Association of Caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure

Context: Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis.
Objective: To study the association of CAV1 gene variation with kidney transplant outcome, using kidney transplantation as a model of accelerated fibrosis.
Design, Setting, and Patients: Candidate gene association and validation study. Genomic DNA from 785 white kidney transplant donors and their respective recipients (transplantations in Birmingham, England, between 1996 and 2006; median followup, 81 months) were analyzed for common variation in CAV1 using a singlenucleotide polymorphism (SNP) tagging approach. Validation of positive findings was sought in an independent kidney transplant donor-recipient cohort (transplantations in Belfast, Northern Ireland, between 1986 and 2005; n=697; median follow-up, 69 months). Association between genotype and allograft failure was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model.
Main Outcome Measure: Death-censored allograft failure, defined as a return to dialysis or retransplantation.
Results: The presence of donor AA genotype for the CAV1 rs4730751 SNP was associated with increased risk of allograft failure in the Birmingham group (donor AA vs non-AA genotype in adjusted Cox model, hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.29-3.16; P=.002). No other tag SNPs showed a significant association. This finding was validated in the Belfast cohort (in adjusted Cox model, HR, 1.56; 95% CI, 1.07-2.27; P=.02). Overall graft failure rates were as follows: for the Birmingham cohort, donor genotype AA, 22 of 57 (38.6%); genotype CC, 96 of 431 (22.3%); and genotype AC, 66 of 297 (22.2%); and for the Belfast cohort, donor genotype AA, 32 of 48 (67%); genotype CC, 150 of 358 (42%); and genotype AC, 119 of 273 (44%).
Conclusion: Among kidney transplant donors, the CAV1 rs4730751 SNP was significantly associated with allograft failure in 2 independent cohorts.

Murine Models of Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction

Left ventricular diastolic dysfunction leads to heart failure with preserved ejection fraction, an increasingly prevalent condition largely driven by modern day lifestyle risk factors. As heart failure with preserved ejection fraction accounts for almost one-half of all patients with heart failure, appropriate nonhuman animal models are required to improve our understanding of the pathophysiology of this syndrome and to provide a platform for preclinical investigation of potential therapies. Hypertension, obesity, and diabetes are major risk factors for diastolic dysfunction and heart failure with preserved ejection fraction. This review focuses on murine models reflecting this disease continuum driven by the aforementioned common risk factors. We describe various models of diastolic dysfunction and highlight models of heart failure with preserved ejection fraction reported in the literature. Strengths and weaknesses of the different models are discussed to provide an aid to translational scientists when selecting an appropriate model. We also bring attention to the fact that heart failure with preserved ejection fraction is difficult to diagnose in animal models and that, therefore, there is a paucity of well described animal models of this increasingly important condition.

Automated mixed dimensional modelling from 2D and 3D CAD models

The motivation for this paper is to present procedures for automatically creating idealised finite element models from the 3D CAD solid geometry of a component. The procedures produce an accurate and efficient analysis model with little effort on the part of the user. The technique is applicable to thin walled components with local complex features and automatically creates analysis models where 3D elements representing the complex regions in the component are embedded in an efficient shell mesh representing the mid-faces of the thin sheet regions. As the resulting models contain elements of more than one dimension, they are referred to as mixed dimensional models. Although these models are computationally more expensive than some of the idealisation techniques currently employed in industry, they do allow the structural behaviour of the model to be analysed more accurately, which is essential if appropriate design decisions are to be made. Also, using these procedures, analysis models can be created automatically whereas the current idealisation techniques are mostly manual, have long preparation times, and are based on engineering judgement. In the paper the idealisation approach is first applied to 2D models that are used to approximate axisymmetric components for analysis. For these models 2D elements representing the complex regions are embedded in a 1D mesh representing the midline of the cross section of the thin sheet regions. Also discussed is the coupling, which is necessary to link the elements of different dimensionality together. Analysis results from a 3D mixed dimensional model created using the techniques in this paper are compared to those from a stiffened shell model and a 3D solid model to demonstrate the improved accuracy of the new approach. At the end of the paper a quantitative analysis of the reduction in computational cost due to shell meshing thin sheet regions demonstrates that the reduction in degrees of freedom is proportional to the square of the aspect ratio of the region, and for long slender solids, the reduction can be proportional to the aspect ratio of the region if appropriate meshing algorithms are used.

Mitochondrial Transfer via Tunneling Nanotubes (TNT) is an Important Mechanism by which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the in vitro and in vivo Models of ARDS

Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in pre-clinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the anti-microbial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC anti-microbial effect in the in vivo model of E.coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct co-culture of MSC with monocyte-derived macrophages (MDMs) enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through TNT-like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the anti-microbial effect of MSC in vivo.

Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the anti-microbial effect of MSC in ARDS.

Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure

BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF.

METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich α2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P≤0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-α (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-βR1 (P<0.001) and α-smooth muscle actin (P=0.025) expression.

CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, β-blocker therapy, and BNP.

Multi-ionization of helium and lithium using the independent electron and independent event models with intrinsic CDW

Cross sections for the multi-ionization of He and Li are presented for impact energies in the range of 50 to 1000 keV/amu. These are calculated using the eikonal initial state approximation to represent the input and exit channels of the active electrons. The ionization process is simulated in a variety of ways, most notably an attempt to account for the effects of electron correlation via the inclusion of a continuum density of states (CDS) term. Inadequacies, of the CDW formulation at small impact parameters, and of the models themselves, are discussed and conclusions are drawn on what repercussions this has for the cross sections calculated.

Willingness to Pay for Rural Landscape Improvements: Combining Mixed Logit and Random-Effects Models

This paper reports the findings from a discrete-choice experiment designed to estimate the economic benefits associated with rural landscape improvements in Ireland. Using a mixed logit model, the panel nature of the dataset is exploited to retrieve willingness-to-pay values for every individual in the sample. This departs from customary approaches in which the willingness-to-pay estimates are normally expressed as measures of central tendency of an a priori distribution. Random-effects models for panel data are subsequently used to identify the determinants of the individual-specific willingness-to-pay estimates. In comparison with the standard methods used to incorporate individual-specific variables into the analysis of discrete-choice experiments, the analytical approach outlined in this paper is shown to add considerable explanatory power to the welfare estimates.

Coordination and movement pathology: models of structure and function

Here we consider the role of abstract models in advancing our understanding of movement pathology. Models of movement coordination and control provide the frameworks necessary for the design and interpretation of studies of acquired and developmental disorders. These models do not however provide the resolution necessary to reveal the nature of the functional impairments that characterise specific movement pathologies. In addition, they do not provide a mapping between the structural bases of various pathologies and the associated disorders of movement. Current and prospective approaches to the study and treatment of movement disorders are discussed. It is argued that the appreciation of structure-function relationships, to which these approaches give rise, represents a challenge to current models of interlimb coordination, and a stimulus for their continued development. (C) 2002 Elsevier Science B.V. All rights reserved.