Baseline MELD Score Predicts Hepatic Decompensation during Antiviral Therapy in Patients with Chronic Hepatitis C and Advanced Cirrhosis

Background and Aims

In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.

Methods

In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).

Results

Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).

Conclusions

Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.     

Total variance should drive data handling strategies in third generation proteomic studies

Quantitative proteomics is entering its “third generation,” where intricate experimental designs aim to increase the spatial and temporal resolution of protein changes. This paper re‐analyses multiple internally consistent proteomic datasets generated from whole cell homogenates and fractionated brain tissue samples providing a unique opportunity to explore the different factors influencing experimental outcomes. The results clearly indicate that improvements in data handling are required to compensate for the increased mean CV associated with complex study design and intricate upstream tissue processing. Furthermore, applying arbitrary inclusion thresholds such as fold change in protein abundance between groups can lead to unnecessary exclusion of important and biologically relevant data.     

Influence of parameter settings in automated scoring of AFLPs on population genetic analysis

The use of procedures for the automated scoring of amplified fragment length polymorphisms (AFLP) fragments has recently increased. Corresponding software does not only automatically score the presence or absence of AFLP fragments, but also allows an evaluation of how different settings of scoring parameters influence subsequent population genetic analyses. In this study, we used the automated scoring package rawgeno to evaluate how five scoring parameters influence the number of polymorphic bins and estimates of pairwise genetic differentiation between populations (F_st). Steps were implemented in r to automatically run the scoring process in rawgeno for a set of different parameter combinations. While we found the scoring parameters minimum bin width and minimum number of samples per bin to have only weak influence on pairwise F_st values, maximum bin width and bin reproducibility had much stronger effects. The minimum average bin fluorescence scoring parameter affected F_st values in an only moderate way. At a range of scoring parameters around the default settings of rawgeno , the number of polymorphic bins as well as pairwise F_st values stayed rather constant. This study thus shows the particularities of AFLP scoring, be it either manual or automatical, can have profound effects on subsequent population genetic analysis.     

Aprotinin May Increase Mortality in Low and Intermediate Risk but Not in High Risk Cardiac Surgical Patients Compared to Tranexamic Acid and ε-Aminocaproic Acid – A Meta-Analysis of Randomised and Observational Trials of over 30.000 Patients

Background

To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and ε-aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery.

Methods and Findings

We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively.Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13–2.21), p<0.001 in the low (n = 14,297) and in the intermediate risk subgroup (1.42 (1.09–1.84), p<0.001; n = 14,427), respectively. Contrarily, in the subgroup of high risk patients (n = 4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67–1.58), p = 0.90).

Conclusion

Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.     

Nuclear Envelope Composition Determines the Ability of Neutrophil-type Cells to Passage through Micron-scale Constrictions

Neutrophils are characterized by their distinct nuclear shape, which is thought to facilitate the transit of these cells through pore spaces less than one-fifth of their diameter. We used human promyelocytic leukemia (HL-60) cells as a model system to investigate the effect of nuclear shape in whole cell deformability. We probed neutrophil-differentiated HL-60 cells lacking expression of lamin B receptor, which fail to develop lobulated nuclei during granulopoiesis and present an in vitro model for Pelger-Huët anomaly; despite the circular morphology of their nuclei, the cells passed through micron-scale constrictions on similar timescales as scrambled controls. We then investigated the unique nuclear envelope composition of neutrophil-differentiated HL-60 cells, which may also impact their deformability; although lamin A is typically down-regulated during granulopoiesis, we genetically modified HL-60 cells to generate a subpopulation of cells with well defined levels of ectopic lamin A. The lamin A-overexpressing neutrophil-type cells showed similar functional characteristics as the mock controls, but they had an impaired ability to pass through micron-scale constrictions. Our results suggest that levels of lamin A have a marked effect on the ability of neutrophils to passage through micron-scale constrictions, whereas the unusual multilobed shape of the neutrophil nucleus is less essential.     

Growth energetics of juvenile herring,Clupea harengus L.: food conversion efficiency and temperature dependency of metabolic rate

The relationship between rates of food consumption (C) and somatic growth (G) and the effect of temperature (T) on rates of mass lost during food deprivation were examined in 9–10 cm total length (TL) [1.0–1.5 g dry mass (DM)] juvenile Atlantic herring (Clupea harengus L.) in the laboratory. One feeding‐growth trial was conducted at 16°C using groups of herring feeding on known rations of brine shrimp (Artemia spp.) nauplii to quantify gross and net growth efficiency. Rates of mass lost by groups of herring (a proxy for metabolic rate, M) were measured in trials conducted at 9.7, 14.2 and 17.9°C. Gross growth efficiency (GGE = 100*G*C^?1) at 16°C was 25% at the highest rations (5.8–6.6% DM). The maintenance ration (C_main = C at zero G) was equal to 432 J*fish^?1*d^?1 or 2.0% DM*d^?1. At 16°C, net growth efficiency (100*G*(C?C_main)^?1) was 42%. The nucleic acid content (RNA‐DNA ratio, RD) in herring muscle tissue was strongly related to somatic growth (G, % DM*d^?1 = ?0.36*RD² + 3.21*RD ?3.92, r² = 0.90, P < 0.05, n = 8 groups). The effect of T (9.7–17.9°C) on M was described by a second order polynomial equation M = ?1.24*T + 38.2*T ? 218 (J*g DM^?1*d^?1) and M = ?10*T + 310*T ? 1815 (J*fish^?1*d^?1). This was the first study to investigate the influence of temperature on the metabolic rate of juvenile Atlantic herring under stress‐free conditions in the laboratory and provides the first estimates of gross and net growth efficiency for this species feeding on live prey.     

Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes

Contradictory results for concentrations of vitamin B12, holotranscobalamin (holoTC), and methylmalonic acid (MMA) have been reported. We tested the hypothesis that the extracellular vitamin B12 markers are not reflecting the intracellular vitamin B12-dependent biochemical reactions in individuals with type 2 diabetes. The study included 92 patients with diabetes and 72 controls with similar age and sex distribution. We measured vitamin B12 markers [MMA, total serum vitamin B12, holoTC, total homocysteine (tHcy)], red blood cell (RBC)-B12, and the plasma concentrations of the methylation markers [S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH)]. In comparison to controls, diabetic patients showed significantly higher concentrations of plasma SAH (median 15.1 vs. 11.8 nmol/L; p < 0.001) and lower SAM/SAH ratio (9.1 vs. 8.2; p = 0.006). Concentrations of total vitamin B12 and holoTC did not differ significantly between the groups, but plasma MMA concentrations were significantly higher in diabetics (250 vs. 206 nmol/L). However, RBC-B12 was lower in diabetics compared to controls (median 230 vs. 260 pmol/L; p = 0.001). The inverse correlation between MMA and RBC-B12 was stronger in the controls compared to that in the patients (correlation coefficient in controls R = −0.446, p = 0.001; in patients R = −0.289, p = 0.022). Metformin treatment was associated with a lower total serum vitamin B12, but a comparable RBC-B12 and a slightly lower MMA and better methylation index. In conclusion, patients with type 2 diabetes showed normal extracellular vitamin B12, but disturbed intracellular B12-dependent biochemical reactions. Metformin treatment was associated with low serum vitamin B12 and improved intracellular vitamin B12 metabolism despite low serum vitamin B12.     

Potential for optimized production and use of rapeseed biodiesel. Based on a comprehensive real-time LCA case study in Denmark with multiple pathways

Purpose

Several factors contribute to the current increased focus on alternative fuels such as biodiesel, including an increasing awareness of the environmental impact of petrochemical (PC) oil products such as PC diesel, the continuously increasing price of PC oil, and the depletion of PC oil. For these reasons, the European Union has enacted a directive requiring each member state to ensure that the share of energy from renewable sources in transport be at least 10 % of the final consumption of energy by 2020 (The European Parliament and the Council 2009). This LCA study assesses the specific environmental impacts from the production and use of biodiesel as it is today (real-time), based on rapeseed oil and different types of alcohols, and using technologies that are currently available or will be available shortly. Different options are evaluated for the environmental improvement of production methods. The modeling of the LCA is based on a specific Danish biodiesel production facility.

Methods

The functional unit is “1,000 km transportation for a standard passenger car.” All relevant process stages are included, such as rapeseed production including carbon sequestration and N₂O balances, and transportation of products used in the life cycle of biodiesel. System expansion has been used to handle allocation issues.

Results and discussion

The climate change potential from the production and use of biodiesel today is 57 kg CO₂-eq/1,000 km, while PC diesel is 214 kg CO₂-eq/1,000 km. Options for improvement include the increased use of residual straw from rapeseed fields for combustion in a power plant where carbon sequestration is considered, and a change in transesterification from a conventional process to an enzymatic process when using bioethanol instead of PC methanol. This research also evaluates results for land use, respiratory inorganics potential, human toxicity (carc) potential, ecotoxicity (freshwater) potential, and aquatic eutrophication (N) potential. Different sources for uncertainty are evaluated, and the largest drivers for uncertainty are the assumptions embedded into the substitution effects. The results presented should not be interpreted as a blueprint for the increased production of biodiesel but rather as a benchmarking point for the present, actual impact in a well-to-wheels perspective of biodiesel, with options for improving production and use.

Conclusions

Based on this analysis, we recommend investigating additional options and incentives regarding the increased use of rape straw, particularly considering the carbon sequestration issues (from the perspective of potential climate change) of using bioalcohol instead of PC alcohol for the transesterification process.     

Analysis of the link between a definition of sustainability and the life cycle methodologies

Purpose

It has been claimed that in order to assess the sustainability of products, a combination of the results from a life cycle assessment (LCA), social life cycle assessment (SLCA) and life cycle costing (LCC) is needed. Despite the frequent reference to this claim in the literature, very little explicit analysis of the claim has been made. The purpose of this article is to analyse this claim.

Methods

An interpretation of the goals of sustainability, as outlined in the report Our Common Future (WCED 1987), which is the basis for most literature on sustainability assessment in the LCA community, is presented and detailed to a level enabling an analysis of the relation to the impact categories at midpoint level considered in life cycle (LC) methodologies.

Results

The interpretation of the definition of sustainability as outlined in Our Common Future (WCED 1987) suggests that the assessment of a product's sustainability is about addressing the extent to which product life cycles affect poverty levels among the current generation, as well as changes in the level of natural, human and produced and social capital available for the future population. It is shown that the extent to which product life cycles affect poverty to some extent is covered by impact categories included in existing SLCA approaches. It is also found that the extent to which product life cycles affect natural capital is well covered by LCA, and human capital is covered by both LCA and SLCA but in different ways. Produced capital is not to any large extent considered in any of the LC methodologies. Furthermore, because of the present level of knowledge about what creates and destroys social capital, it is difficult to assess how it relates to the LC methodologies. It is also found that the LCC is only relevant in the context of a life cycle sustainability assessment (LCSA) if focusing on the monetary gains or losses for the poor. Yet, this is an aspect which is already considered in several SLCA approaches.

Conclusions

The current consensus that LCSA can be performed through combining the results from an SLCA, LCA and LCC is only partially supported in this article: The LCSA should include both an LCA and an SLCA, which should be expanded to better cover how product life cycles affect poverty and produced capital. The LCC may be included if it has as a focus to asses income gains for the poor.     

Surface modification of polyacrylonitrile with nitrile hydratase and amidase from Agrobacterium tumefaciens

A new strain of Agrobacterium tumefaciens (BST05) was found to grow on polyacrylonitrile (PAN; ¹³C labelled) converting the polymer to polyacrylic acid as shown by solid state NMR. When cultivated in a medium containing acetonitrile the bacterium produced nitrile hydratase and amidase activity. Activity recovery after lyophilisation and enzyme stability was significantly enhanced in the presence of 5% sorbitol leading to half life times of 12, 72 and 154 days at 25°C, 4°C and –20°C. The enzymes were able to convert 1.1% of the nitrile groups of PAN-powder to the corresponding acids. PAN fabrics were mainly converted to the amides as shown by an 80% increase of the O/C ratio in ESCA analysis. These data were confirmed by cationic dyeing and FTIR-ATR analysis.