| 1. |
- Borggren, Marie, et al.
(författare)
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Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-I variants emerging during AIDS progression
- 2008
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Ingår i: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 5:28
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Tidskriftsartikel (refereegranskat)abstract
- Background: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. Results: Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DCSIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the transinfection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. Conclusion: Results of our study suggest R5 virus variants with diverse fitness for direct and DCSIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses.
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| 2. |
- Cornelissen, Johannes H C, et al.
(författare)
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Global negative vegetation feedback to climate warming responses of leaf litter decomposition rates in cold biomes
- 2007
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 10:7, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- Whether climate change will turn cold biomes from large long-term carbon sinks into sources is hotly debated because of the great potential for ecosystem-mediated feedbacks to global climate. Critical are the direction, magnitude and generality of climate responses of plant litter decomposition. Here, we present the first quantitative analysis of the major climate-change-related drivers of litter decomposition rates in cold northern biomes worldwide.Leaf litters collected from the predominant species in 33 global change manipulation experiments in circum-arctic-alpine ecosystems were incubated simultaneously in two contrasting arctic life zones. We demonstrate that longer-term, large-scale changes to leaf litter decomposition will be driven primarily by both direct warming effects and concomitant shifts in plant growth form composition, with a much smaller role for changes in litter quality within species. Specifically, the ongoing warming-induced expansion of shrubs with recalcitrant leaf litter across cold biomes would constitute a negative feedback to global warming. Depending on the strength of other (previously reported) positive feedbacks of shrub expansion on soil carbon turnover, this may partly counteract direct warming enhancement of litter decomposition.
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| 5. |
- Engström, Björn E., et al.
(författare)
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Meal suppression of circulating ghrelin is normalized in obese individuals following gastric bypass surgery
- 2007
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 31:3, s. 476-480
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: It has been proposed that the success of maintained weight loss in morbidly obese subjects following Roux-en-Y gastric bypass (RYGBP) surgery depends on inappropriately low circulating concentrations of the appetite-stimulating peptide ghrelin, being unresponsive to food intake. In this study, this hypothesis was examined. DESIGN: Cross-sectional study with repeated blood samples in 40 subjects after 14 h of prolonged overnight fasting followed by a standardized mixed meal (770 kcal). SUBJECTS: Twenty men and 20 women were included: 10 middle-aged morbidly obese (body mass index (BMI) 43.9+/-3.3 kg/m(2)), 10 middle-aged subjects who had undergone RYGBP at the Uppsala University Hospital (BMI 34.7+/-5.8 kg/m(2)), 10 middle-aged non-obese (BMI 23.5+/-2.2 kg/m(2)) and 10 young non-obese (BMI 22.7+/-1.8 kg/m(2)). MEASUREMENTS: Ghrelin, glucose and insulin levels were analysed pre- and postprandially. RESULTS: In the morbidly obese, ghrelin concentrations were lower in the morning than in the RYGBP group and did not change following the meal. In the RYGBP group, fasting ghrelin levels fell after meal intake and showed similar suppression as both age-matched and young non-obese controls. The RYGBP surgery resulted in an increased meal-induced insulin secretion, which was related to the degree of postprandial ghrelin suppression. CONCLUSION: The present study demonstrates low circulating concentrations of ghrelin and blunted responses to fast and feeding in morbidly obese subjects. Marked weight reduction after RYGBP at our hospital is followed by a normalization of ghrelin secretion, illustrated by increased fasting levels compared to the preoperative obese state and regain of meal-induced ghrelin suppression.
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| 6. |
- Eriksson, A., et al.
(författare)
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Short-term effects of metformin in type 2 diabetes
- 2007
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 9:3, s. 330-336
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined early effects on glucose and lipid metabolism, and on certain adipose tissue and inflammatory markers during treatment for 28 days.Methods: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in week 1, 500 mg twice daily in week 2 and 1000 mg twice daily in week 3 and 4.Results: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared with baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total and LDL-cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin.Conclusions: The data demonstrate that in type 2 diabetes metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.
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| 7. |
- Fernebro, Josefin, et al.
(författare)
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Genetic profiling differentiates second primary tumors from metastases in adult metachronous soft tissue sarcoma.
- 2008
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Ingår i: Sarcoma. - : Hindawi Limited. - 1357-714X .- 1369-1643. ; 2008:2009 Feb 2
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. Patients with soft tissue sarcomas (STS) are at increased risk of second primary malignancies, including a second STS, but distinction between metastases and a second primary STS is difficult. Patients and Methods. Array-based comparative genomic hybridization (aCGH) was applied to 30 multiple STS of the extremities and the trunk wall from 13 patients. Different histotypes were present with malignant fibrous histiocytomas/undifferentiated pleomorphic sarcomas being the predominant subtype. Results. aCGH profiling revealed genetic complexity with multiple gains and losses in all tumors. In an unsupervised hierarchical cluster analysis, similar genomic profiles and close clustering between the first and subsequent STS were identified in 5 cases, suggesting metastatic disease, whereas the tumors from the remaining 8 patients did not cluster and showed only weak pairwise correlation, suggesting development of second primary STS. Discussion. The similarities and dissimilarities identified in the first and second STS suggest that genetic profiles can be used to distinguish soft tissue metastases from second primary STS. The demonstration of genetically different soft tissue sarcomas in the same patient suggests independent tumor origin and serves as a reminder to consider development of second primary STS, which has prognostic and therapeutic implications.
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| 8. |
- Jensen, Richard A., et al.
(författare)
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Multiple factors affect the loss of measurable C-peptide over 6 years in newly diagnosed 15- to 35-year-old diabetic subjects
- 2007
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Ingår i: Journal of diabetes and its complications. - : Elsevier BV. - 1056-8727 .- 1873-460X. ; 21:4, s. 205-213
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study is to identify risk factors for the loss of measurable plasma C-peptide in newly diagnosed 15- to 35-year-old diabetic subjects. Methods: This Swedish study included 778 subjects. C-peptide levels were obtained each year for 6 years after diagnosis. Loss of measurable C-peptide was defined as a level at or below the lower detection limit of the local assay (0.13 nmol/l). In addition to C-peptide, other baseline covariates included gender, age, body mass index, HLA genotype, and autoantibody levels. Results: Compared with autoantibody-negative subjects, autoantibody-positive subjects had lower median baseline C-peptide (0.27 vs. 0.50, P<001), their levels declined over the study period, and the risk of losing measurable C-peptide was significantly higher when more than one autoantibody was present [odds ratio (OR), 4.0; 95% confidence interval (CI), 2.13-7.54]. Among autoantibody-positive individuals, the presence of GAD65Ab (OR, 1.8; 95% Cl, 1.24-2.51) and islet cell antibodies (OR, 1.6; 95% CI, 1.19-2.18) conferred a higher risk for loss of measurable C-peptide as did female gender (OR, 1.6; 95% CI, 1.17-2.11) and time after diagnosis (OR, 1.5 for each additional year postdiagnosis; 95% CI, 1.41-1.57). Higher baseline C-peptide levels were protective (OR, 0.5 for each additional log nanomoles per liter; 95% CI, 0.36-0.58). Conclusions: This study identified autoantibody status, gender, and baseline C-peptide levels as factors that will be useful for predicting the disease course of 15- to 35-year-old diabetic individuals.
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| 9. |
- Johansson, H.-E., et al.
(författare)
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Gastric bypass alters the dynamics and metabolic effects of insulin and proinsulin secretion
- 2007
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 24:11, s. 1213-1220
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Tidskriftsartikel (refereegranskat)abstract
- Aims Hyperproinsulinaemia is associated with obesity and is a risk factor for Type 2 diabetes. We explored the dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in subjects who had undergone gastric bypass (GBP) surgery compared with morbidly obese (MO) subjects and normal weight control subjects (NW). Methods Subjects free from diabetes were recruited: 10 previously MO subjects [body mass index (BMI) ± SD, 34.8 ± 6.2 kg/m2] who had undergone GBP surgery, 10 MO subjects (BMI 44 ± 3.1 kg/m2) and 12 NW control subjects (BMI 23.2 ± 2.4 kg/m2). After an overnight fast, a standard meal (2400 kJ) was ingested and glucose, proinsulin, insulin free fatty acids and triglycerides were determined up to 180 min. Results Fasting proinsulin was similar in the GBP group and NW control subjects, but threefold increased in MO subjects (P < 0.05). Postprandial AUC for glucose was similar in the three groups and AUC for proinsulin was high in MO, intermediate in the GBP group and lowest in NW control subjects (P for trend = 0.020). Postprandial proinsulin at 60 min was similar in the GBP group and MO subjects and twofold higher than in NW control subjects. Postprandial proinsulin at 180 min was normal in the GBP group, but fivefold increased in MO subjects (P = 0.008). Insulin increased rapidly at 30 min in the GBP group and was normal at 90 min, whereas insulin was still increased at 90-180 min in the MO subjects (P < 0.001). Conclusions MO subjects, free from diabetes, have elevated proinsulin concentrations in the fasting as well as the postprandial phase. After GBP surgery markedly lower fasting and postprandial proinsulin concentrations were observed, although BMI was higher compared with NW control subjects.
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| 10. |
- Juliusson, Gunnar, et al.
(författare)
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Attitude towards remission induction for elderly patients with acute myeloid leukemia influences survival.
- 2006
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 20:1, s. 42-47
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Tidskriftsartikel (refereegranskat)abstract
- Combination chemotherapy may induce remission from acute myeloid leukemia (AML), but validated criteria for treatment of elderly are lacking. The remission intention ( RI) rate for elderly patients, as reported to the Swedish Leukemia Registry, was known to be different when comparing the six health care regions, but the consequences of different management are unknown. The Leukemia Registry, containing 1672 AML patients diagnosed between 1997 and 2001, with 98% coverage and a median follow-up of 4 years, was completed with data from the compulsory cancer and population registries. Among 506 treated and untreated patients aged 70-79 years with AML (non-APL), there was a direct correlation between the RI rate in each health region ( range 36-76%) and the two-year overall survival, with no censored observations (6-21%) ( v 2 for trend = 11.3, P < 0.001; r(2) = 0.86, P < 0.02, nonparametric). A 1-month landmark analysis showed significantly better survival in regions with higher RI rates ( P = 0.003). Differences could not be explained by demographics, and was found in both de novo and secondary leukemias. The 5-year survival of the overall population aged 70-79 years was similar between the regions. Survival of 70-79-year-old AML patients is better in regions where more elderly patients are judged eligible for remission induction.
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