Physiologically Realistic and Validated Mathematical Liver Model Revels Hepatobiliary Transfer Rates for Gd-EOB-DTPA Using Human DCE-MRI Data

Objectives

Diffuse liver disease (DLD), such as non-alcoholic fatty liver disease (NASH) and cirrhosis, is a rapidly growing problem throughout the Westernized world. Magnetic resonance imaging (MRI), based on uptake of the hepatocyte-specific contrast agent (CA) Gd-EOB-DTPA, is a promising non-invasive approach for diagnosing DLD. However, to fully utilize the potential of such dynamic measurements for clinical or research purposes, more advanced methods for data analysis are required.

Methods

A mathematical model that can be used for such data-analysis was developed. Data was obtained from healthy human subjects using a clinical protocol with high spatial resolution. The model is based on ordinary differential equations and goes beyond local diffusion modeling, taking into account the complete system accessible to the CA.

Results

The presented model can describe the data accurately, which was confirmed using chi-square statistics. Furthermore, the model is minimal and identifiable, meaning that all parameters were determined with small degree of uncertainty. The model was also validated using independent data.

Conclusions

We have developed a novel approach for determining previously undescribed physiological hepatic parameters in humans, associated with CA transport across the liver. The method has a potential for assessing regional liver function in clinical examinations of patients that are suffering of DLD and compromised hepatic function.     

Selection of Genetic and Phenotypic Features Associated with Inflammatory Status of Patients on Dialysis Using Relaxed Linear Separability Method

Identification of risk factors in patients with a particular disease can be analyzed in clinical data sets by using feature selection procedures of pattern recognition and data mining methods. The applicability of the relaxed linear separability (RLS) method of feature subset selection was checked for high-dimensional and mixed type (genetic and phenotypic) clinical data of patients with end-stage renal disease. The RLS method allowed for substantial reduction of the dimensionality through omitting redundant features while maintaining the linear separability of data sets of patients with high and low levels of an inflammatory biomarker. The synergy between genetic and phenotypic features in differentiation between these two subgroups was demonstrated.     

The Ethanol-Induced Stimulation of Rat Duodenal Mucosal Bicarbonate Secretion In Vivo Is Critically Dependent on Luminal Cl–

Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS) is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a ∼30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of ⁵¹Cr-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTR_inh172 (i.p. or i.v.) did not change the secretory response to ethanol, while removing Cl⁻ from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v.) but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl⁻ and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.     

Decline in lichen biodiversity on oak trunks due to urbanization

Biodiversity often suffers from urbanization. In the present study, we focused on how the duration of urbanization affects the richness of 17 epiphytic lichen species and their cover on large oaks in urban environments in a city of 100 000 inhabitants in southeast Sweden. We also surveyed trees in adjacent rural areas, selected to have similar distributions of tree trunk circumference and surrounding oak density (within 300 m). Lichen richness and cover were lower on urban trees compared to rural trees. Furthermore, richness and cover decreased with the length of time that urban trees had been surrounded by houses. Most of the species that were analysed demonstrated a decline in occurrence with respect to the duration of housing development. The reduction in the probability of occurrence varied from 60% (Calicium viride, Evernia prunastri), 80% (Chrysothrix candelaris) to 90% (Ramalina spp.) during the considered 160‐year period of urbanization. Therefore, even if valuable trees survive over the course of development, their lichen biota is likely to become depleted over time.     

Contrasting effects of habitat area and connectivity on evenness of pollinator communities

Losses of both habitat area and connectivity have been identified as important drivers of species richness declines, but little theoretical and empirical work exists that addresses the effect of fragmentation on relative commonness of highly mobile species such as pollinating insects. With a large dataset of wild bee and butterfly abundances collected across Europe, we first tested the effect of habitat area and connectivity on evenness in pollinator communities using a large array of indexes that give different weight to dominance and rarity. Second, we tested if traits related to mobility and diet breadth could explain the observed evenness patterns. We found a clear negative effect of area and a weaker, but positive effect of connectivity on evenness. Communities in small habitat fragments were mainly composed of mobile and generalist species. The higher evenness in small fragments could thereby be generated by highly mobile species that maintain local populations with frequent inter‐fragment movements. Trait analysis suggested an increasing importance of dispersal over local recruitment, as we move from large to small fragments and from less to more connected fragments. Species richness and evenness were negatively correlated indicating that the two variables responded differently to habitat area and connectivity, although the mechanisms underlying the observed patterns are difficult to isolate. Even though habitat area and connectivity often decrease simultaneously due to habitat fragmentation, an interesting practical implication of the contrasting effect of the two variables is that the resulting community composition will depend on the relative strength of these two processes.     

Accounting for overfishing in life cycle assessment: new impact categories for biotic resource use

Purpose

Overfishing is a relevant issue to include in all life cycle assessments (LCAs) involving wild caught fish, as overfishing of fish stocks clearly targets the LCA safeguard objects of natural resources and natural ecosystems. Yet no robust method for assessing overfishing has been available. We propose lost potential yield (LPY) as a midpoint impact category to quantify overfishing, comparing the outcome of current with target fisheries management. This category primarily reflects the impact on biotic resource availability, but also serves as a proxy for ecosystem impacts within each stock.

Methods

LPY represents average lost catches owing to ongoing overfishing, assessed by simplified biomass projections covering different fishing mortality scenarios. It is based on the maximum sustainable yield concept and complemented by two alternative methods, overfishing though fishing mortality (OF) and overfishedness of biomass (OB), that are less data-demanding.

Results and discussion

Characterization factors are provided for 31 European commercial fish stocks in 2010, representing 74 % of European and 7 % of global landings. However, large spatial and temporal variations were observed, requiring novel approaches for the LCA practitioner. The methodology is considered compliant with the International Reference Life Cycle Data System (ILCD) standard in most relevant aspects, although harmonization through normalization and endpoint characterization is only briefly discussed.

Conclusions

Seafood LCAs including any of the three approaches can be a powerful communicative tool for the food industry, seafood certification programmes, and for fisheries management.     

Detection and identification of protein isoforms using cluster analysis of MALDI-MS mass spectra

We describe an approach to screen large sets of MALDI-MS mass spectra for protein isoforms separated on two-dimensional electrophoresis gels. Mass spectra are matched against each other by utilizing extracted peak mass lists and hierarchical clustering. The output is presented as dendrograms in which protein isoforms cluster together. Clustering could be applied to mass spectra from different sample sets, dates, and instruments, revealed similarities between mass spectra, and was a useful tool to highlight peptide peaks of interest for further investigation. Shared peak masses in a cluster could be identified and were used to create novel peak mass lists suitable for protein identification using peptide mass fingerprinting. Complex mass spectra consisting of more than one protein were deconvoluted using information from other mass spectra in the same cluster. The number of peptide peaks shared between mass spectra in a cluster was typically found to be larger than the number of peaks that matched to calculated peak masses in databases, thus modified peaks are probably among the shared peptides. Clustering increased the number of peaks associated with a given protein.     

Analysis of the 5-lipoxygenase promoter and characterization of a vitamin D receptor binding site

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and transforming growth factor beta (TGFbeta) potently induce 5-lipoxygenase (5-LO) in myeloid cells. We analyzed vitamin D receptor (VDR) binding to putative vitamin D response elements within the 5-LO promoter and analyzed its function by reporter gene analysis. Binding of VDR and retinoid X receptor to the promoter region was shown in DNase I footprinting, electrophoretic mobility shift and chromatin immunoprecipitation assays. However, the identified VDR binding region did not mediate induction of reporter gene activity by 1,25(OH)(2)D(3)/TGFbeta, neither in the 5-LO promoter context nor with the thymidine kinase (tk) promoter. Insertion of the rat atrial natriuretic factor VDRE in reporter plasmids containing the 5-LO promoter diminished induction by 1,25(OH)(2)D(3)/TGFbeta as compared with the tk promoter. Similarly, low inductions were obtained when cells were transiently or stably transfected with constructs containing various 5-LO promoter regions. Concerning basal promoter activity, we identified a positive regulatory region (-779 to -229), which includes the VDR binding region, in 5-LO-positive MonoMac6 cells. In summary, the VDR/RXR complex binds to putative VDREs in the 5-LO promoter, but other sequences outside the 5-LO promoter seem to be responsible or additionally required for the prominent induction of 5-LO mRNA expression by 1,25(OH)(2)D(3) and TGFbeta.     

The chloroplast‐localized small heat shock protein Hsp21 associates with the thylakoid membranes in heat‐stressed plants

The small heat shock protein (sHsp) chaperones are crucial for cell survival and can prevent aggregation of client proteins that partially unfold under destabilizing conditions. Most investigations on the chaperone activity of sHsps are based on a limited set of thermosensitive model substrate client proteins since the endogenous targets are often not known. There is a high diversity among sHsps with a single conserved β‐sandwich fold domain defining the family, the α‐crystallin domain, whereas the N‐terminal and C‐terminal regions are highly variable in length and sequence among various sHsps and conserved only within orthologues. The endogenous targets are probably also varying among various sHsps, cellular compartments, cell type and organism. Here we have investigated Hsp21, a non‐metazoan sHsp expressed in the chloroplasts in green plants which experience huge environmental fluctuations not least in temperature. We describe how Hsp21 can also interact with the chloroplast thylakoid membranes, both when isolated thylakoid membranes are incubated with Hsp21 protein and when plants are heat‐stressed. The amount of Hsp21 associated with the thylakoid membranes was precisely determined by quantitative mass spectrometry after metabolic ¹⁵N‐isotope labeling of either recombinantly expressed and purified Hsp21 protein or intact Arabidopsis thaliana plants. We found that Hsp21 is among few proteins that become associated with the thylakoid membranes in heat‐stressed plants, and that approximately two thirds of the pool of chloroplast Hsp21 is affected. We conclude that for a complete picture of the role of sHsps in plant stress resistance also their association with the membranes should be considered.     

Parkinson's disease: recent development in therapies for advanced disease with a focus on deep brain stimulation (DBS) and duodenal levodopa infusion

Effective medical treatment for Parkinson's disease has been available for almost 40 years. After several years of treatment with L-dihydroxyphenylalanine (L-dopa, levodopa), however, fluctuations often occur. The patient may then experience random variations of the motor symptoms during the day. The medication becomes increasingly complicated. New therapeutic methods, deep brain stimulation and duodenal infusion of L-dopa, have proven to be very effective in stabilizing the fluctuations. A clinical update of Parkinson's disease is presented together with a short review of these two methods.