Specific glycosaminoglycans promote unseeded amyloid formation from beta2-microglobulin under physiological conditions

Dialysis-related amyloidosis (DRA) is a complication of hemodialysis where beta2-microglobulin (beta2m) forms plaques mainly in cartilaginous tissues. The tissue-specific deposition, along with a known intransigence of pure beta2m to form fibrils in vitro at neutral pH in the absence of preformed fibrillar seeds, suggests a role for factors within cartilage in enhancing amyloid formation from this protein. To identify these factors, we determined the ability of a derivative lacking the N-terminal six amino acids found in ex vivo beta2m amyloid deposits to form amyloid fibrils at pH 7.4 in the absence of fibrillar seeds. We show that the addition of the glycosaminoglycans (GAGs) chrondroitin-4 or 6-sulfate to fibril growth assays results in the spontaneous generation of amyloid-like fibrils. By contrast, no fibrils are observed over the same time course in the presence of hyaluronic acid, a nonsulfated GAG that is abundant in cartilaginous joints. Based on the observation that hyaluronic acid has no effect on fibril stability, while chrondroitin-6-sulfate decreases the rate of fibril disassembly, we propose that the latter GAG enhances amyloid formation by stabilizing the rare fibrils that form spontaneously. This leads to the accumulation of beta2m in fibrillar deposits. Our data rationalize the joint-specific deposition of beta2m amyloid in DRA, suggesting mechanisms by which amyloid formation may be promoted.     

Development of left ventricular hypertrophy in a novel porcine model of mitral regurgitation

Objectives. We aimed to develop a porcine model for chronic nonischemic mitral regurgitation (MR) to investigate left ventricular (LV) enlargement and eccentric hypertrophy. Design. Nonischemic MR was induced in 30 pigs by open-chest immobilization of the posterior mitral leaflet by transannular traction sutures that where applied in transmyocardial fashion. A sham operated control group (n = 13) was included. Echocardiographic LV size and heart weight assessed at euthanasia were used to evaluate the development of LV enlargement and eccentric hypertrophy after 8 weeks follow-up. Results. Eight pigs died and seven were excluded due to mediastinal infection (n = 2) or failure to produce MR (n = 5). Thus, 28 pigs were included and were divided into three groups: controls (n = 12), mild MR (mMR; n = 10), and moderate to severe MR (sMR; n = 6). The change in LV internal diameter in diastole (LVIDd) from baseline to follow-up was significantly higher in the sMR group compared to that of the control group (P = 0.0017). Furthermore, LV weight was significantly increased in the mMR (P = 0.047) and the sMR (P = 0.0087) groups compared to that of the control group. Conclusions. A new model for chronic moderate to severe nonischemic MR with development of LV enlargement and eccentric hypertrophy within 8 weeks has been established in pigs.     

IL‐10‐specific autoantibodies predict major adverse cardiovascular events in kidney transplanted patients ‐ a retrospective cohort study

End‐stage renal failure is associated with persistent systemic inflammation. The aim of this study was to investigate if systemic inflammation at the time of kidney transplantation is linked to poor graft survival, major adverse cardiovascular events (MACE), and increased mortality, and if these processes are modulated by naturally occurring cytokine‐specific autoantibodies (c‐aAbs), which have been shown to regulate cytokine activity in vitro. Serum levels of cytokines, high‐sensitivity C‐reactive protein (hsCRP) and c‐aAbs specific for interleukin (IL)‐1α, tumor necrosis factor (TNF)‐α, IL‐6, and IL‐10 were measured at the time of transplantation in a retrospective cohort study of 619 kidney transplanted patients with a median follow‐up of 4.9 years (range 1.2–8.2 years). Systemic inflammation was associated with all‐cause mortality in simple and multiple Cox regression analyses. IL‐10‐specific c‐aAbs were associated with MACE after transplantation, suggesting that IL‐10 may be a protective factor. Similarly, patients with a history of MACE before transplantation had lower levels of TNF‐α‐specific c‐aAbs, hence we hypothesized that TNF may be a risk factor of MACE. These findings support that pro‐inflammatory activity before transplantation is a pathological driver of MACE and all‐cause mortality after transplantation. This information adds to pretransplantation risk estimation in renal transplant candidates.     

Paediatric trauma mortality in Norway: A population-based study of injury characteristics and urban-rural differences

IntroductionPaediatric injury is a major global public health challenge. Epidemiological research is required for effective primary injury prevention and to develop trauma systems for optimal management of childhood injuries. This study aimed to describe the characteristics and geographical distribution of paediatric trauma deaths and to assess the relationship between rural locations and mortality rates.Materials and methodsBy accessing national registries, all trauma related deaths of persons aged 0–15 years in Norway from 1998 to 2007 were included. Paediatric trauma mortality rates and injury characteristic were analysed in relation to three different measures of municipal rurality: centrality, population density and settlement density.ResultsThere were 462 trauma related deaths during the study period and the national annual paediatric mortality rate was 4.81/100 000. Rural areas had higher mortality rates, and this difference was best predicted by municipal centrality. Rural trauma was characterised by traffic accidents and deaths that occurred prior to reaching hospital. The rural and northernmost county, Finnmark, had a mortality rate three times the national average.ConclusionMortality rates after childhood injury are high in rural areas. Substantiated measures of rurality are required for optimal allocation of primary and secondary preventive measures.     

Bioimpedance as a measure of fluids in patients with septic shock. A prospective observational study

Background

Septic shock is often treated with aggressive fluid resuscitation leading to profound fluid overload. The assessment of fluid status relies on suboptimal measures making treatment difficult. Bioelectrical impedance analysis is an alternative but the validity is unclear. The aim of this study was to determine the validity of bioelectrical impedance analysis for fluid measures in patients with septic shock.

Methods

Single-center, prospective observational cohort study. We included adult ICU patients with septic shock. We evaluated the agreement between measures on the left and right side of the patient and measures 1 h apart by two bioelectrical impedance devices. Results are presented as Bland Altman plots with 95% Limits of Agreements (LoA) and as correlations between bioelectrical impedance analysis results and clinical markers of fluids.

Results

Forty-nine patients were included. The agreement between measures on the left and the right side of the patient and after 1 h was overall without bias, but with wide LoA's. Fluid overload 1 h apart showed the most narrow 95% LoA (−2.4–2.9 L). The same wide limits of agreements were observed when comparing devices. For example, total body water with 95% LoA of −14.8 –16.7 L. Correlations between bioelectrical impedance analysis and clinical measures were low but statistically significant.

Conclusions

In patients with septic shock bioelectrical impedance analysis had no systematic errors or bias, but wide limits of agreement, indicating that the devices have a large and uncorrectable random error. Fluid status by bioelectrical impedance analysis is not sufficiently accurate to guide treatment in this group of patients.