Sveinn Gudmundsson

Identified metabolic signature for assessing red blood cell unit quality is associated with endothelial damage markers and clinical outcomes

There has been interest in determining whether older red blood cell (RBC) units have negative clinical effects. Numerous observational studies have shown that older RBC units are an independent factor for patient mortality. However, recently published randomized clinical trials have shown no difference of clinical outcome for patients receiving old or fresh RBCs. An overlooked but essential issue in assessing RBC unit quality and ultimately designing the necessary clinical trials is a metric for what constitutes an old or fresh RBC unit.

Upper gastrointestinal bleeding: incidence, etiology and outcomes in a population-based setting

Abstract Objective. The authors aimed to investigate the incidence and outcomes of acute upper gastrointestinal bleeding (AUGIB) and to examine the role of drugs potentially associated with AUGIB. Methods. The study was prospective, population-based and consisted of all patients who underwent upper gastrointestinal endoscopy (UGE), during the year of 2010 at the National University Hospital of Iceland. Drug intake of NSAIDs, low-dose aspirin (LDA), warfarin, SSRIs and bisphosphonates prior to GIB was prospectively registered and also checked in a Pharmaceutical Database covering all prescriptions in Iceland. An age- and gender-matched control group consisted of patients who underwent UGE during the study period and were without GIB. Results. A total of 1731 patients underwent 2058 UGEs. Overall, 156 patients had AUGIB. The crude incidence for AUGIB was 87/100,000 inhabitants per year. The most common etiologies were duodenal (21%) and gastric ulcers (15%). Use of LDA (40% vs. 30%), NSAIDs (20% vs. 8%), warfarin (15% vs. 7%), combination of NSAIDs + LDA (8% vs. 1%) and SSRIs + LDA (8% vs. 3%) were significantly more common among bleeders than non-bleeders. Three patients (1.9%) had emergency surgery and two patients died of AUGIB. Independent predictors of clinically significant bleeding were gastric ulcer (OR 6.6, p = 0.012) and NSAIDs (OR 6.6, p = 0.004). Conclusions. LDA, NSAIDs and warfarin play an important role in AUGIB etiology and particularly combinations of drugs. Gastric ulcer and NSAIDs were independent predictors of severe bleeding. Mortality and the need for surgery during hospitalization was low in this population-based setting.

Familial aggregation of IgAD and autoimmunity

BACKGROUND The prevalence of autoimmunity is thought to be increased among IgA deficient (IgAD) individuals. However, it is currently unclear if the two conditions coincide within families. OBJECTIVE To evaluate the prevalence of autoimmunity among IgAD individuals and their 1 degrees relatives. MATERIAL AND METHODS A total of 43 IgAD individuals (32 adults and 11 children) and all available 1 degrees relatives were evaluated by a physician. A family history of autoimmunity was obtained, together with physical examination and a structured questionnaire that focused on symptoms and signs suggestive of autoimmunity. RESULTS Eight of the 32 (25%) adult IgAD, were found to have definite autoimmunity, with organ specific- and systemic autoimmune diseases equally distributed. None of the IgAD children had autoimmunity. Among the 1 degrees relatives, 27/269 (10%) had autoimmunity, compared to an estimate of 5% in the general population (p<0.05). CONCLUSION Autoimmune diseases are highly prevalent in individuals with IgAD and more common in their 1 degrees relatives than expected, thus, suggesting a possible common genetic component.

Biomarkers defining the metabolic age of red blood cells during cold storage

Metabolomic investigations of packed red blood cells (RBCs) stored under refrigerated conditions in saline adenine glucose mannitol (SAGM) additives have revealed the presence of 3 distinct metabolic phases, occurring on days 0-10, 10-18, and after day 18 of storage. Here we used receiving operating characteristics curve analysis to identify biomarkers that can differentiate between the 3 metabolic states. We first recruited 24 donors and analyzed 308 samples coming from RBC concentrates stored in SAGM and additive solution 3. We found that 8 extracellular compounds (lactic acid, nicotinamide, 5-oxoproline, xanthine, hypoxanthine, glucose, malic acid, and adenine) form the basis for an accurate classification/regression model and are able to differentiate among the metabolic phases. This model was then validated by analyzing an additional 49 samples obtained by preparing 7 new RBC concentrates in SAGM. Despite the technical variability associated with RBC processing strategies, verification of these markers was independently confirmed in 2 separate laboratories with different analytical setups and different sample sets. The 8 compounds proposed here highly correlate with the metabolic age of packed RBCs, and can be prospectively validated as biomarkers of the RBC metabolic lesion.

Comprehensive metabolomic study of platelets reveals the expression of discrete metabolic phenotypes during storage

Platelet (PLT) concentrates are routinely stored for 5 to 7 days. During storage they exhibit what has been termed PLT storage lesion (PSL), which is evident by a loss of hemostatic function when transfused into patients. The overall goal of this study was to obtain a comprehensive data set describing PLT metabolism during storage.

Metabolomic analysis of platelets during storage: a comparison between apheresis- and buffy coat–derived platelet concentrates

Platelet concentrates (PCs) can be prepared using three methods: platelet (PLT)‐rich plasma, apheresis, and buffy coat. The aim of this study was to obtain a comprehensive data set that describes metabolism of buffy coat–derived PLTs during storage and to compare it with a previously published parallel data set obtained for apheresis‐derived PLTs.

Inflammatory Cytokines in Relation to Adrenal Response Following Total Hip Replacement

Our objective was to investigate the initiation and course of pro‐ and anti‐inflammatory cytokines in early inflammatory response and to elucidate the cytokine system in relation to the adrenal response caused by stress. Seven blood samples were collected, pre‐ and postoperatively (0–72 h) after total hip replacement (THR) due to osteoarthritis. The following cytokines were measured using Cytometric Bead Array: interleukin‐1β (IL‐1β), IL‐6, tumour necrosis factor‐α, IL‐8, IL‐12 and IL‐10 (B&D). Thirteen patients took part in the study (67 ± 9 years). C‐reactive protein increased from <6 to over 200 mg/l on the second post‐op day. The concentration of IL‐6 increased 10‐fold just 3 h post‐op (4–47 pg/ml) and reached its maximum value 6 h post‐op (77 pg/ml; Wilcoxon test P < 0.01) Repeated measurements were also significant (Friedman P < 0.05). The concentration of IL‐8 doubled the day of surgery but did not reach a significant level (Friedman test =0.069). None of the other cytokines showed any significant changes. The diurnal cortisol rhythm was interrupted after the surgery and there was a significant correlation between the cortisol secretion and IL‐6 response. This study demonstrates an isolated elevation in IL‐6 levels with only a minor elevation in IL‐8 following THR. This pro‐inflammatory response seemed to decline without activation of anti‐inflammatory cytokines (IL‐10), but cortisol seemed to play a complicated role in halting the acute inflammatory response.

Gene expression analysis of hematopoietic progenitor cells identifies Dlg7 as a potential stem cell gene

Inducible hematopoietic stem/progenitor cell lines represent a model for studying genes involved in self‐renewal and differentiation. Here, gene expression was studied in the inducible human CD34+ acute myelogenous leukemia cell line KG1 using oligonucleotide arrays and suppression subtractive cloning. Using this approach, we identified Dlg7, the homolog of the Drosophila Dlg1 tumor suppressor gene, as downregulated at the early stages of KG1 differentiation. Similarly, Dlg7 was expressed in normal purified umbilical cord blood CD34+CD38− progenitors but not in the more committed CD34+CD38+ population. Dlg7 expression was not detected in differentiated cells obtained from hematopoietic colonies, nor was expression detected in purified T‐cells, B‐cells, and monocytes. When analyzed in different types of stem cells, Dlg7 expression was detected in purified human bone marrow‐derived CD133+ progenitor cells, human mesenchymal stem cells, and mouse embryonic stem (ES) cells. Overexpression of Dlg7 in mouse ES cells increased their growth rate and reduced the number of EBs emerging upon differentiation. In addition, the EBs were significantly smaller, indicating an inhibition in differentiation. This inhibition was further supported by higher expression of Bmp4, Oct4, Rex1, and Nanog in EBs overexpressing Dlg7 and lower expression of Brachyury. Finally, the Dlg7 protein was detected in liver and colon carcinoma tumors but not in normal adjacent tissues, suggesting a role for the gene in carcinogenesis. In conclusion, our results suggest that Dlg7 has a role in stem cell survival, in maintaining stem cell properties, and in carcinogenesis.

In vitro bioactivity of different degree of deacetylation chitosan, a potential coating material for titanium implants.

Clinical treatment of orthopaedic tissue injuries often involves the use of titanium and titanium alloys with considerable research focusing on the surface modification of these materials. Chitosan, the partly deacetylated form of chitin, is one of the materials under investigation as surface coating for orthopaedic implants in order to improve osteo-integration and cellular attachment. In this study, we determined the effects of the degree of deacetylation (DD) of chitosan membranes on attachment, proliferation and osteogenic differentiation of MC3T3-E1 mouse preosteoblasts. Chitosan membranes were coated with fibronectin to promote biocompatibility and cellular attachment. Membranes were characterized in terms of wettability and surface topography using water contact angle measurements and atomic force microscopy. The results in this study indicate that the surface roughness and fibronectin adsorption increase with increased DD. A higher DD also facilitates attachment and proliferation of cells, but no induction of spontaneous osteogenic differentiation was observed. Lower DD chitosan membranes were successfully prepared to sustain attachment and were modified by crosslinking with glutaraldehyde to promote long-term studies. The chitosan membranes used in this study are suitable as a potential coating for titanium implants.

Increased expression of interleukin-13 but not interleukin-4 in CD4+ cells from patients with the hyper–IgE syndrome

Hyper IgE syndrome (HIES) is a rare immunodeficiency disorder characterized mainly by high levels of polyclonal IgE in serum and recurrent staphylococcal abscesses of the skin and lungs. The raised IgE levels have led researchers to study the synthesis of cytokines that regulate switching of immunoglobulin production towards IgE such as interleukin‐4 (IL‐4), IL‐12 and interferon‐γ (IFN)‐γ. However, the role of IL‐13 in the disease pathogenesis has not been investigated extensively. In this study, we investigated intracellular expression of IL‐4 and IL‐13 in mononuclear cells and CD4+ cells isolated from patients with HIES and healthy controls. Cells were stained intracellularly with antibodies directed against IL‐4 and IL‐13 and analysed by flow cytometry before and after activation with PMA and calcium ionophore. The mean proportion of resting or activated IL‐4 and IL‐13 expressing mononuclear cells were comparable in the two groups as well as the proportion of IL‐4 expressing CD4+ cells. In contrast, the mean proportion of IL‐13 expressing CD4+ cells was increased significantly in patients with HIES in both the resting and the activated state compared to healthy controls. We conclude that increased expression of IL‐13 in CD4+ cells from patients with HIES could account, at least partly, for raised IgE levels in those individuals.