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- Khan, Omar M., 1980, et al.
(författare)
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Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice.
- 2011
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Ingår i: The Journal of clinical investigation. - 1558-8238. ; 121:2, s. 628-39
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Tidskriftsartikel (refereegranskat)abstract
- RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.
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| 4. |
- Eliassen, A Heather, et al.
(författare)
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Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.
- 2012
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 104:24, s. 1905-16
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Tidskriftsartikel (refereegranskat)abstract
- Background Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. Methods We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Results Statistically significant inverse associations with breast cancer were observed for α-carotene (top vs bottom quintile RR = 0.87, 95% CI = 0.71 to 1.05, Ptrend = .04), β-carotene (RR = 0.83, 95% CI = 0.70 to 0.98, Ptrend = .02), lutein+zeaxanthin (RR = 0.84, 95% CI = 0.70 to 1.01, Ptrend = .05), lycopene (RR = 0.78, 95% CI = 0.62 to 0.99, Ptrend = .02), and total carotenoids (RR = 0.81, 95% CI = 0.68 to 0.96, Ptrend = .01). β-Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER(-)) than for ER(+) tumors (eg, β-carotene: ER(-): top vs bottom quintile RR = 0.52, 95% CI = 0.36 to 0.77, Ptrend = .001; ER(+): RR = 0.83, 95% CI = 0.66 to 1.04, Ptrend = .06; Pheterogeneity = .01). Conclusions This comprehensive prospective analysis suggests women with higher circulating levels of α-carotene, β-carotene, lutein+zeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer.
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| 6. |
- Hultén, Leif, et al.
(författare)
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Sacral nerve stimulation (SNS), posterior tibial nerve stimulation (PTNS) or acupuncture for the treatment for fecal incontinence : a clinical commentary
- 2013
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Ingår i: Techniques in Coloproctology. - Milan, Italy : Springer Milan. - 1123-6337 .- 1128-045X. ; 17:5, s. 589-592
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Tidskriftsartikel (refereegranskat)abstract
- Sacral nerve stimulation (SNS) has become an established therapy worldwide for the treatment for fecal incontinence. A large number of papers have been published over the years, and SNS is generally considered very effective with improved continence and quality of life for most patients. However, the results are mostly expressed in the semi-quantitative terms, that is, patients' diaries translated into score points. The clinical value of SNS is questionable, especially as the patient groups are usually small and/or etiologically heterogenic and the follow-up period mostly short. The Health Technology Assessment organization in the west region of Sweden has recently evaluated the SNS with regard to evidence, efficacy and risks. Economic and ethical aspects raise serious questions on this expensive and not entirely risk-free treatment in routine medical care. Similar criticism has also been raised by other reviewers proposing a more thorough scientific assessment with well-designed randomized trials and comparison with other similar methods of treatment.
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| 7. |
- Hulten, M A., et al.
(författare)
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Trisomy 21 Mosaicism: We May All Have a Touch of Down Syndrome
- 2013
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Ingår i: Cytogenetic and Genome Research. - : Karger. - 1424-8581 .- 1424-859X. ; 139:3, s. 189-192
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Tidskriftsartikel (refereegranskat)abstract
- Ever increasing sophistication in the application of new analytical technology has revealed that our genomes are much more fluid than was contemplated only a few years ago. More specifically, this concerns interindividual variation in copy number (CNV) of structural chromosome aberrations, i.e. microdeletions and microduplications. It is important to recognize that in this context, we still lack basic knowledge on the impact of the CNV in normal cells from individual tissues, including that of whole chromosomes (aneuploidy). Here, we highlight this challenge by the example of the very first chromosome aberration identified in the human genome, i.e. an extra chromosome 21 (trisomy 21, T21), which is causative of Down syndrome (DS). We consider it likely that most, if not all, of us are T21 mosaics, i.e. everyone carries some cells with an extra chromosome 21, in some tissues. In other words, we may all have a touch of DS. We further propose that the occurrence of such tissue-specific T21 mosaicism may have important ramifications for the understanding of the pathogenesis, prognosis and treatment of medical problems shared between people with DS and those in the general non-DS population.
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- van der Pals, J., et al.
(författare)
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Hypothermia in cardiogenic shock reduces systemic t-PA release
- 2011
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 0929-5305 .- 1573-742X. ; 32:1, s. 72-81
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic hypothermia has been found to improve hemodynamic and metabolic parameters in cardiogenic shock. Tissue plasminogen activator (t-PA) is a pro-thrombolytic enzyme, which also possesses pro-inflammatory properties. Interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) are pro-inflammatory cytokines; interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-beta1) are anti-inflammatory cytokines. The aim of this experiment was to investigate the mechanism behind the protective effect of therapeutic hypothermia in cardiogenic shock. This was done by studying the effect of hypothermia on basal t-PA levels, peripheral t-PA release, and on the inflammatory response. Cardiogenic shock was induced by inflation of an angioplasty balloon in the proximal left anterior descending artery for 40 min in 16 pigs, followed by 110 min of reperfusion. The animals were randomized to hypothermia (33 degrees C, n = 8), or normothermia (n = 8) at reperfusion. Hemodynamic parameters were continuously monitored. Plasma was sampled every 30 min for analysis of blood-gases and t-PA, and for analysis of inflammatory markers at baseline and at the end of the experiment. t-PA, IL-6 and TGF-beta1 increased during cardiogenic shock. Apart from favourably affecting hemodynamic and metabolic variables, hypothermia was found to reduce basal arterial and venous t-PA levels, and to inhibit the release of t-PA from the peripheral vascular bed. Hypothermia did not alter the inflammatory response. In conclusion, mild hypothermia improves hemodynamic and metabolic parameters in cardiogenic shock. This is associated with a reduction in basal t-PA levels and t-PA release from the peripheral vascular bed, but not with an altered inflammatory response.
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