| 1. |
- Huang, Shan, et al.
(författare)
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Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood
- 2015
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Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 8:1, s. 31-37
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.METHODS:The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.RESULTS:Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.CONCLUSIONS:Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.
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| 2. |
- Aspegren, Anders
(författare)
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Nuclear Organization of Gene Expression in Adenovirus Infected Cells
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adenovirus infected cells provide a good model system for studying nuclear organization during RNA production and transport. This thesis is focused on the dynamic organization of splicing factors during the late phase of Adenovirus infection in HeLa cells, the nuclear localization of viral RNA, and the pathway used for viral RNA transport to the cytoplasm.Splicing factors are relocalized from interchromatin granule clusters to sites of transcription in Adenovirus infected cells at intermediate times of infection. Later, splicing factors and viral RNA accumulate posttranscriptionally in interchromatin granule clusters. The release of the splicing factors from transcription sites was energy dependent or preceded by energy requiring mechanisms. Our data indicated that phosphorylation events inhibited by staurosporine, and 3' cleavage of the transcript are two possible mechanisms involved prior to the release of the RNP complex from transcription sites.A viral protein derived from orf6 of early region 4, 34K, is important for the nuclear stability and transport of late viral mRNA derived from the major late transcription unit. A viral mutant lacking this region is defective for posttranscriptional accumulation of viral mRNA in interchromatin granule clusters, and for the accumulation of viral RNA in the cytoplasm. These results suggest that posttranscriptional accumulation of viral RNA in interchromatin granule clusters may contribute to the maturation of the RNP complex or sorting of RNAs and proteins, to prepare the final RNP complex for transport to the cytoplasm.A previous model suggested that adenoviral late mRNA is transported to the cytoplasm by utilizing the CRM-1 pathway. This pathway can be blocked by the drug leptomycin B. The data presented in paper IV suggests that this model might not be applicable, since leptomycin B did not inhibit adenoviral late gene expression.
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| 3. |
- Braide, Magnus, 1955, et al.
(författare)
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Can Citrate in PD Fluids Improve Ultrafiltration?
- 2006
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Ingår i: 11th Congress of the International Society for Peritoneal Dialysis, Hong Kong, 060825-060829.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 4. |
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| 5. |
- Broman, Marcus, et al.
(författare)
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Simplified citrate anticoagulation for CRRT without calcium replacement.
- 2015
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Ingår i: ASAIO Journal. - 1538-943X. ; 61:4, s. 437-442
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Tidskriftsartikel (refereegranskat)abstract
- Since 2012 citrate anticoagulation is the recommended anticoagulation strategy for CRRT. The main drawback using citrate compared with heparin as anticoagulant is the need for calcium replacement and the rigorous control of calcium levels. This study investigated the possibility to achieve anticoagulation while eliminating the need for calcium replacement. This was successfully achieved by including citrate and calcium in all CRRT solutions. Thereby the total calcium concentration was kept constant throughout the extracorporeal circuit while the ionized calcium was kept at levels low enough to avoid clotting. Being a completely new concept, only five patients with acute renal failure were included in a short, prospective, intensely supervised non-randomized pilot study.Systemic electrolyte levels and acid-base parameters were stable and remained within physiological levels. Ionized calcium levels declined slightly initially, but stabilized at 1.1 mmol/l. Plasma citrate concentrations stabilized at around 0.6 mmol/l. All post-filter ionized calcium levels were <0.5 mmol/l, i.e. an anticoagulation effect was reached. All filter pressures were normal indicating no clotting problems, and no visible clotting was observed. No calcium replacement was needed.This pilot study suggests that it is possible to perform regional citrate anticoagulation without the need for separate calcium infusion during CRRT.
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| 6. |
- Bryland, Anna, et al.
(författare)
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Citrate treatment reduces endothelial death and inflammation under hyperglycaemic conditions.
- 2012
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Ingår i: Diabetes & Vascular Disease Research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 9:1, s. 42-51
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Tidskriftsartikel (refereegranskat)abstract
- Hyperglycaemia and glucose degradation products (GDPs) are closely associated with oxidative stress and inflammation in diabetic patients, a condition that leads to endothelial dysfunction and cardiovascular problems. We evaluated the effect of citrate and gluconate on glucose- and GDP-induced endothelial inflammation by measuring changes in viability, inflammation and function in primary human umbilical vein endothelial cells (HUVECs). The extent of apoptosis/necrosis was measured by flow cytometry and visualised with confocal microscopy by staining with annexin V or propidium iodide, respectively. Protein kinase C-βII (PKC-βII) activation was evaluated with Western blotting. Incubation with glucose (30 mM) and GDP (50 µM) significantly increased PKC-βII expression, endothelial cell death and inflammation. The addition of citrate decreased hyperglycaemia-induced apoptosis (p = 0.021), necrosis (p = 0.04) and reduced PKC-βII expression (p = 0.021) down to background levels. Citrate improved endothelial function by reducing the inflammatory markers(p = 0.01) and by decreasing neutrophil diapedesis (p = 0.012). These results suggest that citrate may have therapeutic potential by reducing hyperglycaemia-induced endothelial inflammation and abolishing endothelial dysfunction.
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| 7. |
- Bryland, Anna, et al.
(författare)
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Infusion fluids contain harmful glucose degradation products.
- 2010
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; May 4, s. 1213-1220
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Glucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients' blood. METHODS: The content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated. RESULTS: All investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing. CONCLUSIONS: These findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients.
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| 8. |
- Conze, Lei Liu
(författare)
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Understanding the Noise : Spliceosomal snRNA Profiling
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The concept of the gene has been constantly challenged by new discoveries in the life sciences. Recent challenging observations include the high frequency of alternative splicing events and the common transcription of non-protein-coding-RNAs (ncRNAs) from the genome. The latter has long been considered noise in biological systems. Multiple lines of evidence from genomic studies indicate that alternative splicing and ncRNA play important roles in expanding proteome diversity in eukaryotes. Here, the aim is to find the link between alternative splicing and ncRNAs by studying the expression profile of the spliceosomal snRNAs (U snRNA).Spliceosomal snRNAs are essential for pre-mRNA splicing in eukaryotes. They participate in splice site selection, recruitment of protein factors and catalyzing the splicing reaction. Because of this, both the abundance and diversity of U snRNAs were expected to be large. In our study we deeply analyzed the U snRNA population in primates using a combination of bioinformatical, biochemical and high throughput sequencing approaches. This transcriptome profiling has revealed that human, chimpanzee and rhesus have similar U snRNA populations, i.e. the vast majority of U snRNAs originate from few well-defined gene loci and the heterogeneity observed in U snRNA populations was largely due to the presence of SNPs at these loci. It seems that the gene loci that could potentially encode a significantly heterogeneous population of U snRNAs are mostly silent. Only few minority transcripts were detected in our study, and among them three U1-like snRNAs might play a role in the regulation of alternative splicing by recognizing non-canonical splicing sites.Mutations of U snRNA have been shown to impact the splicing process. Therefore, our study provides a reference to study the biological significance of SNPs in U snRNA genes and their association with diseases.
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| 9. |
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| 10. |
- Davies, Simon, et al.
(författare)
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The effects of low-sodium peritoneal dialysis fluids on blood pressure, thirst and volume status
- 2009
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Ingår i: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 24:5, s. 1609-1617
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Tidskriftsartikel (refereegranskat)abstract
- Background. Poor ultrafiltration is associated with worse outcomes in peritoneal dialysis (PD) patients. This might in part reflect problems associated with salt and water excess. Increasing the diffusive component of peritoneal sodium removal using low-sodium PD fluids might have beneficial effects on blood pressure (BP), thirst and fluid status that could translate into clinical benefits. Methods. Using a multicentre, prospective, baseline controlled (1 month), non-randomized intervention (2 months) design, two novel solutions designed from predictions using the three-pore model were investigated. In group A ([Na+] = 115 mmol/l), the glucose (G) was increased to 2.0% to compensate for reduced osmolality whereas in group B ([Na+] = 102 mmol/l), it was unchanged (2.5%). Both solutions were substituted for one 3- to 5-h exchange per day and no change was made to the rest of the dialysis regime. Results. Ten patients in group A and 15 in group B completed the study. Both solutions resulted in significant increases (30-50 mmol/dwell) in diffusive sodium removal during the test exchanges, P < 0.001. Ultrafiltration was maintained in group A but reduced in group B. Ambulatory nocturnal mean BP fell in group A [93.1 +/- 10.6 mmHg (+/- SD) versus 85.1 +/- 10.2 mmHg, P < 0.05], but was stable in group B (95.4 +/- 9.4 versus 95.1.1 +/- 10.7 mmHg, NS). Thirst reduced independent of appetite and mood in both groups by 2 months, more markedly in group A. Indices of fluid status, including TBW by bioimpedance and D dilution also improved in group A, P < 0.05, whereas weight increased in group B. Conclusions. Increasing the diffusive component of sodium removal whilst maintaining ultrafiltration is associated with improvements in BP, thirst and fluid status. The lack of effect seen with uncompensated low-sodium dialysate suggests that these benefits cannot be achieved by manipulation of dialysate sodium removal alone. These observations provide valuable information of the design of future randomized studies to establish the clinical role for low-sodium dialysis fluids.
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