| 1. |
- Gudmundsson, Sanna, et al.
(författare)
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Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
- 2017
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:6, s. 1070-1077
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Tidskriftsartikel (refereegranskat)abstract
- Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.
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| 2. |
- Alsterholm, Mikael, 1977, et al.
(författare)
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Establishment and utility of SwedAD : a nationwide Swedish registry for patients with atopic dermatitis receiving systemic pharmacotherapy
- 2023
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 103
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Tidskriftsartikel (refereegranskat)abstract
- SwedAD, a Swedish nationwide registry for patients with atopic dermatitis receiving systemic pharmacotherapy, was launched on 1 September 2019. We describe here the establishment of a user-friendly registry to the benefit of patients with atopic dermatitis. By 5 November 2022, 38 clinics had recorded 931 treatment episodes in 850 patients with an approximate national coverage rate of 40%. Characteristics at enrolment included median Eczema Area and Severity Index (EASI) 10.2 (interquartile range 4.0, 19.4), Patient-Oriented Eczema Measure (POEM) 18.0 (10.0, 24.0), Dermatology Life Quality Index (DLQI) 11.0 (5.0, 19.0) and Peak Itch Numerical Rating Scale-11 (NRS-11) 6.0 (3.0, 8.0). At 3 months, median EASI was 3.2 (1.0, 7.3) and POEM, DLQI, and NRS-11 were improved. Regional coverage varied, reflecting the distribution of dermatologists, the ratio of public to private healthcare, and difficulties in recruiting certain clinics. This study highlights the importance of a nationwide registry when managing systemic pharmacotherapy of atopic dermatitis.
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| 3. |
- Berner, Logan T., et al.
(författare)
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The Arctic plant aboveground biomass synthesis dataset
- 2024
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Ingår i: Scientific Data. - : Springer Nature. - 2052-4463. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Plant biomass is a fundamental ecosystem attribute that is sensitive to rapid climatic changes occurring in the Arctic. Nevertheless, measuring plant biomass in the Arctic is logistically challenging and resource intensive. Lack of accessible field data hinders efforts to understand the amount, composition, distribution, and changes in plant biomass in these northern ecosystems. Here, we present The Arctic plant aboveground biomass synthesis dataset, which includes field measurements of lichen, bryophyte, herb, shrub, and/or tree aboveground biomass (g m−2) on 2,327 sample plots from 636 field sites in seven countries. We created the synthesis dataset by assembling and harmonizing 32 individual datasets. Aboveground biomass was primarily quantified by harvesting sample plots during mid- to late-summer, though tree and often tall shrub biomass were quantified using surveys and allometric models. Each biomass measurement is associated with metadata including sample date, location, method, data source, and other information. This unique dataset can be leveraged to monitor, map, and model plant biomass across the rapidly warming Arctic.
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| 4. |
- Bornholdt, Dorothea, et al.
(författare)
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Genotype-Phenotype Correlations Emerging from the Identification of Missense Mutations in MBTPS2
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:4, s. 587-594
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Tidskriftsartikel (refereegranskat)abstract
- Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotypephenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.
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| 5. |
- Bygum, Anette, et al.
(författare)
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Generalized and Naevoid Epidermolytic Ichthyosis in Denmark: Clinical and Mutational Findings
- 2013
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 93:3, s. 309-313
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Tidskriftsartikel (refereegranskat)abstract
- A Danish Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations.
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| 6. |
- Chamcheu, Jean Christopher, et al.
(författare)
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Characterization of immortalized human epidermolysis bullosa simplex (KRT5) cell lines : trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress condition
- 2009
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Ingår i: Journal of dermatological science (Amsterdam). - : Elsevier. - 0923-1811 .- 1873-569X. ; 53:3, s. 198-206
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Chamcheu, Jean Christopher
(författare)
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Disease-causing Keratin Mutations and Cytoskeletal Dysfunction in Human Skin : In vitro Models and new Pharmacologic Strategies for Treating Epidermolytic Genodermatoses
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 8. |
- Chamcheu, Jean Christopher, et al.
(författare)
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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
- 2010
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Ingår i: British Journal of Dermatology. - : Wiley InterScience. - 0007-0963 .- 1365-2133. ; 162:5, s. 980-989
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
- Chamcheu, Jean Christopher, et al.
(författare)
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Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype : A useful in vitro model for testing new treatments
- 2011
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Ingår i: British Journal of Dermatology. - : British Association of Dermatologists. - 0007-0963 .- 1365-2133. ; 164:2, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
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| 11. |
- Craiglow, Brittany G., et al.
(författare)
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CARD14-associated papulosquamous eruption : A spectrum including features of psoriasis and pityriasis rubra pilaris
- 2018
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Ingår i: The Journal of American Academy of Dermatology. - : Elsevier BV. - 0190-9622 .- 1097-6787. ; 79:3, s. 487-494
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 12. |
- Dragano, Nico, et al.
(författare)
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Effort-Reward Imbalance at Work and Incident Coronary Heart Disease A Multicohort Study of 90,164 Individuals
- 2017
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Ingår i: Epidemiology. - : Lippincott Williams & Wilkins. - 1044-3983 .- 1531-5487. ; 28:4, s. 619-626
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiologic evidence for work stress as a risk factor for coronary heart disease is mostly based on a single measure of stressful work known as job strain, a combination of high demands and low job control. We examined whether a complementary stress measure that assesses an imbalance between efforts spent at work and rewards received predicted coronary heart disease.Methods: This multicohort study (the "IPD-Work" consortium) was based on harmonized individual-level data from 11 European prospective cohort studies. Stressful work in 90,164 men and women without coronary heart disease at baseline was assessed by validated effort-reward imbalance and job strain questionnaires. We defined incident coronary heart disease as the first nonfatal myocardial infarction or coronary death. Study-specific estimates were pooled by random effects meta-analysis.Results: At baseline, 31.7% of study members reported effort-reward imbalance at work and 15.9% reported job strain. During a mean follow-up of 9.8 years, 1,078 coronary events were recorded. After adjustment for potential confounders, a hazard ratio of 1.16 (95% confidence interval, 1.00-1.35) was observed for effort-reward imbalance compared with no imbalance. The hazard ratio was 1.16 (1.01-1.34) for having either effort-reward imbalance or job strain and 1.41 (1.12-1.76) for having both these stressors compared to having neither effort-reward imbalance nor job strain.Conclusions: Individuals with effort-reward imbalance at work have an increased risk of coronary heart disease, and this appears to be independent of job strain experienced. These findings support expanding focus beyond just job strain in future research on work stress.
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| 13. |
- Ervasti, Jenni, et al.
(författare)
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Sickness absence diagnoses among abstainers, low-risk drinkers and at-risk drinkers : consideration of the U-shaped association between alcohol use and sickness absence in four cohort studies
- 2018
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Ingår i: Addiction. - : Wiley-Blackwell Publishing Inc.. - 0965-2140 .- 1360-0443. ; 113:9, s. 1633-1642
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Tidskriftsartikel (refereegranskat)abstract
- Aims To estimate differences in the strength and shape of associations between alcohol use and diagnosis-specific sickness absence. Design A multi-cohort study. Participants (n = 47 520) responded to a survey on alcohol use at two time-points, and were linked to records of sickness absence. Diagnosis-specific sickness absence was followed for 4-7 years from the latter survey. Setting and participants From Finland, we had population cohort survey data from 1998 and 2003 and employee cohort survey data from 2000-02 and 2004. From France and the United Kingdom, we had employee cohort survey data from 1993 and 1997, and 1985-88 and 1991-94, respectively. Measurements We used standard questionnaires to assess alcohol intake categorized into 0, 1-11 and > 11 units per week in women and 0, 1-34 and > 34 units per week in men. We identified groups with stable and changing alcohol use over time. We linked participants to records from sickness absence registers. Diagnoses of sickness absence were coded according to the International Classification of Diseases. Estimates were adjusted for sex, age, socio-economic status, smoking and body mass index. Findings Women who reported drinking 1-11 units and men who reported drinking 1-34 units of alcohol per week in both surveys were the reference group. Compared with them, women and men who reported no alcohol use in either survey had a higher risk of sickness absence due to mental disorders [rate ratio = 1.51, 95% confidence interval (CI) = 1.22-1.88], musculoskeletal disorders (1.22, 95% CI = 1.06-1.41), diseases of the digestive system (1.35, 95% CI = 1.02-1.77) and diseases of the respiratory system (1.49, 95% CI = 1.29-1.72). Women who reported alcohol consumption of > 11 weekly units and men who reported alcohol consumption of > 34 units per week in both surveys were at increased risk of absence due to injury or poisoning (1.44, 95% CI = 1.13-1.83). Conclusions In Finland, France and the United Kingdom, people who report not drinking any alcohol on two occasions several years apart appear to have a higher prevalence of sickness absence from work with chronic somatic and mental illness diagnoses than those drinking below a risk threshold of 11 units per week for women and 34 units per week for men. Persistent at-risk drinking in Finland, France and the United Kingdom appears to be related to increased absence due to injury or poisoning.
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| 14. |
- Ervasti, Jenni, et al.
(författare)
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Sociodemographic Differences Between Alcohol Use and Sickness Absence : Pooled Analysis of Four Cohort Studies
- 2018
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press. - 0735-0414 .- 1464-3502. ; 53:1, s. 95-103
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We examined differences in sickness absence in relation to at-risk drinking and abstinence, taking into account potential changes in consumption.& para;& para;Methods: We used individual-participant data (n = 46,514) from four prospective cohort studies from Finland, France and the UK. Participants responded to a survey on alcohol use at two time points 4-6 years apart, and were linked to records of sickness absence for an similar to 6-year follow-up after the latter survey. Abstainers were those reporting no alcohol use in either survey. At-risk drinkers at T1 were labelled as 'former', at-risk drinkers at T2 as 'current' and at-risk drinkers at both times as 'consistent' at-risk drinkers. The reference group was low-risk drinkers at both times. Study-specific analyses were stratified by sex and socioeconomic status (SES) and the estimates were pooled using meta-analysis.& para;& para;Results: Among men (n = 17,285), abstainers (6%), former (5%), current (5%) and consistent (7%) at-risk drinkers had an increased risk of sickness absence compared with consistent low-risk drinkers (77%). Among women (n = 29,229), only abstainers (12%) had a higher risk of sickness absence compared to consistent low-risk drinkers (74%). After adjustment for lifestyle and health, abstaining from alcohol was associated with sickness absence among people with intermediate and high SES, but not among people with low SES.& para;& para;Conclusions: The U-shaped alcohol use-sickness absence association is more consistent in men than women. Abstinence is a risk factor for sickness absence among people with higher rather than lower SES. Healthy worker effect and health selection may partly explain the observed differences.& para;& para;Short summary: In a pooled analysis from four cohort studies from three European countries, we demonstrated a U-shaped association between alcohol use and sickness absence, particularly among men. Abstinence from alcohol was associated with increased sickness absenteeism among both sexes and across socioeconomic strata, except those with low SES.
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| 15. |
- Fadista, João, et al.
(författare)
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Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.
- 2018
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 26:4, s. 561-569
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Tidskriftsartikel (refereegranskat)abstract
- ; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.
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| 16. |
- Fransson, Eleonor I, et al.
(författare)
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Job strain and the risk of stroke : an individual-participant data meta-analysis
- 2015
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 46:2, s. 557-559
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Psychosocial stress at work has been proposed to be a risk factor for cardiovascular disease. However, its role as a risk factor for stroke is uncertain.METHODS: We conducted an individual-participant-data meta-analysis of 196 380 males and females from 14 European cohort studies to investigate the association between job strain, a measure of work-related stress, and incident stroke.RESULTS: In 1.8 million person-years at risk (mean follow-up 9.2 years), 2023 first-time stroke events were recorded. The age- and sex-adjusted hazard ratio for job strain relative to no job strain was 1.24 (95% confidence interval, 1.05;1.47) for ischemic stroke, 1.01 (95% confidence interval, 0.75;1.36) for hemorrhagic stroke, and 1.09 (95% confidence interval, 0.94;1.26) for overall stroke. The association with ischemic stroke was robust to further adjustment for socioeconomic status.CONCLUSION: Job strain may be associated with an increased risk of ischemic stroke, but further research is needed to determine whether interventions targeting job strain would reduce stroke risk beyond existing preventive strategies.
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| 17. |
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| 18. |
- Fransson, Eleonor, 1971-, et al.
(författare)
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Job strain as a risk factor for leisure-time physical inactivity : an individual-participant meta-analysis of up to 170,000 men and women
- 2012
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Ingår i: American Journal of Epidemiology. - Cary : Oxford University Press. - 0002-9262 .- 1476-6256. ; 176:12, s. 1078-1089
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Forskningsöversikt (refereegranskat)abstract
- Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 19851988 to 20062008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50 women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 29 years. In cross-sectional analyses, the odds for physical inactivity were 26 higher (odds ratio 1.26, 95 confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21 higher (odds ratio 1.21, 95 confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21 and 20 higher for those with high-strain (odds ratio 1.21, 95 confidence interval: 1.11, 1.32) and passive (odds ratio 1.20, 95 confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.
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| 19. |
- Gånemo, Agneta, et al.
(författare)
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Autosomal recessive congenital ichthyosis in Sweden and Estonia: clinical, genetic and ultrastructural findings in eithty-three patients
- 2003
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Ingår i: Acta Dermato-Venereologica. - 0001-5555 .- 1651-2057. ; 83:1, s. 24-30
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Tidskriftsartikel (refereegranskat)abstract
- Congenital (non-bullous) ichthyosis is a rare group of keratinizing disorders which can be tentatively subclassified based on clinical criteria, analysis of transglutaminase 1 gene mutations and electron microscopy of epidermis. We studied 83 patients who were all on topical therapy and in 16 cases also on oral retinoids. Three main groups of patients were distinguished: (A) those with transglutaminase 1 gene mutations (n=44), (B) those without transglutaminase 1 gene mutations showing a coarse, generalized scaling (n=19), and (C) those without transglutaminase 1 gene mutations showing only fine or focal scaling (n=20). On clinical scoring, patients in group A were more hyperkeratotic and less erythematous than those in group B (p < 0.05). Anhidrosis was recorded in nearly all patients (> or = 80%), but ectropion and a collodion phenotype at birth were more common in group A versus other groups. Ultrastructurally, a high frequency of type I (Anton-Lamprecht's classification) was found in all three groups (37-63%), 20 cases of type II in group A and a few cases of types III and IV in groups B and C, respectively. In conclusion, transglutaminase 1 gene mutation is a major cause of congenital ichthyosis in Sweden and Estonia, and is often associated with severe scaling and ultrastructural type II in corneocytes. The transglutaminase-unrelated cases are more heterogeneous, probably reflecting a more varied aetiology.
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| 20. |
- Haghighi, Mona, et al.
(författare)
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A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.
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| 21. |
- Halme, Marie, et al.
(författare)
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Educational level and the use of mental health services, psychotropic medication and psychotherapy among adults with a history of physician diagnosed mental disorders
- 2023
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Ingår i: International Journal of Social Psychiatry. - : Sage Publications. - 0020-7640 .- 1741-2854. ; 69:2, s. 493-502
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalence of mental disorders is increased among people of low socioeconomic status or educational level, but it remains unclear whether their access to treatment matches their increased need.Aims: Our objective was to examine whether educational level as an indicator of socioeconomic status is associated with use of mental health services, psychotropic medication and psychotherapy in Finland.Method: Cross-sectional data from a follow-up survey of a longitudinal, population-based cohort study were used to form a sample of 3,053 men and women aged 24 to 68 with a current or previous physician diagnosed mental disorder. The prevalence of mental disorders, mental health service use and educational level were assessed with self-report questionnaire. Educational level was determined by the highest educational attainment and grouped into three levels: high, intermediate and low. The associations between educational level and mental health service -related outcomes were assessed with binary logistic regression. Covariates in the fully adjusted model were age, gender and number of somatic diseases.Results: Compared to high educational level, low educational level was associated with higher odds of using antidepressants (OR 1.35, 95% CI [1.09, 1.66]), hypnotics (OR 1.33, 95% CI [1.07, 1.66]) and sedatives (OR 2.17, 95% CI [1.69, 2.78]), and lower odds of using mental health services (OR 0.80, 95% CI [0.65, 0.98]). No associations were found between educational level and use of psychotherapy.Conclusions: The results do not suggest a general socioeconomic status related mismatch. A pharmacological emphasis was observed in the treatment of low educational background participants, whereas overall mental health service use was emphasized among high educational background participants.
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| 22. |
- Heikkila, Katriina, et al.
(författare)
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Job Strain and Alcohol Intake : A Collaborative Meta-Analysis of Individual-Participant Data from 140 000 Men and Women
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7, s. Art. no. e40101-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake. Methodology and Principal Findings: We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1-14, men: 1-21 drinks/week), intermediate (women: 15-20, men: 22-27 drinks/week) and heavy (women: > 20, men: > 27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake. Conclusions: Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.
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| 23. |
- Heikkila, Katriina, et al.
(författare)
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Job Strain and Tobacco Smoking : An Individual-Participant Data Meta-Analysis of 166 130 Adults in 15 European Studies
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tobacco smoking is a major contributor to the public health burden and healthcare costs worldwide, but the determinants of smoking behaviours are poorly understood. We conducted a large individual-participant meta-analysis to examine the extent to which work-related stress, operationalised as job strain, is associated with tobacco smoking in working adults. Methodology and Principal Findings: We analysed cross-sectional data from 15 European studies comprising 166 130 participants. Longitudinal data from six studies were used. Job strain and smoking were self-reported. Smoking was harmonised into three categories never, ex- and current. We modelled the cross-sectional associations using logistic regression and the results pooled in random effects meta-analyses. Mixed effects logistic regression was used to examine longitudinal associations. Of the 166 130 participants, 17% reported job strain, 42% were never smokers, 33% ex-smokers and 25% current smokers. In the analyses of the cross-sectional data, current smokers had higher odds of job strain than never-smokers (age, sex and socioeconomic position-adjusted odds ratio: 1.11, 95% confidence interval: 1.03, 1.18). Current smokers with job strain smoked, on average, three cigarettes per week more than current smokers without job strain. In the analyses of longitudinal data (1 to 9 years of follow-up), there was no clear evidence for longitudinal associations between job strain and taking up or quitting smoking. Conclusions: Our findings show that smokers are slightly more likely than non-smokers to report work-related stress. In addition, smokers who reported work stress smoked, on average, slightly more cigarettes than stress-free smokers.
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| 24. |
- Heikkilä, Katriina, et al.
(författare)
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Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116 000 European men and women
- 2013
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Ingår i: The BMJ. - : BMJ. - 1756-1833. ; 345:f165
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate whether work related stress, measured and defined as job strain, is associated with the overall risk of cancer and the risk of colorectal, lung, breast, or prostate cancers.Design Meta-analysis of pooled prospective individual participant data from 12 European cohort studies including 116 056 men and women aged 17-70 who were free from cancer at study baseline and were followed-up for a median of 12 years. Work stress was measured and defined as job strain, which was self reported at baseline. Incident cancers (all n=5765, colorectal cancer n=522, lung cancer n=374, breast cancer n=1010, prostate cancer n=865) were ascertained from cancer, hospital admission, and death registers. Data were analysed in each study with Cox regression and the study specific estimates pooled in meta-analyses. Models were adjusted for age, sex, socioeconomic position, body mass index (BMI), smoking, and alcohol intakeResults A harmonised measure of work stress, high job strain, was not associated with overall risk of cancer (hazard ratio 0.97, 95% confidence interval 0.90 to 1.04) in the multivariable adjusted analyses. Similarly, no association was observed between job strain and the risk of colorectal (1.16, 0.90 to 1.48), lung (1.17, 0.88 to 1.54), breast (0.97, 0.82 to 1.14), or prostate (0.86, 0.68 to 1.09) cancers. There was no clear evidence for an association between the categories of job strain and the risk of cancer.Conclusions These findings suggest that work related stress, measured and defined as job strain, at baseline is unlikely to be an important risk factor for colorectal, lung, breast, or prostate cancers.
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| 25. |
- Kabosova, Andrea, et al.
(författare)
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Compositional differences between infant and adult human corneal basement membranes
- 2007
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 48:11, s. 4989-4999
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Adult human corneal epithelial basement membrane ( EBM) and Descemet's membrane ( DM) components exhibit heterogeneous distribution. The purpose of the study was to identify changes of these components during postnatal corneal development. METHODS. Thirty healthy adult corneas and 10 corneas from 12-day- to 3-year-old children were studied by immunofluorescence with antibodies against BM components. RESULTS. Type IV collagen composition of infant corneal central EBM over Bowman's layer changed from alpha 1-alpha 2 to alpha 3-alpha 4 chains after 3 years of life; in the adult, alpha 1-alpha 2 chains were retained only in the limbal BM. Laminin alpha 2 and beta 2 chains were present in the adult limbal BM where epithelial stem cells are located. By 3 years of age, beta 2 chain appeared in the limbal BM. In all corneas, limbal BM contained laminin gamma 3 chain. In the infant DM, type IV collagen alpha 1-alpha 6 chains, perlecan, nidogen-1, nidogen-2, and netrin-4 were found on both faces, but they remained only on the endothelial face of the adult DM. The stromal face of the infant but not the adult DM was positive for tenascin-C, fibrillin-1, SPARC, and laminin-332. Type VIII collagen shifted from the endothelial face of infant DM to its stromal face in the adult. Matrilin-4 largely disappeared after the age of 3 years. CONCLUSIONS. The distribution of laminin gamma 3 chain, nidogen-2, netrin-4, matrilin-2, and matrilin-4 is described in the cornea for the first time. The observed differences between adult and infant corneal BMs may relate to changes in their mechanical strength, corneal cell adhesion and differentiation in the process of postnatal corneal maturation.
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| 26. |
- Karlsson, Teresa, et al.
(författare)
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Topical retinoic acid alters the expression of cellular retinoic acid-binding protein-I and cellular retinoic acid-binding protein-II in non-lesional but not lesional psoriatic skin
- 2002
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Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 11:2, s. 143-152
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic retinoids have profound effects on psoriatic skin pathology but their interactions with various retinoid-binding proteins in lesional vs non-lesional skin have not been investigated. Using quantitative real-time PCR the mRNA expression of cellular retinol-binding protein I (CRBPI) and retinoic acid-binding protein I/II (CRABPI/CRABPII) was studied in psoriatic and healthy control (=normal) skin after 4 days of occlusive RA/vehicle treatment (n=6). Untreated psoriatic lesions showed a markedly elevated CRABPII/CRABPI ratio, while the CRBPI level was reduced in lesional and non-lesional skin as compared to normal skin. In RA-treated normal and non-lesional skin, the mRNA expression of CRBPI was unaltered while that of CRABPI and CRABPII was reduced by approximately 80% and increased approximately 5-fold, respectively, as compared to vehicle-treated skin. In contrast, lesional skin exposed to RA showed an almost 90% increase in CRBPI transcripts but unaltered expression of CRABPI and CRABPII, yet, the mRNA expression of several inflammatory mediators, e.g. inducible nitric oxide synthase, interferon-gamma and interleukin-1beta, was clearly reduced. Immunohistochemistry localized CRABPII to suprabasal keratinocytes in normal skin and revealed markedly elevated levels in lesional skin. RA treatment induced CRABPII protein expression in normal and non-lesional skin, to similar levels as in untreated lesions. The results indicate that the effects of RA differ in normal/non-lesional psoriatic skin and lesional skin. Whether the high expression of CRABPII in psoriatic skin lesions is due to increased amounts of endogenous retinoids in lesional skin or reflects an abnormal regulation of the CRABPII gene in psoriasis remains to be studied.
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| 27. |
- Kivimäki, Mika, et al.
(författare)
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Associations of job strain and lifestyle risk factors with risk of coronary artery disease : a meta-analysis of individual participant data
- 2013
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Ingår i: CMJA. Canadian Medical Association Journal. Onlineutg. Med tittel. - : CMA Joule Inc.. - 0820-3946 .- 1488-2329. ; 185:9, s. 763-769
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease.Methods: We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985–2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2–4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death).Results: There were 1086 incident events in 743 948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18–2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06–1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000).Interpretation: The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain.
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| 28. |
- Kivimäki, Mika, et al.
(författare)
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Overweight, obesity, and risk of cardiometabolic multimorbidity : pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe
- 2017
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Ingår i: The Lancet Public Health. - : The Lancet Publishing Group. - 2468-2667. ; 2:6, s. e277-e285
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight.METHODS: ) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis.FINDINGS: Participants were 120 813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease.INTERPRETATION: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes.FUNDING: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.
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| 29. |
- Kivimäki, Mika, et al.
(författare)
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Physical inactivity, cardiometabolic disease, and risk of dementia : an individual-participant meta-analysis
- 2019
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Ingår i: The BMJ. - ENGLAND : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 365
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To examine whether physical inactivity is a risk factor for dementia, with attention to the role of cardiometabolic disease in this association and reverse causation bias that arises from changes in physical activity in the preclinical (prodromal) phase of dementia. DESIGN Meta-analysis of 19 prospective observational cohort studies. DATA SOURCES The Individual-Participant-Data Meta-analysis in Working Populations Consortium, the Inter-University Consortium for Political and Social Research, and the UK Data Service, including a total of 19 of a potential 9741 studies. REVIEW METHOD The search strategy was designed to retrieve individual-participant data from prospective cohort studies. Exposure was physical inactivity; primary outcomes were incident all-cause dementia and Alzheimer's disease; and the secondary outcome was incident cardiometabolic disease (that is, diabetes, coronary heart disease, and stroke). Summary estimates were obtained using random effects meta-analysis. RESULTS Study population included 404 840 people (mean age 45.5 years, 57.7% women) who were initially free of dementia, had a measurement of physical inactivity at study entry, and were linked to electronic health records. In 6.0 million person-years at risk, we recorded 2044 incident cases of all-cause dementia. In studies with data on dementia subtype, the number of incident cases of Alzheimer's disease was 1602 in 5.2 million person-years. When measured < 10 years before dementia diagnosis (that is, the preclinical stage of dementia), physical inactivity was associated with increased incidence of all-cause dementia (hazard ratio 1.40, 95% confidence interval 1.23 to 1.71) and Alzheimer's disease (1.36, 1.12 to 1.65). When reverse causation was minimised by assessing physical activity >= 10 years before dementia onset, no difference in dementia risk between physically active and inactive participants was observed (hazard ratios 1.01 (0.89 to 1.14) and 0.96 (0.85 to 1.08) for the two outcomes). Physical inactivity was consistently associated with increased risk of incident diabetes (hazard ratio 1.42, 1.25 to 1.61), coronary heart disease (1.24, 1.13 to 1.36), and stroke (1.16, 1.05 to 1.27). Among people in whom cardiometabolic disease preceded dementia, physical inactivity was non-significantly associated with dementia (hazard ratio for physical activity assessed > 10 before dementia onset 1.30, 0.79 to 2.14). CONCLUSIONS In analyses that addressed bias due to reverse causation, physical inactivity was not associated with all-cause dementia or Alzheimer's disease, although an indication of excess dementia risk was observed in a subgroup of physically inactive individuals who developed cardiometabolic disease.
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| 30. |
- Kivimäki, Mika, et al.
(författare)
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Work stress and risk of death in men and women with and without cardiometabolic disease : a multicohort study
- 2018
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Ingår i: The Lancet Diabetes and Endocrinology. - : Elsevier. - 2213-8587 .- 2213-8595. ; 6:9, s. 705-713
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although some cardiovascular disease prevention guidelines suggest a need to manage work stress in patients with established cardiometabolic disease, the evidence base for this recommendation is weak. We sought to clarify the status of stress as a risk factor in cardiometabolic disease by investigating the associations between work stress and mortality in men and women with and without pre-existing cardiometabolic disease.METHODS: In this multicohort study, we used data from seven cohort studies in the IPD-Work consortium, initiated between 1985 and 2002 in Finland, France, Sweden, and the UK, to examine the association between work stress and mortality. Work stress was denoted as job strain or effort-reward imbalance at work. We extracted individual-level data on prevalent cardiometabolic diseases (coronary heart disease, stroke, or diabetes [without differentiation by diabetes type]) at baseline. Work stressors, socioeconomic status, and conventional and lifestyle risk factors (systolic and diastolic blood pressure, total cholesterol, smoking status, BMI, physical activity, and alcohol consumption) were also assessed at baseline. Mortality data, including date and cause of death, were obtained from national death registries. We used Cox proportional hazards regression to study the associations of work stressors with mortality in men and women with and without cardiometabolic disease.RESULTS: We identified 102 633 individuals with 1 423 753 person-years at risk (mean follow-up 13·9 years [SD 3·9]), of whom 3441 had prevalent cardiometabolic disease at baseline and 3841 died during follow-up. In men with cardiometabolic disease, age-standardised mortality rates were substantially higher in people with job strain (149·8 per 10 000 person-years) than in those without (97·7 per 10 000 person-years; mortality difference 52·1 per 10 000 person-years; multivariable-adjusted hazard ratio [HR] 1·68, 95% CI 1·19-2·35). This mortality difference for job strain was almost as great as that for current smoking versus former smoking (78·1 per 10 000 person-years) and greater than those due to hypertension, high total cholesterol concentration, obesity, physical inactivity, and high alcohol consumption relative to the corresponding lower risk groups (mortality difference 5·9-44·0 per 10 000 person-years). Excess mortality associated with job strain was also noted in men with cardiometabolic disease who had achieved treatment targets, including groups with a healthy lifestyle (HR 2·01, 95% CI 1·18-3·43) and those with normal blood pressure and no dyslipidaemia (6·17, 1·74-21·9). In all women and in men without cardiometabolic disease, relative risk estimates for the work stress-mortality association were not significant, apart from effort-reward imbalance in men without cardiometabolic disease (mortality difference 6·6 per 10 000 person-years; multivariable-adjusted HR 1·22, 1·06-1·41).INTERPRETATION: In men with cardiometabolic disease, the contribution of job strain to risk of death was clinically significant and independent of conventional risk factors and their treatment, and measured lifestyle factors. Standard care targeting conventional risk factors is therefore unlikely to mitigate the mortality risk associated with job strain in this population.FUNDING: NordForsk, UK Medical Research Council, and Academy of Finland.
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| 31. |
- Lundgren, Markus, et al.
(författare)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 32. |
- Långberg, Marie
(författare)
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Passivity & Breakdown of Super Duplex Stainless Steel : Studied with Electrochemical & Synchrotron Techniques
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Super duplex stainless steel consists of two phases: austenite and ferrite, and is a highly corrosion resistant material, with a wide range of applications. The corrosion resistance of stainless steels is determined by the performance of a spontaneously formed thin Cr oxide rich film with a thickness of 1-3 nm. This film makes the stainless steel passive towards further oxidation processes, corrosion. The passive film is a dynamic system where degradation and formation reactions occur simultaneously. Super duplex stainless steel is a multi-phase, multielement material which has a high corrosion resistance and the question is whether its microstructure and alloying elements are affecting its passive film properties. This thesis contains two parts: real time synchrotron measurements to study the degradation mechanism during anodic polarization which pushes the material toward oxidation processes; and ex-situ measurements to map the lateral thickness and microscopic elemental distribution in the passive film. The in-situ/operando synchrotron experiments combined several experimental techniques, including X-ray reflectivity (XRR), X-ray diffraction (XRD), X-ray fluorescence (XRF) and electrochemical impedance spectroscopy (EIS), to simultaneously characterize the structure and chemical/electrochemical properties, as well as their changes of the surface region of the samples. It was found that the oxide film became more defective with increasing potential, leading to a decreased density of the passive film. On the other hand, the Ni rich alloy surface layer below the oxide film showed an increasing density, indicating an increased concentration of heavy elements (Mo and Ni). The XRD data showed evidence of nanocrystalline passive film whereas the amorphousness of the passive film increased with increasing potential. The ex-situ investigations employed by hard X-ray photoelectron emission microscopy (HAXPEEM), providing chemical data from individual grains with different crystallographic orientations parallel to the sample plane. The Cr content was higher on the ferrite than the austenite, whereas the thickness was rather uniform. The grain orientation has a small but detectable influence on the thickness and Cr content of the native passive film.
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| 33. |
- Nyberg, Solja T., et al.
(författare)
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Association of alcohol use with years lived without major chronic diseases : A multicohort study from the IPD-Work consortium and UK Biobank
- 2022
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Ingår i: The Lancet Regional Health - Europe. - : Elsevier. - 2666-7762. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background Heavy alcohol consumption increases the risk of several chronic diseases. In this multicohort study, we estimated the number of life-years without major chronic diseases according to different characteristics of alcohol use.Methods In primary analysis, we pooled individual-level data from up to 129,942 adults across 12 cohort studies with baseline data collection on alcohol consumption, drinking patterns, and history between 1986 and 2005 (the IPD-Work Consortium). Self-reported alcohol consumption was categorised according to UK guidelines - non-drinking (never or former drinkers); moderate consumption (1-14 units); heavy consumption (>14 units per week). We further subdivided moderate and heavy drinkers by binge drinking pattern (alcohol-induced loss of consciousness). In addition, we assessed problem drinking using linked data on hospitalisations due to alcohol abuse or poisoning. Follow-up for chronic diseases for all participants included incident type 2 diabetes, coronary heart disease, stroke, cancer, and respiratory disease (asthma and chronic obstructive pulmonary disease) as ascertained via linkage to national morbidity and mortality registries, repeated medical examinations, and/or self-report. We estimated years lived without any of these diseases between 40 and 75 years of age according to sex and characteristics of alcohol use. We repeated the main analyses using data from 427,621 participants in the UK Biobank cohort study.Findings During 1.73 million person-years at risk, 22,676 participants in IPD-Work cohorts developed at least one chronic condition. From age 40 to 75 years, never-drinkers [men: 29.3 (95%CI 27.9-30.8) years, women 29.8 (29.2 - 30.4) years)] and moderate drinkers with no binge drinking habit [men 28.7 (28.4-29.0) years, women 29.6 (29.4-29.7) years] had the longest disease-free life span. A much shorter disease-free life span was apparent in participants who experienced alcohol poisoning [men 23.4 (20.9-26.0) years, women 24.0 (21.4-26.5) years] and those with self-reported heavy overall consumption and binge drinking [men: 26.0 (25.3-26.8), women 27.5 (26.4 - 28.5) years]. The pattern of results for alcohol poisoning and self-reported alcohol consumption was similar in UK Biobank. In IPD-Work and UK Biobank, differences in disease-free years between self-reported moderate drinkers and heavy drinkers were 1.5 years or less.Interpretation Individuals with alcohol poisonings or heavy self-reported overall consumption combined with a binge drinking habit have a marked 3- to 6-year loss in healthy longevity. Differences in disease-free life between categories of self-reported weekly alcohol consumption were smaller.
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| 34. |
- Nyberg, Solja T., et al.
(författare)
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Association of Healthy Lifestyle With Years Lived Without Major Chronic Diseases
- 2020
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Ingår i: JAMA Internal Medicine. - : American Medical Association (AMA). - 2168-6106 .- 2168-6114. ; 180:5, s. 760-768
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Tidskriftsartikel (refereegranskat)abstract
- This cohort study examines disease-free life-years in participants with varying combinations of lifestyle risk factors.Question: Are different combinations of lifestyle factors associated with years lived without chronic diseases?Findings: In a multicohort study of 116 & x202f;043 participants, a statistically significant association between overall healthy lifestyle score and an increased number of disease-free life-years was noted. Of 16 different lifestyle profiles studied, the 4 that were associated with the greatest disease-free life years included body mass index lower than 25 and at least 2 of 3 factors: never smoking, physical activity, and moderate alcohol consumption.Meaning: Various healthy lifestyle profiles appear to be associated with extended gains in life lived without type 2 diabetes, cardiovascular and respiratory diseases, and cancer.Importance: It is well established that selected lifestyle factors are individually associated with lower risk of chronic diseases, but how combinations of these factors are associated with disease-free life-years is unknown.Objective: To estimate the association between healthy lifestyle and the number of disease-free life-years.Design, Setting, and Participants: A prospective multicohort study, including 12 European studies as part of the Individual-Participant-Data Meta-analysis in Working Populations Consortium, was performed. Participants included 116 & x202f;043 people free of major noncommunicable disease at baseline from August 7, 1991, to May 31, 2006. Data analysis was conducted from May 22, 2018, to January 21, 2020.Exposures: Four baseline lifestyle factors (smoking, body mass index, physical activity, and alcohol consumption) were each allocated a score based on risk status: optimal (2 points), intermediate (1 point), or poor (0 points) resulting in an aggregated lifestyle score ranging from 0 (worst) to 8 (best). Sixteen lifestyle profiles were constructed from combinations of these risk factors.Main Outcomes and Measures: The number of years between ages 40 and 75 years without chronic disease, including type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease.Results: Of the 116 & x202f;043 people included in the analysis, the mean (SD) age was 43.7 (10.1) years and 70 & x202f;911 were women (61.1%). During 1.45 million person-years at risk (mean follow-up, 12.5 years; range, 4.9-18.6 years), 17 & x202f;383 participants developed at least 1 chronic disease. There was a linear association between overall healthy lifestyle score and the number of disease-free years, such that a 1-point improvement in the score was associated with an increase of 0.96 (95% CI, 0.83-1.08) disease-free years in men and 0.89 (95% CI, 0.75-1.02) years in women. Comparing the best lifestyle score with the worst lifestyle score was associated with 9.9 (95% CI 6.7-13.1) additional years without chronic diseases in men and 9.4 (95% CI 5.4-13.3) additional years in women (P < .001 for dose-response). All of the 4 lifestyle profiles that were associated with the highest number of disease-free years included a body-mass index less than 25 (calculated as weight in kilograms divided by height in meters squared) and at least 2 of the following factors: never smoking, physical activity, and moderate alcohol consumption. Participants with 1 of these lifestyle profiles reached age 70.3 (95% CI, 69.9-70.8) to 71.4 (95% CI, 70.9-72.0) years disease free depending on the profile and sex.Conclusions and Relevance: In this multicohort analysis, various healthy lifestyle profiles appeared to be associated with gains in life-years without major chronic diseases.
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| 35. |
- Pavez Loriè, Elizabeth, 1976-
(författare)
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Retinoic Acid Metabolism Blocking Agents and the Skin : In vivo and in vitro Studies of the Effects on Normal and Diseased Human Epidermis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Retinoic Acid Metabolism Blocking Agents (RAMBAs) increase the endogenous levels of all-trans retinoic acid (RA) by inhibiting CYP26 enzymes. Thus they are believed to mimic the effects of retinoid treatment. Their mechanism of action and effects on vitamin A metabolism in keratinocytes are however uncertain. To explore this and the function of CYP26 in human skin was the main purpose of the project.The effects of two RAMBAs (talarozole and liarozole) on the expression of retinoid biomarkers in epidermis were studied in vivo and in vitro. Normal human skin (n=16) exposed to topical talarozole for 9 days showed similar response as previously reported for topical RA, even though no skin inflammation occurred. Lamellar ichthyosis patients (n=11) treated systemically with liarozole showed variable clinical improvement after 4 weeks with only mild effects on the retinoid biomarkers and the expression did not always correlate at the protein and mRNA levels. In these studies the proinflammatory transcripts IL-1α and TNFα were down-regulated by RAMBAs. In vitro, using an organotypic epidermis model we first studied how the RA metabolism was affected by adding RA and/or RAMBAs. We next examined the effects of the same agents on the expression of vitamin A metabolising enzymes in monolayer cultures of proliferating and differentiating keratinocytes. The results show among other things that CYP26 A1 and B1 are both involved in the catabolism of RA, and that talarozole potently increases the level of endogenous RA, primarily by inhibiting CYP26B1. However the drug´s biological effects cannot be solely attributed to increased RA levels.In conclusion, RAMBAs are promising new drugs for treatment of skin disorders, but further studies on their mechanism of action are needed.
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| 36. |
- Petropoulos, Fotios, et al.
(författare)
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Operational Research : methods and applications
- 2024
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Ingår i: Journal of the Operational Research Society. - : Taylor & Francis Group. - 0160-5682 .- 1476-9360. ; 75:3, s. 423-617
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Forskningsöversikt (refereegranskat)abstract
- Throughout its history, Operational Research has evolved to include methods, models and algorithms that have been applied to a wide range of contexts. This encyclopedic article consists of two main sections: methods and applications. The first summarises the up-to-date knowledge and provides an overview of the state-of-the-art methods and key developments in the various subdomains of the field. The second offers a wide-ranging list of areas where Operational Research has been applied. The article is meant to be read in a nonlinear fashion and used as a point of reference by a diverse pool of readers: academics, researchers, students, and practitioners. The entries within the methods and applications sections are presented in alphabetical order. The authors dedicate this paper to the 2023 Turkey/Syria earthquake victims. We sincerely hope that advances in OR will play a role towards minimising the pain and suffering caused by this and future catastrophes.
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| 37. |
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| 38. |
- Pigg, Maritta H., et al.
(författare)
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Spectrum of Autosomal Recessive Congenital Ichthyosis in Scandinavia : Clinical Characteristics and Novel and Recurrent Mutations in 132 Patients
- 2016
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 96:7, s. 932-
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of coz1r-nification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth, a collodion membrane or similar severe hyperkeratosis was reported in almost all patients with HI and LI, and in nearly half of patients with CIE and PI. Persistent ectropion was more common in HI (85%) and LI (57%), than in CIE (35%) and PI (5%). Anhidrosis was a frequent problem in all 4 groups (58-100%). A scoring (0-4) of ichthyosis/erythema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27A4 (n = 5), CYP4F22 (n = 3), PNPLA1 (n = 1) and ABHD5 (n = 1). In conclusion, by performing a deep phenotyping and gene screening, ARCI can be definitely diagnosed in 85% of cases in Scandinavia, with a prevalence of 1: 100,000 and >8 different aetiologies.
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| 39. |
- Prusti, T., et al.
(författare)
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The Gaia mission
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 595
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Tidskriftsartikel (refereegranskat)abstract
- Gaia is a cornerstone mission in the science programme of the European Space Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach. Both the spacecraft and the payload were built by European industry. The involvement of the scientific community focusses on data processing for which the international Gaia Data Processing and Analysis Consortium (DPAC) was selected in 2007. Gaia was launched on 19 December 2013 and arrived at its operating point, the second Lagrange point of the Sun-Earth-Moon system, a few weeks later. The commissioning of the spacecraft and payload was completed on 19 July 2014. The nominal five-year mission started with four weeks of special, ecliptic-pole scanning and subsequently transferred into full-sky scanning mode. We recall the scientific goals of Gaia and give a description of the as-built spacecraft that is currently (mid-2016) being operated to achieve these goals. We pay special attention to the payload module, the performance of which is closely related to the scientific performance of the mission. We provide a summary of the commissioning activities and findings, followed by a description of the routine operational mode. We summarise scientific performance estimates on the basis of in-orbit operations. Several intermediate Gaia data releases are planned and the data can be retrieved from the Gaia Archive, which is available through the Gaia home page.
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| 40. |
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| 41. |
- Theorell, Töres, et al.
(författare)
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Job Strain as a Risk Factor for Type 2 Diabetes : A Pooled Analysis of 124,808 Men and Women
- 2014
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 37:8, s. 2268-2275
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE The status of psychosocial stress at work as a risk factor for type 2 diabetes is unclear because existing evidence is based on small studies and is subject to confounding by lifestyle factors, such as obesity and physical inactivity. This collaborative study examined whether stress at work, defined as "job strain," is associated with incident type 2 diabetes independent of lifestyle factors. RESEARCH DESIGN AND METHODS We extracted individual-level data for 124,808 diabetes-free adults from 13 European cohort studies participating in the IPD-Work Consortium. We measured job strain with baseline questionnaires. Incident type 2 diabetes at follow-up was ascertained using national health registers, clinical screening, and self-reports. We analyzed data for each study using Cox regression and pooled the study-specific estimates in fixed-effect meta-analyses. RESULTS There were 3,703 cases of incident diabetes during a mean follow-up of 10.3 years. After adjustment for age, sex, and socioeconomic status (SES), the hazard ratio (HR) for job strain compared with no job strain was 1.15 (95% CI 1.06-1.25) with no difference between men and women (1.19 [1.06-1.34] and 1.13 [1.00-1.28], respectively). In stratified analyses, job strain was associated with an increased risk of diabetes among those with healthy and unhealthy lifestyle habits. In a multivariable model adjusted for age, sex, SES, and lifestyle habits, the HR was 1.11 (1.00-1.23). CONCLUSIONS Findings from a large pan-European dataset suggest that job strain is a risk factor for type 2 diabetes in men and women independent of lifestyle factors.
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| 42. |
- Theorell, Töres, et al.
(författare)
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Obesity and loss of disease-free years owing to major non-communicable diseases : a multicohort study
- 2018
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Ingår i: The Lancet Public Health. - : Elsevier Ltd. - 2468-2667. ; 3:10, s. e490-e497
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity increases the risk of several chronic diseases, but the extent to which the obesity-related loss of disease-free years varies by lifestyle category and across socioeconomic groups is unclear. We estimated the number of years free from major non-communicable diseases in adults who are overweight and obese, compared with those who are normal weight. Methods: We pooled individual-level data on body-mass index (BMI) and non-communicable diseases from men and women with no initial evidence of these diseases in European cohort studies from the Individual-Participant-Data Meta-Analysis in Working Populations consortium. BMI was assessed at baseline (1991–2008) and non-communicable diseases (incident type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease) were ascertained via linkage to records from national health registries, repeated medical examinations, or self-report. Disease-free years from age 40 years to 75 years associated with underweight (BMI <18·5 kg/m2), overweight (≥25 kg/m2 to <30 kg/m2), and obesity (class I [mild] ≥30 kg/m2 to <35 kg/m2; class II–III [severe] ≥35 kg/m2) compared with normal weight (≥18·5 kg/m2 to <25 kg/m2) were estimated. Findings: Of 137 503 participants from ten studies, we excluded 6973 owing to missing data and 10 349 with prevalent disease at baseline, resulting in an analytic sample of 120 181 participants. Of 47 127 men, 211 (0·4%) were underweight, 21 468 (45·6%) normal weight, 20 738 (44·0%) overweight, 3982 (8·4%) class I obese, and 728 (1·5%) class II–III obese. The corresponding numbers among the 73 054 women were 1493 (2·0%), 44 760 (61·3%), 19 553 (26·8%), 5670 (7·8%), and 1578 (2·2%), respectively. During 1 328 873 person-years at risk (mean follow-up 11·5 years [range 6·3–18·6]), 8159 men and 8100 women developed at least one non-communicable disease. Between 40 years and 75 years, the estimated number of disease-free years was 29·3 (95% CI 28·8–29·8) in normal-weight men and 29·4 (28·7–30·0) in normal-weight women. Compared with normal weight, the loss of disease-free years in men was 1·8 (95% CI −1·3 to 4·9) for underweight, 1·1 (0·7 to 1·5) for overweight, 3·9 (2·9 to 4·9) for class I obese, and 8·5 (7·1 to 9·8) for class II–III obese. The corresponding estimates for women were 0·0 (−1·4 to 1·4) for underweight, 1·1 (0·6 to 1·5) for overweight, 2·7 (1·5 to 3·9) for class I obese, and 7·3 (6·1 to 8·6) for class II–III obese. The loss of disease-free years associated with class II–III obesity varied between 7·1 and 10·0 years in subgroups of participants of different socioeconomic level, physical activity level, and smoking habit. Interpretation: Mild obesity was associated with the loss of one in ten, and severe obesity the loss of one in four potential disease-free years during middle and later adulthood. This increasing loss of disease-free years as obesity becomes more severe occurred in both sexes, among smokers and non-smokers, the physically active and inactive, and across the socioeconomic hierarchy. Funding: NordForsk, UK Medical Research Council, US National Institute on Aging, Academy of Finland, Helsinki Institute of Life Science, and Cancer Research UK.
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| 43. |
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| 44. |
- Vahlquist, Anders, et al.
(författare)
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A Scandinavian case of skin fragility, alopecia and cardiomyopathy caused by DSP mutations
- 2014
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Ingår i: Clincal and Experimental Dermatology. - : Oxford University Press (OUP). - 0307-6938 .- 1365-2230. ; 39:1, s. 30-34
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Tidskriftsartikel (refereegranskat)abstract
- Congenital skin fragility is a heterogeneous disorder with epidermolysis bullosa and various skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause skin fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy.
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| 45. |
- Vahlquist, Anders, et al.
(författare)
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Congenital ichthyosis : an overview of current and emerging therapies
- 2008
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 0001-5555 .- 1651-2057. ; 88:1, s. 4-14
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Forskningsöversikt (refereegranskat)abstract
- Congenital ichthyosis is a collective name for a group of monogenetic disorders of cornification, sometimes associated with systemic symptoms. There may be an abnormal quality or quantity of scale produced, abnormal thickness of stratum corneum or abnormal keratinocyte kinetics, often associated with skin inflammation. Pruritus, skin fragility, ectropion and anhidrosis are sometimes associated with the rare types of ichthyosis. Three important mechanisms are involved in the action of topical agents used in the treatment of ichthyosis: hydration, lubrication and keratolysis. The latter effect can also be achieved with systemic retinoids. For ichthyosis with an increased tendency towards skin infections, antimicrobials are another group of widely used agents. Considering that patients with ichthyosis are potential mega-users of topical therapy, with an estimated lifetime consumption of approximately one tonne cream per capita, surprisingly few controlled trials of the various treatments have been performed. Moreover, nearly all therapeutic principles were established long before the recent increase in knowledge about the aetiology and pathophysiology of ichthyosis. This calls for new ideas and intensified efforts to develop future ichthyosis therapies.
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| 46. |
- Vahlquist, Anders, et al.
(författare)
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Genotypic and clinical spectrum of self-improving collodion ichthyosis : ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients
- 2010
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 130:2, s. 438-443
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Tidskriftsartikel (refereegranskat)abstract
- Infants born with autosomal recessive congenital ichthyosis (ARCI) are often encapsulated in a collodion membrane, which shows a lamellar or erythrodermic type of ichthyosis upon shedding. However, some babies show a nearly normal underlying skin after several weeks, a phenotype called "self-healing collodion baby" (SHCB). Mutations in two genes, TGM1 and ALOX12B, have previously been implicated in the etiology of SHCB, but the full genotypic spectrum remains to be determined. DNA sequencing in 11 Swedish and 4 Danish SHCB patients showed ALOX12B mutations in eight cases, ALOXE3 mutations in three cases, and TGM1 mutations in one case. In three patients, we could not find mutations in any of the known ARCI genes. In all cases, a spontaneous shedding of the collodion membrane occurred 2-4 weeks after birth. When re-examined at 2-37 years of age, the patients showed skin xerosis, a mild or focal scaling, palmar hyperlinearity with keratoderma, and a frequent appearance of red cheeks and anhidrosis. Thus, we propose replacing SHCB with the term "self-improving collodion ichthyosis" (SICI). In conclusion, ALOX12B mutations are the leading cause of SICI in Scandinavia, followed by ALOXE3 mutations, which have not been previously associated with this variant of ARCI.
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| 47. |
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| 48. |
- Virtanen, Marie, et al.
(författare)
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Keratin 4 upregulation by retinoic acid in vivo : a sensitive marker for retinoid bioactivity in human epidermis
- 2000
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 114:3, s. 487-493
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Tidskriftsartikel (refereegranskat)abstract
- Retinoids affect keratinocyte differentiation and modulate the expression of many epidermal proteins, among them cellular retinoic acid-binding protein II and the family of cytokeratins. The upregulation of the former protein is a well-known phenomenon, whereas the retinoid-induced regulation of epidermal keratin expression is more complex and only partially understood. We studied the effect of topical retinoids on the expression in healthy skin of cellular retinoic acid-binding protein II, tazarotene-induced genes 1 and 2, several epidermal keratins (K1, K2e, and K10), and two mucous keratins (K4 and K13) known to appear in epidermis under certain abnormal conditions. Reverse transcription-polymerase chain reaction experiments showed that the K4 expression was the one most overtly induced by 2 wk of open treatment with 0.05% of retinoic acid and tazarotene. Using real-time quantitative polymerase chain reaction (TaqMan) and normalization of the mRNA values to beta-actin, the increase in K4 was found to be 100-1000-fold. In comparison, the expression of K13 and cellular retinoic acid-binding protein II was increased 10-50-fold, the K1 and K10 mRNA levels remained unchanged, and the K2e level decreased by a factor of 100-1000. In parallel biopsies, immunohistochemistry showed no change in K1, K2e, or K10 staining, but a strong de novo appearance of K4 in the granular layer after retinoid treatment. In a separate study, occlusive application of 0.025% retinoic acid in four healthy subjects produced a maximal K4 mRNA signal after 48 h and strong K4 staining after 80 h. Finally, a dose-response study showed that the de novo appearance of K4 can be utilized as a sensitive test for retinoid bioactivity in epidermis in vivo.
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| 49. |
- Virtanen, Marie, et al.
(författare)
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Keratins 2 and 4/13 in reconstituted human skin are reciprocally regulated by retinoids binding to nuclear receptor RAR alpha
- 2010
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Ingår i: Experimental dermatology. - : Wiley. - 0906-6705 .- 1600-0625. ; 19:7, s. 674-681
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Tidskriftsartikel (refereegranskat)abstract
- Disorders of keratinization are often treated with vitamin A derivatives (retinoids) which affect keratinocyte differentiation, including keratin (KRT) gene expression. In vivo, suprabasal keratinocytes normally express only keratin (K) 1, K2 and K10, but after topical application of all-trans retinoic acid (ATRA), the granular cells will additionally express K4 and K13, i.e. keratins normally present in oral mucosa and in cultured epidermal keratinocytes. To learn more about the retinoid regulation of keratin expression under in vivo-like conditions, we cultured keratinocytes on de-epidermized dermis in only 0.5% serum. These cells produce a normal-looking epidermis that expresses high mRNA levels of KRT1, KRT2 and KRT10, but minimal amounts of KRT4 and KRT13. Addition of ATRA to the medium for 48 h caused a dose-dependent increase in KRT4/KRT13 and a down-regulation of KRT2 mRNA. An increase in K4 protein was also found. The response was greater than the up-regulation of another retinoid-regulated gene, CRABPII. By studying 10 retinoids with different affinities for the retinoic acid receptors (RAR) and retinoid X receptors (RXR) isoforms, the reciprocal expression of KRT2 and KRT4/KRT13 could be connected with agonists for RAR alpha. Two of these agonists, CD336/Am580 and CD2081, altered the expression profile with similar potency as the pan-RAR agonists ATRA and CD367. Co-addition of a pan-RAR antagonist (CD3106/AGN193109) markedly inhibited the induction of KRT4/KRT13 expression, whereas the down-regulation of KRT2 was less affected. In conclusion, RAR alpha agonists elicit a reciprocal modulation of KRT2 and KRT4/KRT13 expression in human epidermis, but whether or not the keratin genes also possess RAR alpha-specific regulatory elements is still unclear.
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| 50. |
- Virtanen, Marianna, et al.
(författare)
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Lifestyle factors and risk of sickness absence from work : a multicohort study
- 2018
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Ingår i: Lancet Public Health. - : Elsevier. - 2468-2667. ; 3:11, s. E545-E554
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Tidskriftsartikel (refereegranskat)abstract
- Background Lifestyle factors influence the risk of morbidity and mortality, but the extent to which they are associated with employees' absence from work due to illness is unclear. We examined the relative contributions of smoking, alcohol consumption, high body-mass index, and low physical activity to diagnosis-specific sickness absence. Methods We did a multicohort study with individual-level data of participants of four cohorts from the UK, France, and Finland. Participants' responses to a lifestyle survey were linked to records of sickness absence episodes, typically lasting longer than 9 days; for each diagnostic category, the outcome was the total number of sickness absence days per year. We estimated the associations between lifestyle factors and sickness absence by calculating rate ratios for the number of sickness absence days per year and combining cohort-specific estimates with meta-analysis. The criteria for assessing the evidence included the strength of association, consistency across cohorts, robustness to adjustments and multiple testing, and impact assessment by use of population attributable fractions (PAF), with both internal lifestyle factor prevalence estimates and those obtained from European populations (PAF external). Findings For 74 296 participants, during 446 478 person-years at risk, the most common diagnoses for sickness absence were musculoskeletal diseases (70.9 days per 10 person-years), depressive disorders (26.5 days per 10 person-years), and external causes (such as injuries and poisonings; 12.8 days per 10 person-years). Being overweight (rate ratio [adjusted for age, sex, socioeconomic status, and chronic disease at baseline] 1.30, 95% CI 1.21-1.40; PAF external 8.9%) and low physical activity (1.23, 1.14-1.34; 7.8%) were associated with absences due to musculoskeletal diseases; heavy episodic drinking (1.90, 1.41-2.56; 15.2%), smoking (1.70, 1.42-2.03; 11.8%), low physical activity (1.67, 1.42-1.96; 19.8%), and obesity (1.38, 1.11-1.71; 5.6%) were associated with absences due to depressive disorders; heavy episodic drinking (1.64, 1.33-2.03; 11.3%), obesity (1.48, 1.27-1.72; 6.6%), smoking (1.35, 1.20-1.53; 6.3%), and being overweight (1.20, 1.08-1.33; 6.2%) were associated with absences due to external causes; obesity (1.82, 1.40-2.36; 11.0%) and smoking (1.60, 1.30-1.98; 10.3%) were associated with absences due to circulatory diseases; low physical activity (1.37, 1.25-1.49; 12.0%) and smoking (1.27, 1.16-1.40; 4.9%) were associated with absences due to respiratory diseases; and obesity (1.67, 1.34-2.07; 9.7%) was associated with absences due to digestive diseases. Interpretation Lifestyle factors are associated with sickness absence due to several diseases, but observational data cannot determine the nature of these associations. Future studies should investigate the cost-effectiveness of lifestyle interventions aimed at reducing sickness absence and the use of information on lifestyle for identifying groups at risk.
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