risk of preterm birth (OR 1.18; 95% CI 1.07 to 1.30), low birth weight (OR 1.32; 95% CI 1.18 to 1.48) as well as small for gestational age (OR 1.20; 95% CI 1.04 to 1.39). The increased risks were driven by exposure to iron particles. No increased risks were found in association with exposure to stone and concrete particles. High exposure to welding fumes was associated with an increased risk of low birth weight (OR 1.22; 95% CI 1.02 to 1.45) and preterm birth (OR 1.24; 95% CI 1.07 to 1.42). Conclusions The results indicate that pregnant women should not be exposed to high levels of iron particles or welding fumes.
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| 20. |
- Norlén, Filip, et al.
(författare)
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Occupational exposure to organic particles and combustion products during pregnancy and birth outcome in a nationwide cohort study in Sweden
- 2019
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Ingår i: Occupational and environmental medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 76:8, s. 537-544
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study if children of women exposed to organic particles and combustion products at work during pregnancy, have an increased risk of low birth weight, preterm birth or small for gestational age. Methods: A nationwide cohort of all occupationally active mothers and their children from single births during 1994 to the end of 2012 (1 182 138 observations) was formed. Information on birth outcome was obtained from the medical birth register. Information on absence from work, education, occupation, age, nationality and smoking habits was obtained from national registers. A job exposure matrix (FINJEM) was used to assess the exposure. Results: Pregnant women with low absence from work and high (>50th percentile) exposure to organic particles had an increased risk of giving birth to children with low birth weight (OR=1.19; 95% CI: 1.07 to 1.32), small for gestational age (OR=1.22; 95% CI: 1.07 to 1.38) or preterm birth (OR=1.17; 95% CI: 1.08 to 1.27). Subgroup analyses showed an increased risk of small for gestational age in association with exposure to oil mist. Exposure to oil mist and cooking fumes was associated with low birth weight. Paper and other organic dust was associated with preterm birth. Exposure to combustion products showed an increased risk of small for gestational age (OR=1.40; 95% CI: 1.15 to 1.71). Conclusions: The results indicate that occupational exposure to organic particles or combustion products during pregnancy is associated with restriction of fetal growth and preterm birth. More studies are needed to confirm a casual association.
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| 21. |
- Norlén, Lars Petter Oskar
(författare)
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The skin barrier : structure and physical function
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The objective of the project "The skin barrier - structure and physical function" was to characterise in detail the human skin barrier structurally and functionally. The thesis work includes in-vivo studies, in-vitro studies and studies on pure model systems. In the pursuit of the thesis work several new techniques and one new skin barrier model system have been developed; (a) a new technique for thickness and area measurements of isolated stratum corneum using confocal laser scanning microscopy (CLSM) and digitising tablet, (b) a new technique for separation and quantitation of stratum corneum lipids using high pressure liquid chromatography with light scattering detection (HPLC/LSD), (c) a new technique for extraction of inner stratum corneum lipids in-vivo, (d) a new technique for measurements of water diffusion through stratum corneum and lipid phases using an Evaporimeter in-vitro, (e) a new skin barrier lipid model system including both crystalline and liquid crystalline phases in equilibrium. The biophysical and analytical techniques that have been employed in addition to those mentioned above include gas chromatography (GC) with flame ionisation detection (FID), mass spectrometry (MS), thin layer chromatography (TLC), X-ray diffraction (SAXD and WAXD), transepidermal water loss TEWL), skin electrical impedance (EI) and capacitance measurements (CM). Also, during my PhD work I have had the opportunity to work briefly with supercritical carbon dioxide extraction and separation (SC-CO2), differential scanning calorimetry (DSC) and atomic force microscopy (AFM). Paper 1 shows that the swelling of the stratum corneum is most pronounced in the thickness dimension and that the corneocytes are permeable to water at a time-scale relevant for water diffusion. Paper 2 and 3 address the crucial problem of the existence of a liquid crystalline structure in the stratum corneum. Paper 2 focus on the stratum corneum free fatty acid fraction and paper 3 discusses the role of cholesterol for the barrier properties. Paper 4 and 5 treat diffusional pathways for water through stratum corneum and through lipid skin barrier model mixtures respectively. A new structural and functional model for the mammalian skin barrier, The "Plastic" Model, is postulated. A single "plastic" structure ([alpha]-form stabilised by cholesterol and "impurities" in hydrocarbon chainlength distributions), with virtually no "phase" borders, is proposed to be directly responsible for the extraordinary barrier capacity of mammalian skin. It is prophesied that the true, intact barrier, i.e., the single "plastic" structure ([alpha]-form), is only located to the lower part of stratum corneum where the water concentration is high, promoting higher degree of alkyl chain rotational disorder. At higher levels of stratum corneum the lipid morphology of the intercellular space becomes more heterogeneous (i.e., "phase" separation occurs) due to (a) lower water concentration (inducing "phase" transitions and "phase" separation) and (b) lipid degrading and recycling processes during cell shedding, and intermixing with sebaceous gland lipids (resulting in suboptimal cholesterol concentrations and introduction of unsaturated and medium chain lipid species).
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| 22. |
- Skröder, Helena, et al.
(författare)
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Occupational exposure to whole-body vibrations and pregnancy complications : a nationwide cohort study in Sweden
- 2020
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Ingår i: Occupational and Environmental Medicine. - : BMJ Publishing Group Ltd. - 1351-0711 .- 1470-7926. ; 77:10, s. 691-698
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Pregnancy complications are common contributors to perinatal mortality and morbidity. Still, the cause(s) of gestational hypertensive disorders and diabetes are largely unknown. Some occupational exposures have been inconsistently associated with pregnancy complications, but exposure to whole-body vibrations (WBV) has been largely overlooked even though it has been associated with adverse birth outcomes. Therefore, the aim was to assess whether occupational WBV exposure during pregnancy is associated with pregnancy complications in a nationwide, prospective cohort study.Methods: The Fetal Air Pollution Exposure cohort was formed by merging multiple Swedish, national registers containing information on occupation during pregnancy and diagnosis codes, and includes all working women who gave birth between 1994 and 2014 (n=1 091 044). WBV exposure was derived from a job-exposure matrix and was divided into categories (0, 0.1–0.2, 0.3–0.4 and ≥0.5 m/s2). ORs with 95% CIs were calculated using logistic regression adjusted for potential confounders.Results: Among women working full time (n=646 490), we found increased risks of all pregnancy complications in the highest exposure group (≥0.5 m/s2), compared with the lowest. The adjusted ORs were 1.76 (95% CI 1.41 to 2.20), 1.55 (95% CI 1.26 to 1.91) and 1.62 (95% CI 1.07 to 2.46) for preeclampsia, gestational hypertension and gestational diabetes, respectively, and were similar in all sensitivity analyses. There were no clear associations for part-time workers.Conclusions: The results suggest that women should not be exposed to WBV at/above the action limit value of 0.5 m/s2 (European directive) continuously through pregnancy. However, these results need further confirmation.
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| 23. |
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| 24. |
- Wennberg, Christian, et al.
(författare)
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Structural transitions in ceramide cubic phases during formation of the human skin barrier
- 2018
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Ingår i: Biophysical Journal. - : Cell Press. - 0006-3495 .- 1542-0086.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The stratum corneum is the outer-most layer of the human skin, and constitutes the primary barrier to penetration of external substances. The barrier function of the stratum corneum is primarily located to its extracellular space, which consists of long-chain ceramides, free fatty acids and cholesterol organised into a stacked lamellar bilayer structure. Recent experimental studies have shown that these lamellar structures are formed through a structural reorganization of glycosylceramide-based bilayers, folded in three dimensions with a cubic-like symmetry. Here we present coarse-grained molecular dynamics simulations of human ceramide- and glycosylceramide bilayer structures with gyroid cubic symmetry. The bilayer structures with glycosylceramides are able to maintain the cubic symmetry, while the bilayer structures with ceramides collapse into a stacked lamellar bilayer structure as the water content is reduced.
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| 25. |
- Wennberg, Christian, et al.
(författare)
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Understanding Drug Skin Permeation Enhancers Using Molecular Dynamics Simulations
- 2023
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:15, s. 4900-4911
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Tidskriftsartikel (refereegranskat)abstract
- Our skin constitutes an effective permeability barrier that protects the body from exogenous substances but concomitantly severely limits the number of pharmaceutical drugs that can be delivered transdermally. In topical formulation design, chemical permeation enhancers (PEs) are used to increase drug skin permeability. In vitro skin permeability experiments can measure net effects of PEs on transdermal drug transport, but they cannot explain the molecular mechanisms of interactions between drugs, permeation enhancers, and skin structure, which limits the possibility to rationally design better new drug formulations. Here we investigate the effect of the PEs water, lauric acid, geraniol, stearic acid, thymol, ethanol, oleic acid, and eucalyptol on the transdermal transport of metronidazole, caffeine, and naproxen. We use atomistic molecular dynamics (MD) simulations in combination with developed molecular models to calculate the free energy difference between 11 PE-containing formulations and the skin’s barrier structure. We then utilize the results to calculate the final concentration of PEs in skin. We obtain an RMSE of 0.58 log units for calculated partition coefficients from water into the barrier structure. We then use the modified PE-containing barrier structure to calculate the PEs’ permeability enhancement ratios (ERs) on transdermal metronidazole, caffeine, and naproxen transport and compare with the results obtained from in vitro experiments. We show that MD simulations are able to reproduce rankings based on ERs. However, strict quantitative correlation with experimental data needs further refinement, which is complicated by significant deviations between different measurements. Finally, we propose a model for how to use calculations of the potential of mean force of drugs across the skin’s barrier structure in a topical formulation design.
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