| 1. |
- Cui, Qiao-Yu, et al.
(författare)
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The role of tree composition in Holocene fire history of the hemiboreal and southern boreal zones of southern Sweden, as revealed by the application of the Landscape Reconstruction Algorithm : Implications for biodiversity and climate-change issues
- 2013
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 23:12, s. 1747-1763
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Tidskriftsartikel (refereegranskat)abstract
- We present a quantitative reconstruction of local forest history at two sites, Stavsåkra (hemiboreal zone) and Storasjö (southern boreal zone), in southern Sweden (province of Småland) to evaluate possible causes of contrasting Holocene fire histories in mid- and late Holocene. The Landscape Reconstruction Algorithm (LRA) is applied to evaluate between-site differences in the relative abundance of deciduous trees and Pinus (pine) and landscape/woodland openness during the Holocene. The LRA estimates of local vegetation abundance are compared with other proxies of local vegetation, that is, plant and beetle remains. The LRA results suggest that Pinus was a major tree taxon in the woodlands of Storasjö during mid- and late Holocene, while Tilia(linden) and Betula (birch) were dominant at Stavsåkra. The contrasting fire histories are shown to be strongly related to between-site differences in tree composition during mid-Holocene, 4000–2000 BC in particular. The archaeological/historical and beetle data indicate contrasting land uses from c. 1000BC (late Bronze Age/early Iron Age), grazing in open Calluna heaths at Stavsåkra and woodland grazing at Storasjö. Between-site differences in fire historyduring late Holocene were likely due to different land-use practices. Between-site differences in tree composition in mid-Holocene are best explainedby local climatic and geological/geomorphological differences between the hemiboreal and southern boreal zones of Småland, which might also be the primary cause of between-site differences in land-use histories during late Holocene. Maintenance of biodiversity at the landscape scale in the studyarea requires that existing old pine woodlands and Calluna heath are managed with fire and cattle grazing. Further climate warming might lead to higherprobabilities of climate-induces fire, in particular in pine-dominated woodlands.
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| 2. |
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| 3. |
- Cunningham, Janet L., et al.
(författare)
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Connective tissue growth factor expression in endocrine tumors is associated with high stromal expression of alpha-smooth muscle actin
- 2010
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Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 163:4, s. 691-697
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Complications due to fibrosis development are common in patients with well-differentiated endocrine carcinomas in the small intestine (ileal carcinoids). Connective tissue growth factor (CTGF) expression in ileal carcinoids may be related to this fibrosis development. This study aimed to examine CTGF expression in relation to local myofibroblast differentiation in a large series of ileal carcinoids and in different types of endocrine tumors. METHODS Immunoreactivity (IR) for CTGF and α-smooth muscle actin (α-SMA), a marker for myofibroblasts, was compared in serial tumor tissue sections from 42 patients with ileal carcinoids and from 80 patients with other endocrine tumors. Western blot was performed on an additional 21 patients with ileal carcinoids. RESULTS CTGF IR was present in >50% of tumor cells in all 42 ileal carcinoids and in 2 out of 14 endocrine pancreatic tumors, 4 out of 6 rectal carcinoids, and 1 out of 5 lung carcinoids. Tumors with abundant CTGF expression also displayed α-SMA IR in stromal fibroblast-like cells, whereas other endocrine tumors displayed less or no CTGF and α-SMA IR. Protein bands corresponding to full-length CTGF (36-42 kDa) were detected in protein lysates from ileal carcinoids. CONCLUSION CTGF is uniquely prevalent in ileal carcinoids when compared with most other endocrine tumor types. Immunoreactive cells are adjacent areas with increased fibrovascular stroma that express α-SMA. This supports a potential role for CTGF in myofibroblast-mediated fibrosis associated with ileal carcinoids, and indicates that CTGF should be investigated as a target for future therapy.
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| 4. |
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| 5. |
- Englund, Gunilla, et al.
(författare)
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Efflux transporters in ulcerative colitis : decreased expression of BCRP (ABCG2) and Pgp (ABCB1)
- 2007
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Ingår i: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998 .- 1536-4844. ; 13:3, s. 291-297
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Tidskriftsartikel (refereegranskat)abstract
- Background: Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). Methods: Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1β and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. Results: BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. Conclusions: Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.
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| 6. |
- Göransson, Viktoria, et al.
(författare)
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Renal hyaluronan accumulation and hyaluronan synthase expression after ischaemia-reperfusion injury in the rat.
- 2004
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Ingår i: Nephrol Dial Transplant. - 0931-0509. ; 19:4, s. 823-30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hyaluronan (HA) is a connective tissue component with unique water binding and pro-inflammatory properties. It has been suggested that HA is involved in normal renal water handling but also in several pathological conditions such as organ rejection and ischaemia-reperfusion (IR) injury. METHODS: In anaesthetized normal rats we investigated if renal cortical HA accumulation and the intrarenal distribution and expression of HA synthases (Has 1, 2 and 3) correlate with renal dysfunction after renal IR injury. After 20, 30 or 45 min of unilateral renal ischaemia and 72 h of reperfusion, renal function and cortical HA content were measured. Has 1, 2 and 3 mRNA were determined in control and IR kidneys subjected to 45 min ischaemia and 72 h reperfusion. RESULTS: IR kidneys had reduced urine concentrating ability, potassium excretion, glomerular filtration rate (GFR) and renal blood flow. On average, IR kidneys had more than 10 times higher amounts of cortical HA than the contralateral control kidney and their water content was elevated while medullary HA was largely unaffected. Has 2 expression in the cortex was heavily up-regulated in IR kidneys while Has 3 remained at control levels. Has 1 could never be detected. There was a direct correlation between the amount of cortical HA and the time period of ischaemia and also between the cortical amount of HA and depression of functional parameters. CONCLUSIONS: IR injury depresses parameters of renal function, which coincides with an elevated cortical HA content and Has 2 expression. The enhanced Has 2 expression indicates that the cortical HA accumulation is primarily dependent on increased HA synthesis and not impaired degradation/elimination. The water binding and pro-inflammatory properties of HA may contribute to renal dysfunction after IR.
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| 7. |
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| 8. |
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| 9. |
- Hu, Lijuan, et al.
(författare)
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Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:10, s. e13305-
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Tidskriftsartikel (refereegranskat)abstract
- It has been shown that high vitamin A intake is associated with bone fragility and fractures in both animals and humans. However, the mechanism by which vitamin A affects bones is unclear. In the present study, the direct effects of retinoic acid (RA) on human and murine osteoclastogenesis were evaluated using cultured peripheral blood CD14(+) monocytes and RAW264.7 cells. Both the activity of the osteoclast marker tartrate resistant acid phosphatase (TRAP) in culture supernatant and the expression of the genes involved in osteoclast differentiation together with bone resorption were measured. To our knowledge, this is the first time that the effects of RA on human osteoclast progenitors and mature osteoclasts have been studied in vitro. RA stimulated proliferation of osteoclast progenitors both from humans and mice. In contrast, RA inhibited differentiation of the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis of human and murine osteoclast progenitors via retinoic acid receptors (RARs). We also show that the mRNA levels of receptor activator of nuclear factor κB (RANK), the key initiating factor and osteoclast associated receptor for RANKL, were potently suppressed by RA in osteoclast progenitors. More importantly, RA abolished the RANK protein in osteoclast progenitors. This inhibition could be partially reversed by a RAR pan-antagonist. Furthermore, RA treatment suppressed the expression of the transcription factor nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and increased the expression of interferon regulatory factor-8 (IRF-8) in osteoclast progenitors via RARs. Also, RA demonstrated differential effects depending on the material supporting the cell culture. RA did not affect TRAP activity in the culture supernatant in the bone slice culture system, but inhibited the release of TRAP activity if cells were cultured on plastic. In conclusion, our results suggest that retinoic acid increases proliferation of human osteoclast progenitors and that it inhibits RANK-stimulated osteoclast differentiation by suppressing RANK.
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| 10. |
- Jacobson, Annica, et al.
(författare)
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Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?
- 2004
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Ingår i: BMC Blood Disorders. - : Springer Science and Business Media LLC. - 1471-2326. ; 4:1, s. 5-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained.
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| 11. |
- Jacobson, Annica, et al.
(författare)
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Connective tissue growth factor in tumor pathogenesis
- 2012
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Ingår i: Fibrogenesis & Tissue Repair. - 1755-1536. ; 5:Suppl.1, s. S8-S8
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Tidskriftsartikel (refereegranskat)abstract
- Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood.High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors.
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| 12. |
- Jacobson, Annica, et al.
(författare)
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Expression of hyaluronan synthase 2 or hyaluronidase 1 differentially affect the growth rate of transplantable colon carcinoma cell tumors.
- 2002
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Ingår i: Int J Cancer. - : Wiley. ; 102:3, s. 212-9
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Tidskriftsartikel (refereegranskat)abstract
- Advanced colorectal cancers are often associated with elevated amounts of hyaluronan. To investigate the importance of hyaluronan in colon carcinoma tumor progression, we have expressed by stable transfection hyaluronan synthase 2 (Has2) and hyaluronidase 1 (Hyal1) in the rat colon carcinoma cell line, PROb. We found that hyaluronan overproduction led to a higher growth rate of tumor cells in vitro, and to a faster development of transplantable tumors in syngeneic rats, compared to the mock-transfectants. Has2 transfected PROb cells gave rise to tumors that were significantly less vascularized, but had a significantly larger viable tumor fraction compared to tumors generated from mock-transfectants. In contrast, Hyal1 overexpression suppressed the growth rate of tumor cells both in vitro and in vivo. Moreover, tumors derived from Hyal1-transfected cells had a significantly larger necrotic area than tumors derived from mock- and Has2-transfectants. Our study demonstrates that Has2 overproduction promotes tumorigenicity, whereas Hyal1 overexpression suppresses tumorigenicity in an experimental model for colon carcinoma.
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| 13. |
- Jacobson, Annica, et al.
(författare)
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Hyaluronan content in experimental carcinoma is not correlated to interstitial fluid pressure.
- 2003
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Ingår i: Biochem. Biophys. Res. Commun.. ; 305, s. 1017-1023
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Tidskriftsartikel (refereegranskat)abstract
- Mechanism(s) for generation of the high tumor interstitial fluid pressure (TIFP) that is characteristic of carcinoma is not known. We investigated the role of hyaluronan, the major water-binding polysaccharide of the extracellular matrix, for the generation of a high TIFP. A human anaplastic thyroid carcinoma (KAT-4) xenografted to athymic mice and a syngeneic rat colon carcinoma (PROb) were used. Neither KAT-4 nor PROb cells produced hyaluronan (HA) in culture, however, both cell lines produced factors that stimulated HA-synthesis by cultured fibroblasts. Modulating hyaluronan levels by transfection of PROb carcinoma cells with hyaluronan synthase-2 revealed no correlation between hyaluronan content and TIFP. Furthermore, lowering of TIFP by treating KAT-4 tumors with a specific inhibitor of TGF-beta 1 and -beta 3 did not change the concentration of hyaluronan in the tumors. In summary, our results suggest that a modulation of hyaluronan content is not a major pathogenetic mechanism for the generation of the characteristically high TIFP in malignant carcinomas.
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| 14. |
- Jacobson, Annica, 1974-
(författare)
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Regulation of hyaluronan biosynthesis : Expression in vitro and importance for tumor progression
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyaluronan, a component of the extracellular matrix, is synthesized by either of three hyaluronan-synthesizing enzymes termed Has1, Has2 and Has3. The expression level of each Has gene varies between cell types of mesenchymal origin and is differentially regulated in response to external stimuli. For example, stimulation of mesothelial cells with PDGF-BB induced an up-regulation of the Has2 gene, whereas the Has1 and Has3 genes remained unaffected. The induction of Has2 gene expression correlated well with increased Has2 protein levels and accumulation of hyaluronan. Moreover, treatment of mesothelial cells with hydrocortisone suppressed hyaluronan synthesis in cell culture primarily through down-regulation of the Has2 gene. Thus, among the Has isoforms, Has2 seems to be most markedly regulated in response to external stimuli.In an attempt to investigate the importance of hyaluronan in tumor progression, the hyaluronan synthesizing enzyme Has2 and the hyaluronan degrading enzyme Hyal1 were over-expressed in a rat colon adenocarcinoma cell line, PROb. We found that Has2 gene over-expression in colon carcinoma cells promoted cell growth in vitro and progression of transplantable tumors. In contrast, over-expression of Hyal1 lead to a considerable reduction of growth rates both in vivo and in vitro. A linear correlation between tumor growth rate and hyaluronan amount in tumor tissue was observed. In another tumor model, experimental anaplastic thyroid carcinoma, the effects of TGF-β inhibition on hyaluronan and collagen contents in tumor xenografts were investigated. We found that inhibition of TGF-β, a stimulator of hyaluronan and collagen synthesis, lead to reduced collagen deposition whereas the hyaluronan levels in stromal tissue only marginally differed. Our results indicate that a high ratio of collagen to hyaluronan may be characteristic of a pathogenic mechanism that leads to elevated interstitual tumor pressure.
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| 15. |
- Jacobson, Annica, et al.
(författare)
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Vitamin A differentiall regulates RANKL and OPG expression in human osteoblasts
- 2004
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 322:1, s. 162-167
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Tidskriftsartikel (refereegranskat)abstract
- All-trans-retinoic acid (ATRA) induces bone resorption, but the molecular mechanisms are unknown. We have studied the effect of ATRA on osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) expression in human MG-63 osteosarcoma cells and primary osteoblast-like cultures. ATRA dose-dependently down-regulated protein levels of OPG in MG-63 cells, with a maximum (-56%) observed at a dose of 10(-6)M. This effect was confirmed with quantitative real-time PCR, where OPG mRNA was decreased after 4h (-68%) in primary cultures and after 8h (-87%) in MG-63 cells. The reduction in OPG expression was inhibited by a retinoic acid receptor (RAR)-antagonist and was mimicked by a RARbeta,gamma-agonist, indicating that the ATRA effect is mediated by these receptors. In primary cultures we found a threefold induction of RANKL mRNA expression. Thus, the RANKL/OPG ratio was markedly increased, suggesting a potential mechanism of ATRA-induced bone resorption.
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| 16. |
- Khoschnau, Shwan, et al.
(författare)
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Type I collagen alpha1 Sp1 polymorphism and the risk of cruciate ligament ruptures or shoulder dislocations
- 2008
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Ingår i: American Journal of Sports Medicine. - : SAGE Publications. - 0363-5465 .- 1552-3365. ; 36:12, s. 2432-2436
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cruciate ligament ruptures and shoulder dislocations are often caused by trauma, but predisposing intrinsic factors might also influence the risk. These injuries are more common in those with a previously injured sibling, an observation that might indicate a genetic predisposition. It is well known that polymorphisms in the collagen I gene are associated not only with osteoporosis and osteoporotic fracture risk, but also with osteoarthritis. HYPOTHESIS: Because collagen I is abundant in ligaments and tendons, the authors hypothesized that collagen I alpha1 Sp1 polymorphism also was related to the occurrence of cruciate ligament ruptures and shoulder dislocations. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 358 patients and 325 randomly selected population-based female controls were included in the study. Of the cases, 233 had a cruciate ligament rupture and 126 had had a shoulder dislocation. Age-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) estimated by unconditional logistic regression were used as measures of association. RESULTS: Compared with the homozygous SS category, the heterozygous participants displayed a similar risk (OR, 1.06; 95% CI, 0.76-1.49), whereas the ss genotype was underrepresented in the injured population compared with the controls (OR, 0.15; 95% CI, 0.03-0.68). This latter estimate was similar for both cruciate ligament ruptures and shoulder dislocations, and was furthermore not modified by general joint laxity. CONCLUSION: The authors found a substantially decreased risk of these injuries associated with collagen type I alpha1 Sp1 polymorphism. The study might encourage other investigators to consider further research in the area of genes and soft tissue injuries.
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| 17. |
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| 18. |
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| 19. |
- Lind, Thomas, et al.
(författare)
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High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats
- 2011
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 48:3, s. 496-506
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A (retinol) is the only molecule known to induce spontaneous fractures in laboratory animals and we have identified retinol as a risk factor for fracture in humans. Since subsequent observational studies in humans and old animal data both show that high retinol intake appears to only have small effects on bone mineral density (BMD) we undertook a mechanistic study of how excess retinol reduces bone diameter while leaving BMD essentially unaffected. We fed growing rats high doses of retinol for only 1week. Bone analysis involved antibody-based methods, histology, pQCT, biomechanics and bone compartment-specific PCR together with Fourier Transform Infrared Spectroscopy of bone mineral. Excess dietary retinol induced weakening of bones with little apparent effect on BMD. Periosteal osteoclasts increased but unexpectedly endosteal osteoclasts disappeared and there was a reduction of osteoclastic serum markers. There was also a lack of capillary erythrocytes, endothelial cells and serum retinol transport protein in the endosteal/marrow compartment. A further indication of reduced endosteal/marrow blood flow was the increased expression of hypoxia-associated genes. Also, in contrast to the inhibitory effects in vitro, the marrow of retinol-treated rats showed increased expression of osteogenic genes. Finally, we show that hypervitaminotic bones have a higher degree of mineralization, which is in line with biomechanical data of preserved stiffness in spite of thinner bones. Together these novel findings suggest that a rapid primary effect of excess retinol on bone tissue is the impairment of endosteal/marrow blood flow leading to hypoxia and pathological endosteal mineralization.
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| 20. |
- Lind, Thomas, et al.
(författare)
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Microarray Profiling of Diaphyseal Bone of Rats Suffering from Hypervitaminosis A
- 2012
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Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 90:3, s. 219-229
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone-specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures.
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| 21. |
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| 22. |
- Michaëlsson, Karl, 1959-, et al.
(författare)
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The Free Hormone Hypothesis : Is Free Serum 25-Hydroxyvitamin D a Better Marker for Bone Mineral Density in Older Women?
- 2018
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Ingår i: JBMR plus. - : Wiley. - 2473-4039. ; 2:6, s. 367-374
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Tidskriftsartikel (refereegranskat)abstract
- It is presently unclear whether free serum 25-hydroxyvitamin D (S-25(OH)D) better reflects bone health than total S-25(OH)D. We have previously shown that summer total S-25(OH)D values are more useful to predict bone mineral density (BMD) than winter values. Our objective was therefore to compare the relative importance of free and total S-25(OH)D for BMD by season. BMD was measured by dual-energy X-ray absorptiometry (DXA) in 5002 Swedish women (mean age 68 years) randomly selected from a large population-based longitudinal cohort study. Free S-25(OH)D was analyzed by a commercial ELISA and total S-25(OH)D by HPLC-tandem mass spectrometry (MS/MS). Free and total S-25(OH)D co-varied with season, with 26% and 29% higher values in August compared with those in January-March (nadir). There were no differences in mean BMD between categories of free or total S-25(OH)D in samples collected during winter. Women with higher total S-25(OH)D measured during summer had higher BMD at the total hip. Compared with women who had total S-25(OH)D values above 80 nmol/L during summer, adjusted BMD at the total hip was 6% (95% CI, 1% to 11%) lower for S-25(OH)D concentrations between 30 and 40 mmol/L, and 11% (95% CI, 3% to 19%) lower for those with total S-25(OH)D <30 nmol/L. In contrast, free S-25(OH)D measured during summer was not associated with BMD. Compared with women who had highest free S-25(OH)D measured during summer (>8.8 pmol/L), those with intermediate (2.4-3.5 pmol/L) and lowest (<2.4 pmol/L) free S-25(OH)D during summer did not have lower total hip BMD values (3% [95% CI, -2% to 7%] and -2% [95% CI, -8% to 4%]). In addition, we found no added value for the prediction of BMD with the combined measurement of total and free S-25(OH)D during summer or winter. We conclude that vitamin D status assessed by direct measurements of free S-25(OH)D does not reflect BMD better than total S-25(OH)D. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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| 23. |
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| 24. |
- Montazerolghaem, Maryam, 1985-, et al.
(författare)
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Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption
- 2016
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Ingår i: Journal of materials science. Materials in medicine. - : Springer Science and Business Media LLC. - 0957-4530 .- 1573-4838. ; 27:5
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Tidskriftsartikel (refereegranskat)abstract
- Simvastatin, a cholesterol lowering drug, has been shown to have positive effects on fracture healing and bone regeneration based on its dual effect; bone anabolic and anti-resorptive. In this study the focus has been on the anti-resorptive effect of the drug and its impact on the degradation of acidic calcium phosphate cement. The drug was added to the pre-mixed acidic cement in three different doses (0.1, 0.25 and 0.5 mg/g cement) and the release was measured. Furthermore the effect of the loaded cements on osteoclast differentiation and resorption was evaluated by TRAP activity, number of multinucleated cells, gene expression and calcium ion concentration in vitro using murine bone marrow macrophages. The simvastatin did not affect the cell proliferation while it clearly inhibited osteoclastic differentiation at all three doses as shown by TRAP staining, TRAP activity and gene expression. Consistent with these results, simvastatin also impaired resorption of cements by osteoclasts as indicated by reduced calcium ion concentrations. In conclusion, our findings suggest that simvastatin-doped pre-mixed acidic calcium phosphate cement inhibits the osteoclastic mediated resorption of the cement thus slowing down the degradation rate. In addition with simvastatin's bone anabolic effect it makes the cement-drug combination a promising bone graft material, especially useful for sites with compromised bone formation.
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| 25. |
- Shankaranarayanan, Pattabhiraman, et al.
(författare)
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Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic death pathway by NO.
- 2009
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 16:3, s. 220-31
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Tidskriftsartikel (refereegranskat)abstract
- Growth factor (GF) deprivation and/or blocking of cognate signaling can induce apoptosis and is the basis of several cancer treatment paradigms. We observed that RXR agonists (rexinoids) induce apoptosis of tumor cells when GF support is abrogated. This "rexinoid apoptosis" involves activation of both iNOS and eNOS by RXR-PPARgamma and results in production of apoptogenic NO. IGF/EGF-induced IGF receptor 1-mediated MAP kinase blocks rexinoid apoptosis by RXR phosphorylation. Combining rexinoids with the MAPK inhibitor U0126 induced apoptosis in human cancer cells in vitro and ex vivo and blocked xenograft growth in vivo. Our results suggest a regulatory mechanism in which GF signaling antagonizes RXR-PPARgamma-mediated default apoptosis to sustain cell life.
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| 26. |
- Sundberg, Isak, et al.
(författare)
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Daytime melatonin levels in saliva are associated with inflammatory markers and anxiety disorders
- 2020
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 0306-4530 .- 1873-3360. ; 112
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The bidirectional interaction between melatonin and the immune system has largely gone unexplored in a clinical context and especially in a psychiatric population. This study explored the association between melatonin during the day and inflammatory cytokines in young adult patients seeking psychiatric care.METHODS: Samples and data were collected from 108 young adults (mean age 21, SD = 2) at an outpatient clinic for affective disorders. Daytime saliva melatonin levels were analyzed with enzyme-linked immunosorbent assay (ELISA) in relation to normalized serum expression levels of 72 inflammatory markers in a proximity extension assay (PEA). In a post hoc analysis the markers associated with melatonin were tested in a generalized linear model to see whether there is a relationship to anxiety disorder or depression.RESULTS: After Bonferroni correction for multiple testing, melatonin levels at 11:00 were positively correlated with CD5 (p = 4.2e-4). Melatonin levels after lunch were correlated with CCL2/MCP-1 (p = 4.2e-4), CCL3/MPI-1α (p = 6.5e-4) and VEGF-A (p = 5.3e-6). In the generalized linear model, positive associations were found for the presence of any anxiety disorder with melatonin after lunch (p = 0.046), VEGF-A (p = 0.001) and CCL3/MPI-1α (p = 0.001).CONCLUSION: Daytime saliva levels of melatonin were related to several inflammatory markers in young adults with psychiatric disorders. This observation likely reflects the bidirectional relationship between melatonin production and the immune system. These findings may have relevance for the understanding of psychiatric disorders and other conditions associated with low-grade inflammation.
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| 27. |
- Söderquist, Fanny, 1985-, et al.
(författare)
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Gastrointestinal symptoms, depression and trait anxiety in young adults seeking psychiatric care
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and aim: Patients with functional gastrointestinal (GI) disorders have a high psychiatric co-morbidity, especially for mood and anxiety disorders. This study aimed to investigate and characterise GI symptoms in relation to depressive symptoms and trait anxiety in a well-defined population of young adult outpatients seeking psychiatric care.Material and methods: Patients, aged 18-25 years from the Uppsala Psychiatric Patient Samples (UPP) cohort seeking psychiatric care for primarily mood and anxiety disorders (n=491) were compared with healthy controls (n=85) for GI symptoms (measured using the Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome, GSRS-IBS and depressive symptoms (measured using the Montgomery-Åsberg Depression Rating Scale – Self-Assessment, MADRS-S. Personality traits were assessed using the Swedish Universities Scales of Personality (SSP), in which three anxiety-related personality traits (stress susceptibility, psychic trait anxiety somatic trait anxiety) were assessed.Results: Patients, both on psychotropic medication and those not currently on psychotropic medication reported more GI symptoms than controls (median 30 vs. 22, p<0.001). GI symptom burden was higher in women than men (median 32 vs. 28, p<0.001). A principal component analysis produced a six-factor structure explaining 63% of the total variance in the data set. A cluster analysis was performed that allowed the identification of six cluster groups, characterised by the varying levels of these factors. The total GSRS-IBS score significantly correlated with depressive symptom severity (r=0.391, p<0.001), a relationship that remained after adjusting for possible confounders (sex, body mass index, bulimia). The total GSRS-IBS score correlated with the three SSP subscales: somatic trait anxiety (r=0.313, p<0.001), psychic trait anxiety (r=0.147, p=0.001) and stress susceptibility (r=0.233, p<0.001).Conclusion: GI symptoms are highly prevalent in young adult psychiatric outpatients compared with controls, regardless of whether the patient is currently on psychotropic medication or not. Depressive symptom severity and degree of trait anxiety are independently related to the total IBS symptoms score.
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| 28. |
- Söderquist, Fanny
(författare)
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Melatonin in the gastrointestinal tract
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Melatonin is recognised as the pineal hormone regulating sleep and circadian rhythm. It has also been identified in peripheral tissues (mainly in animals) and thought to display a variety of actions, including anti-inflammatory properties, regulation of gastrointestinal (GI) functions, glucose homeostasis and beneficial effects in different tumour types. Patients with irritable bowel disorder commonly exhibit psychiatric co-morbidity and disturbances of the gut-brain axis have been proposed to play a role in these disorders. The focus of this thesis was to study melatonin and melatonin receptors in the normal human GI tract, the pancreas and small intestinal neuroendocrine tumours. The thesis also explores the complex relationship between GI symptoms and underlying psychiatric traits in the context of elevated levels of peripheral melatonin during waking hours.In paper I-II, tissue samples from the normal human GI tract and pancreas and tumour tissue from small intestinal neuroendocrine tumours were analysed for expression of melatonin and melatonin receptors using immunohistochemistry. For tumour patients, melatonin was also analysed in plasma and set in relation to symptoms and outcome. In paper III-IV, a cohort of young adults (18-25 years) seeking psychiatric care was examined for GI symptoms, melatonin levels in saliva, depressive symptoms and anxiety traits. Psychiatric assessments were performed using structured or semi structured interviews. Depressive symptoms were measured using the self-rating version of the Montgomery-Åsberg Depression Rating Scale; GI symptoms were measured using the Gastrointestinal Symptoms Rating Scale for Irritable Bowel Syndrome; and personality traits were evaluated using the Swedish Universities Scales of Personality.Melatonin and melatonin receptors were widely expressed in the normal human gut and pancreas (paper I) but even in small intestinal neuroendocrine tumours known to produce serotonin (paper II). The intensity of the melatonin immunoreactivity in tumour tissue was found to correlate with lower proliferation index. After treatment, plasma levels of melatonin were reduced in tumour patients. Young adult patients seeking psychiatric care reported more GI symptoms than healthy controls, regardless of the currently active psychotropic medication. The level of GI symptoms was associated with severity of depressive symptoms and trait anxiety (paper III). Higher postprandial levels of melatonin were associated with the GI symptoms of bloating and pain (paper IV).In summary, these findings demonstrate the widespread presence of melatonin in the human gut and confirm a link between melatonin, psychiatric health and GI symptoms.
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