Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: a randomized controlled trial

Aims The most effective regimen for the prevention of contrast-induced nephropathy (CIN) remains uncertain. Our purpose was to compare two regimens of sodium bicarbonate with 24 h sodium chloride 0.9% infusion in the prevention of CIN. Methods and results We performed a prospective, randomized trial between March 2005 and December 2009, including 258 consecutive patients with renal insufficiency undergoing intravascular contrast procedures. Patients were randomized to receive intravenous volume supplementation with either (A) sodium chloride 0.9% 1 mL/kg/h for at least 12h prior and after the procedure or (B) sodium bicarbonate (166 mEq/L) 3 mL/kg for 1h before and 1 mL/kg/h for 6h after the procedure or (C) sodium bicarbonate (166 mEq/L) 3 mL/kg over 20min before the procedure plus sodium bicarbonate orally (500 mg per 10 kg). The primary endpoint was the change in estimated glomerular filtration rate (eGFR) within 48h after contrast. Secondary endpoints included the development of CIN. The maximum change in eGFR was significantly greater in Group B compared with Group A {mean difference −3.9 [95% confidence interval (CI), −6.8 to −1] mL/min/1.73 m2, P = 0.009} and similar between Groups C and B [mean difference 1.3 (95% CI, −1.7-4.3) mL/min/1.73 m2, P = 0.39]. The incidence of CIN was significantly lower in Group A (1%) vs. Group B (9%, P = 0.02) and similar between Groups B and C (10%, P = 0.9). Conclusion Volume supplementation with 24 h sodium chloride 0.9% is superior to sodium bicarbonate for the prevention of CIN. A short-term regimen with sodium bicarbonate is non-inferior to a 7 h regimen. ClinicalTrials.gov Identifier: NCT0013059

The Synthetic Potential of Fungal Feruloyl Esterases : A Correlation with Current Classification Systems and Predicted Structural Properties

Twenty-eight fungal feruloyl esterases (FAEs) were evaluated for their synthetic abilities in a ternary system of n-hexane: t-butanol: 100 mM MOPS-NaOH pH 6.0 forming detergentless microemulsions. Five main derivatives were synthesized, namely prenyl ferulate, prenyl caffeate, butyl ferulate, glyceryl ferulate, and l-arabinose ferulate, offering, in general, higher yields when more hydrophilic alcohol substitutions were used. Acetyl xylan esterase-related FAEs belonging to phylogenetic subfamilies (SF) 5 and 6 showed increased synthetic yields among tested enzymes. In particular, it was shown that FAEs belonging to SF6 generally transesterified aliphatic alcohols more efficiently while SF5 members preferred bulkier l-arabinose. Predicted surface properties and structural characteristics were correlated with the synthetic potential of selected tannase-related, acetyl-xylan-related, and lipase-related FAEs (SF1-2, -6, -7 members) based on homology modeling and small molecular docking simulations.Peer reviewe

Genetic Evidence Supporting the Association of Protease and Protease Inhibitor Genes with Inflammatory Bowel Disease: A Systematic Review

As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium

Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. Methods and results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals

Automatic identification of variables in epidemiological datasets using logic regression

textabstractBackground: For an individual participant data (IPD) meta-analysis, multiple datasets must be transformed in a consistent format, e.g. using uniform variable names. When large numbers of datasets have to be processed, this can be a time-consuming and error-prone task. Automated or semi-automated identification of variables can help to reduce the workload and improve the data quality. For semi-automation high sensitivity in the recognition of matching variables is particularly important, because it allows creating software which for a target variable presents a choice of source variables, from which a user can choose the matching one, with only low risk of having missed a correct source variable. Methods: For each variable in a set of target variables, a number of simple rules were manually created. With logic regression, an optimal Boolean combination of these rules was searched for every target variable, using a random subset of a large database of epidemiological and clinical cohort data (construction subset). In a second subset of this database (validation subset), this optimal combination rules were validated. Results: In the construction sample, 41 target variables were allocated on average with a positive predictive value (PPV) of 34%, and a negative predictive value (NPV) of 95%. In the validation sample, PPV was 33%, whereas NPV remained at 94%. In the construction sample, PPV was 50% or less in 63% of all variables, in the validation sample in 71% of all variables. Conclusions: We demonstrated that the application of logic regression in a complex data management task in large epidemiological IPD meta-analyses is feasible. However, the performance of the algorithm is poor, which may require backup strategies

Presence of protein production enhancers results in significantly higher methanol-induced protein production in Pichia pastoris

Abstract Background The yeast Komagataella phaffii, better known as Pichia pastoris, is a commonly used host for recombinant protein production. Here expression vectors are reported that address the different steps of the transcription–translation–secretion pathway of heterologous protein production. Results Transcription and translation enhancing elements were introduced in an expression cassette for the production of recombinant Aspergillus niger feruloyl esterase A. The yield was increased by threefold as compared to the yield without these elements. Multiple copy strains were selected using a zeocin resistance marker in the expression cassette and showed another sixfold higher yield. Modification of the C-terminal amino acid sequence of the secretion signal did not significantly improve the production yield. Similar data were obtained for the production of another protein, recombinant human interleukin 8. Upscaling to fed-batch fermentation conditions resulted in a twofold increase for reference strains, while for strains with enhancing elements a tenfold improvement was observed. Conclusions Pichia pastoris is used for recombinant protein production in industrial fermentations. By addressing the transcription and translation of mRNA coding for recombinant protein, significant yield improvement was obtained. The yield improvement obtained under microscale conditions was maintained under fed-batch fermentation conditions. These data demonstrate the potential of these expression vectors for large scale application as improved production of proteins has major implications on the economics and sustainability of biocatalyst dependent production processes e.g. for the production of pharmaceuticals and for the bioconversions of complex molecules

Glycosylation influences activity, stability and immobilization of the feruloyl esterase 1a from Myceliophthora thermophila

Heterologous protein production is widely used in industrial biotechnology. However, using non-native production hosts can lead to enzymes with altered post-translational modifications, such as glycosylation. We have investigated how production in a non-native host affects the physicochemical properties and enzymatic activity of a feruloyl esterase from Myceliophthora thermophila, MtFae1a. The enzyme was produced in two microorganisms that introduce glycosylation (M. thermophila and Pichia pastoris) and in Escherichia coli (non-glycosylated). Mass spectrometric analysis confirmed the presence of glycosylation and revealed differences in the lengths of glycan chains between the enzymes produced in M. thermophila and P. pastoris. The melting temperature and the optimal temperature for activity of the non-glycosylated enzyme were considerably lower than those of the glycosylated enzymes. The three MtFae1a versions also exhibited differences in specific activity and specificity. The catalytic efficiency of the glycosylated enzymes were more than 10 times higher than that of the non-glycosylated one. In biotechnology, immobilization is often used to allow reusing enzyme and was investigated on mesoporous silica particles. We found the binding kinetics and immobilization yield differed between the enzyme versions. The largest differences were observed when comparing enzymes with and without glycosylation, but significant variations were also observed between the two differently glycosylated enzymes. We conclude that the biotechnological value of an enzyme can be optimized for a specific application by carefully selecting the production host

Seed bank dynamics of a semi-arid coastal shrub community in Pakistan

The relationship between the seed bank and existing vegetation was studied. Seed bank flora and existing vegetation show a high degree of similarity and Cressa cretica dominated both; a few rare species were also present. Seasonal variation in the seed bank was also studied for the 1989–90 and 1990–91 growing seasons. Most species demonstrated the persistent nature of the seed bank with their numbers increasing after seed dispersal and decreasing in subsequent months. The seed bank of a coastal community in Sindh, Pakistan could be used to predict existing vegetation