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- Mobini Far, Hamid Reza, et al.
(author)
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Administration of the anabolic androgenic steroid nandrolone decanoate to female rats causes alterations in the morphology of their uterus and a reduction in reproductive capacity
- 2007
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In: European Journal of Obstetrics, Gynecology, and Reproductive Biology. - : Elsevier BV. - 0301-2115 .- 1872-7654. ; 131:2, s. 189-197
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of the present investigation was to characterize the effects of supraphysiological doses of the anabolic androgenic steroid nandrolone decanoate (ND) on the fertility of female rats, as well as on the morphology of their uterus. STUDY DESIGN: Female Wistar rats (n=15) received a subcutaneous injection of ND (15 mg/kg) once daily during a 2-week period, while the control animals (n=10) were administered vehicle alone (arachidis oleum) in the same manner. Estrus behavior was evaluated 4 weeks after termination of this treatment and in cases where signs of receptivity were present, the female rat was given the opportunity to copulate with a male. After breeding, the female animals were sacrificed and their uteri examined histomorphologically. RESULTS: All ND-treated animals exhibited abnormal vaginal smears, whereas all of the control smears were normal. Most (73%) of the treated females demonstrated normal estrus behavior (i.e., willingness) on the day of mating, but none got pregnant; whereas all of the control rats became pregnant. The female rats receiving the ND showed an enhanced rate of weight gain and the myometrium thickness of their uteri was significantly increased, while the endometrium was significantly thinner. Furthermore, ND caused a significant proportion of the treated animals to display tortuous and irregularly branching endometrial glands, as well as a lack of the physiologically normal infiltration of eosinophilic leukocytes into the endometrium (endometrial eosinophilic homing), a finding that has not been reported previously. CONCLUSION: The present findings indicate that high doses of ND cause morphological and physiological alterations in the uterus of female rats that are associated with a suppression of their reproductive capacity.
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| 2. |
- Andersson, Bert, 1952, et al.
(author)
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Longitudinal myocardial contraction improves early during titration with metoprolol CR/XL in patients with heart failure.
- 2002
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In: Heart (British Cardiac Society). - 1468-201X. ; 87:1, s. 23-8
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Journal article (peer-reviewed)abstract
- To investigate diastolic and systolic left ventricular recovery during titration with metoprolol CR/XL (controlled release/extended release).Placebo run in, followed by an open study.University hospital.14 patients with chronic heart failure.Metoprolol CR/XL titrated from 12.5 mg once daily to 200 mg once daily.M mode recordings of atrioventricular (AV) plane displacement, Doppler measurement of transmitral flow and pulmonary venous flow, two dimensional ejection fraction, and measurement of venous plasma concentration of noradrenaline. Patients were investigated after 2, 4, 6, and 24 weeks of treatment.A reduction of heart rate was observed on the first dose (12.5 mg once daily), from a mean (SD) of 74 (11) to 67 (11) beats/min, p < 0.05. This was accompanied by prominent effects on AV plane filling parameters, including an increase in early diastolic filling period from 87 (28) to 105 (33) ms (p < 0.05), and in the lateral AV plane fractional shortening from 8.7 (2.7)% to 10.2 (2.8)% (p < 0.05). An early trend towards improvement in global systolic left ventricular function was also seen, although this was not significant until six weeks. Ejection fraction increased from 33 (7.5)% to 38 (11)% (p < 0.05).First effects of left ventricular recovery during beta blocker treatment were seen in recordings of longitudinal performance, as expressed by AV plane displacement. Doppler flow dynamics as well as global systolic recovery appeared several weeks later, emphasising the importance of longitudinal performance in evaluating left ventricular function.
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| 3. |
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| 4. |
- Barrenäs, Fredrik, 1981, et al.
(author)
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Network properties of complex human disease genes identified through genome-wide association studies.
- 2009
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In: PloS one. - San Francisco, CA San Francisco, CA, United StatesUnited States : Public Library of Science (PLoS). - 1932-6203. ; 4:11
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Journal article (peer-reviewed)abstract
- BACKGROUND: Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias. PRINCIPAL FINDINGS: We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process. CONCLUSIONS: This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.
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| 5. |
- Benson, Mikael, 1954, et al.
(author)
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A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis.
- 2009
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In: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 64:9, s. 1286-91
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Journal article (peer-reviewed)abstract
- BACKGROUND: Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway. OBJECTIVE: To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR. METHODS: CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. RESULTS: Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls. CONCLUSION: Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR.
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| 6. |
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| 7. |
- Benson, Mikael, et al.
(author)
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Systembiologin kan förändra sjukvården radikalt. Ger underlag för individualiserad prediktion, prevention och behandling : [Systems biology can radically change health care. Basis for individualized prediction, prevention and treatment]
- 2007
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In: Läkartidningen. - : Läkartidningen. - 0023-7205 .- 1652-7518. ; 104:42, s. 3037-3041
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Journal article (peer-reviewed)abstract
- Vanliga sjukdomar som allergi, diabetes och cancer är komplexa, dvs de beror på obalans mellan ett stort antal gener och miljöfaktorer, snarare än på enskilda »felande« gener. Det finns teknik för att samtidigt analysera mRNA- och proteinuttryck för alla människans gener. Detta har resulterat i väldiga datamängder, som kan bidra till att öka förståelsen av komplexa sjukdomar. Problemet är att strukturera och tolka informationen.Systembiologi syftar till att konstruera ett teoretiskt ramverk för att beskriva hur molekylära signalvägar och nätverk, snarare än enskilda molekyler, orsakar sjukdom. Detta har börjat ge kliniska resultat, tex individualiserad medicinering vid behandling av cancer.Inom de närmsta decennierna förutspås systembiologisk forskning få klinisk betydelse, inte bara för att individualisera behandling, utan även för att förutsäga eller förebygga sjukdomar. Läkemedelsindustrin gör också stora systembiologiska satsningar för att utveckla nya mediciner.Det är därför angeläget att svenska kliniker, forskare och beslutsfattare snarast tar ställning till hur klinisk systembiologisk forskning ska bedrivas i Sverige.I denna artikel ges en introduktion till nya tekniker för att samtidigt studera människans alla gener. Dessutom beskrivs systembiologiska principer för att tolka resultaten och vilka kliniska konsekvenser detta kan få.
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| 8. |
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| 9. |
- Bruhn, Sören, et al.
(author)
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Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis
- 2012
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In: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley and Sons. - 0105-4538 .- 1398-9995. ; 67:1, s. 33-40
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Journal article (peer-reviewed)abstract
- Background: The transcription factor (TF) IRF4 is involved in the regulation of Th1, Th2, Th9, and Th17 cells, and animal studies have indicated an important role in allergy. However, IRF4 and its target genes have not been examined in human allergy. Methods: IRF4 and its target genes were examined in allergen-challenged CD4+ cells from patients with IAR, using combined gene expression microarrays and chromatin immunoprecipitation chips (ChIP-chips), computational target prediction, and RNAi knockdowns. Results: IRF4 increased in allergen-challenged CD4+ cells from patients with IAR, and functional studies supported its role in Th2 cell activation. IRF4 ChIP-chip showed that IRF4 regulated a large number of genes relevant to Th cell differentiation. However, neither Th1 nor Th2 cytokines were the direct targets of IRF4. To examine whether IRF4 induced Th2 cytokines via one or more downstream TFs, we combined gene expression microarrays, ChIP-chips, and computational target prediction and found a putative intermediary TF, namely ETS1 in allergen-challenged CD4+ cells from allergic patients. ETS1 increased significantly in allergen-challenged CD4+ cells from patients compared to controls. Gene expression microarrays before and after ETS1 RNAi knockdown showed that ETS1 induced Th2 cytokines as well as disease-related pathways. Conclusions: Increased expression of IRF4 in allergen-challenged CD4+ cells from patients with intermittent allergic rhinitis leads to activation of a complex transcriptional program, including Th2 cytokines.
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| 10. |
- Chaudhari, Aditi, et al.
(author)
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ARAP2 promotes GLUT1-mediated basal glucose uptake through regulation of sphingolipid metabolism
- 2016
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In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1861:11, s. 1643-1651
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Journal article (peer-reviewed)abstract
- Lipid droplet formation, which is driven by triglyceride synthesis, requires several droplet-associated proteins. We identified ARAP2 (an ADP-ribosylation factor 6 GTPase-activating protein) in the lipid droplet proteome of NIH-3T3 cells and showed that knockdown of ARAP2 resulted in decreased lipid droplet formation and triglyceride synthesis. We also showed that ARAP2 knockdown did not affect fatty acid uptake but reduced basal glucose uptake, total levels of the glucose transporter GLUT1, and GLUT1 levels in the plasma membrane and the lipid micro-domain fraction (a specialized plasma membrane domain enriched in sphingolipids). Microarray analysis showed that ARAP2 knockdown altered expression of genes involved in sphingolipid metabolism. Because sphingolipids are known to play a key role in cell signaling, we performed lipidomics to further investigate the relationship between ARAP2 and sphingolipids and potentially identify a link with glucose uptake. We found that ARAP2 knockdown increased glucosylceramide and lactosylceramide levels without affecting ceramide levels, and thus speculated that the rate-limiting enzyme in glycosphingolipid synthesis, namely glucosylceramide synthase (GCS), could be modified by ARAP2. In agreement with our hypothesis, we showed that the activity of GCS was increased by ARAP2 knockdown and reduced by ARAP2 overexpression. Furthermore, pharmacological inhibition of GCS resulted in increases in basal glucose uptake, total GLUT1 levels, triglyceride biosynthesis from glucose, and lipid droplet formation, indicating that the effects of GCS inhibition are the opposite to those resulting from ARAP2 knockdown. Taken together, our data suggest that ARAP2 promotes lipid droplet formation by modifying sphingolipid metabolism through GCS.
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