Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Statins exert anti-inflammatory effects and downregulate matrix metalloproteinases (MMPs) expression, thus contributing to restore cardiovascular homeostasis in cardiovascular diseases. We aimed at comparing the effects of different statins (simvastatin, atorvastatin, and pravastatin) on MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios released by human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA). HUVECs were incubated with statins (0.1-10 mu M) for 12 h before stimulation with PMA 100 nM. Monolayers were used to perform cell viability assays and the supernatants were collected to determine MMPs and TIMPs levels by gelatin zymography and/or enzyme immunoassay. While treatment with PMA increased MMP-9 and TIMP-1 levels (by 556% and 159%, respectively; both P < 0.05), it exerted no effects on MMP-2 and TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, attenuated PMA-induced increases in MMP-9 levels (P < 0.05). Only atorvastatin decreased baseline MMP-2 levels significantly (P < 0.05). We found no effects on TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, decreased MMP-9/TIMP-1 ratio significantly (both P < 0.05), whereas atorvastatin and pravastatin, but not simvastatin, decreased MMP-2/TIMP-2 ratio significantly (both P < 0.05). Our data support the notion that statins with different physicochemical features exert variable effects on MMP/TIMP ratios (which reflect net MMP activity). Our results suggest that more lipophilic statins (simvastatin and atorvastatin), but not the hydrophilic statin pravastatin, downregulate net MMP-9 activity. However, atorvastatin and pravastatin may downregulate net MMP-2 activity. The clinical implications of the present findings deserve further investigation.

Matrix-product codes over Fq

Codes C-1,...,C-M of length it over F-q and an M x N matrix A over F-q define a matrix-product code C = [C-1 (...) C-M] (.) A consisting of all matrix products [c(1) (...) c(M)] (.) A. This generalizes the (u/u + v)-, (u + v + w/2u + v/u)-, (a + x/b + x/a + b + x)-, (u + v/u - v)- etc. constructions. We study matrix-product codes using Linear Algebra. This provides a basis for a unified analysis of /C/, d(C), the minimum Hamming distance of C, and C-perpendicular to. It also reveals an interesting connection with MDS codes. We determine /C/ when A is non-singular. To underbound d(C), we need A to be 'non-singular by columns (NSC)'. We investigate NSC matrices. We show that Generalized Reed-Muller codes are iterative NSC matrix-product codes, generalizing the construction of Reed-Muller codes, as are the ternary 'Main Sequence codes'. We obtain a simpler proof of the minimum Hamming distance of such families of codes. If A is square and NSC, C-perpendicular to can be described using C-1(perpendicular to),...,C-M(perpendicular to) and a transformation of A. This yields d(C-perpendicular to). Finally we show that an NSC matrix-product code is a generalized concatenated code.

Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs.

In population pharmacokinetic studies, the precision of parameter estimates is dependent on the population design. Methods based on the Fisher information matrix have been developed and extended to population studies to evaluate and optimize designs. In this paper we propose simple programming tools to evaluate population pharmacokinetic designs. This involved the development of an expression for the Fisher information matrix for nonlinear mixed-effects models, including estimation of the variance of the residual error. We implemented this expression as a generic function for two software applications: S-PLUS and MATLAB. The evaluation of population designs based on two pharmacokinetic examples from the literature is shown to illustrate the efficiency and the simplicity of this theoretic approach. Although no optimization method of the design is provided, these functions can be used to select and compare population designs among a large set of possible designs, avoiding a lot of simulations.

Relationship of glycosaminoglycan and matrix changes to vascular smooth cell phenotype modulation in rabbit arteries after acute injury

Purpose: The phenotype of vascular smooth muscle cells (SMCs) is altered in several arterial pathologies, including the neointima formed after acute arterial injury. This study examined the time course of this phenotypic change in relation to changes in the amount and distribution of matrix glycosaminoglycans. Methods: The immunochemical staining of heparan sulphates (HS) and chondroitin sulphates (CS) in the extracellular matrix of the arterial wall was examined at early points after balloon catheter injury of the rabbit carotid artery. SMC phenotype was assessed by means of ultrastructural morphometry of the cytoplasmic volume fraction of myofilaments. The proportions of cell and matrix components in the media were analyzed with similar morphometric techniques. Results: HS and CS were shown in close association with SMCs of the uninjured arterial media as well as being more widespread within the matrix. Within 6 hours after arterial injury, there was loss of the regular pericellular distribution of both HS and CS, which was associated with a significant expansion in the extracellular space. This preceded the change in ultrastructural phenotype of the SMCs. The glycosaminoglycan loss was most exaggerated at 4 days, after which time the HS and CS reappeared around the medial SMCs. SMCs of the recovering media were able to rapidly replace their glycosaminoglycans, whereas SMCs of the developing neointima failed to produce HS as readily as they produced CS. Conclusions: These studies indicate that changes in glycosaminoglycans of the extracellular matrix precede changes in SMC phenotype after acute arterial injury. In the recovering arterial media, SMCs replace their matrix glycosaminoglycans rapidly, whereas the newly established neointima fails to produce similar amounts of heparan sulphates.

Lanczos subspace filter diagonalization: Homogeneous recursive filtering and a low-storage method for the calculation of matrix elements

We develop a new iterative filter diagonalization (FD) scheme based on Lanczos subspaces and demonstrate its application to the calculation of bound-state and resonance eigenvalues. The new scheme combines the Lanczos three-term vector recursion for the generation of a tridiagonal representation of the Hamiltonian with a three-term scalar recursion to generate filtered states within the Lanczos representation. Eigenstates in the energy windows of interest can then be obtained by solving a small generalized eigenvalue problem in the subspace spanned by the filtered states. The scalar filtering recursion is based on the homogeneous eigenvalue equation of the tridiagonal representation of the Hamiltonian, and is simpler and more efficient than our previous quasi-minimum-residual filter diagonalization (QMRFD) scheme (H. G. Yu and S. C. Smith, Chem. Phys. Lett., 1998, 283, 69), which was based on solving for the action of the Green operator via an inhomogeneous equation. A low-storage method for the construction of Hamiltonian and overlap matrix elements in the filtered-basis representation is devised, in which contributions to the matrix elements are computed simultaneously as the recursion proceeds, allowing coefficients of the filtered states to be discarded once their contribution has been evaluated. Application to the HO2 system shows that the new scheme is highly efficient and can generate eigenvalues with the same numerical accuracy as the basic Lanczos algorithm.

Working memory in schizophrenia and mania: Correlation with symptoms during the acute and subacute phases

Objective: The aims of this study were to examine working memory in the acute-subacute phase of schizophrenia and mania and to examine correlations between working memory and specific symptom domains. Method: Visuospatial working memory and symptom profiles were assessed in three groups (schizophrenia group, n=19; mania, n=12; controls, n=19) on two occasions separated by 4 weeks. Results: Both patient groups had significant deficits on working memory compared to the well controls and the schizophrenia and mania groups were equally impaired. All groups showed equivalent improvement over time. In the patient groups, impaired working memory was significantly correlated with the presence of both negative symptoms and positive thought disorder. Conclusion: Impaired wet-king memory is found in both schizophrenia and mania during the acute-subacute phases. Further research is required in order to clarify the neurocognitive mechanisms linking impaired working memory with both negative symptoms and positive thought disorder.

Freeform fabrication of aluminum metal-matrix composites

A series of metal-matrix composites were formed by extrusion freeform, fabrication of a sinterable aluminum alloy in combination with silicon carbide particles and whiskers, carbon fibers, alumina particles, and hollow flyash cenospheres. Silicon carbide particles were most successful in that the composites retained high density with up to 20 vol% of reinforcement and the strength approximately doubles over the strength of the metal matrix alone. Comparison with simple models suggests that this unexpectedly high degree of reinforcement can be attributed to the concentration of small silicon carbide particles around the larger metal powder. This fabrication method also allows composites to be formed with hollow spheres that cannot be formed by other powder or melt methods.

Phyllodes tumors of the breast: Correlation of nucleolar organizer regions with histopathological malignancy grading, flow cytometric DNA analysis and clinical outcome

To examine whether nucleolar organizer regions detected by argyrophilia (Ag-NOR counts) can be used as a prognostic indicator in phyllodes tumors of the breast, and to compare its usefulness with that of DNA flow cytometric analysis, 28 cases of breast phyllodes tumors (including 15 benign, two borderline and 11 malignant tumors) were subjected to Ag-NOR staining and counting as well as DNA flow cytometric analysis. S-phase fraction and DNA ploidy analysis showed useful trends for improving outcome predictions in malignant phyllodes tumors. However, high Ag-NOR counts were significant in predicting survival status (P = 0.013) and reached near statistical significance in predicting survival times (P = 0.07). In predicting survival status, results for Ag-NOR counts were significantly better than those for ploidy analysis (P = 0.02) and S-phase fraction (P < 0.01). Only S-phase fraction was significantly predictive of survival times (P = 0.025). It is concluded that Ag-NOR counts and DNA flow cytometric analysis, easily performed using paraffin sections, give information that can improve predictions made by histopathological classification. Ag-NOR counts are significant in predicting survival in the presence of histopathological features of malignancy.

Effects of moist chilling and solid matrix priming on germination of loblolly pine (Pinus taeda L.) seeds

Loblolly pine ( Pinus taeda L.) seeds from sources with a mild climate under maritime influence (North Carolina) required shorter moist chilling to achieve maximum germination vigor than seeds from sources with a harsher continental climate (Oklahoma). Solid matrix priming (SMP) for 6 d achieved as much as 60 d of moist chilling to improve rapidity, synchrony and completeness of germination for three of the four families studied. SMP after moist chilling increased the rapidity, synchrony and completeness of germination. The benefit of SMP was greatest for non-stratified seeds and the benefit decreased with length of moist chilling. In general, delaying planting for one week after SMP had minor effects on germination when seeds were kept in the SMP matrix at 4 degreesC. Delayed planting after SMP can increase germination rapidity and synchrony of seeds that have received long moist chilling and reduce the benefit of SMP in non-moist-chilled seeds.

The plausibility of long-wavelength stress correlation or stress magnitude as a mechanism for precursory seismicity: Results from two simple elastic models

Observations of accelerating seismic activity prior to large earthquakes in natural fault systems have raised hopes for intermediate-term eartquake forecasting. If this phenomena does exist, then what causes it to occur? Recent theoretical work suggests that the accelerating seismic release sequence is a symptom of increasing long-wavelength stress correlation in the fault region. A more traditional explanation, based on Reid's elastic rebound theory, argues that an accelerating sequence of seismic energy release could be a consequence of increasing stress in a fault system whose stress moment release is dominated by large events. Both of these theories are examined using two discrete models of seismicity: a Burridge-Knopoff block-slider model and an elastic continuum based model. Both models display an accelerating release of seismic energy prior to large simulated earthquakes. In both models there is a correlation between the rate of seismic energy release with the total root-mean-squared stress and the level of long-wavelength stress correlation. Furthermore, both models exhibit a systematic increase in the number of large events at high stress and high long-wavelength stress correlation levels. These results suggest that either explanation is plausible for the accelerating moment release in the models examined. A statistical model based on the Burridge-Knopoff block-slider is constructed which indicates that stress alone is sufficient to produce accelerating release of seismic energy with time prior to a large earthquake.

Clinicopathological significance of the 'keloid-like' collagen and myxoid stroma in advanced rectal cancer

Aim: To establish the histological categorization of fibrotic stroma which reflects the biological behaviour of advanced rectal cancer. Methods and results: Six hundred and twenty-seven surgically resected cases of advanced rectal carcinoma were examined. We histologically categorized fibrotic stroma in the invasive frontal region into three groups: type A, multiple fine and mature fibres were stratified into layers: type B, broad bands of eosinophilic hyalinized collagen ('keloid-like' collagen) were intermingled: type C, myxoid stroma. Type A stroma was observed in 63% of patients, type B stroma in 25%, type C stroma in 12%.. The incidence of type A stroma decreased in accordance with Dukes stage (98% in Dukes A: 73% in B: 41%, in C1: 29% in C2) and conversely, there was an increase of C type (0%, in Dukes A; 4%, in B: 20% in C1: 54% in C2). Stroma type had a significant correlation with long-term survival (80% of 5-year survival in type A stroma: 54% in type B: 26% in type C). Based on multivariate analysis. it was found that the stromal pattern had independent prognostic value, together with nodal involvement. growth pattern. and lymphocyte infiltration. Conclusions: Tumour fibrotic stroma may play an important role as a regulator of neoplastic behaviour. Pathological categorization of the fibrotic stroma is helpful for predicting the prognostic outcome of patients with rectal carcinoma.

Integrability and exact solution for coupled BCS systems associated with the su(4) Lie algebra

We introduce an integrable model for two coupled BCS systems through a solution of the Yang-Baxter equation associated with the Lie algebra su(4). By employing the algebraic Bethe ansatz, we determine the exact solution for the energy spectrum. An asymptotic analysis is conducted to determine the leading terms in the ground state energy, the gap and some one point correlation functions at zero temperature. (C) 2002 Published by Elsevier Science B.V.

Positive genetic correlation between female preference and offspring fitness

In many species, females display preferences for extreme male signal traits, but it has not been determined if such preferences evolve as a consequence of females gaining genetic benefits from exercising choice. If females prefer extreme male traits because they indicate male genetic quality that will enhance the fitness of offspring, a genetic correlation will evolve between female preference genes and genes that confer offspring fitness. We show that females of Drosophila serrata prefer extreme male cuticular hydrocarbon (CHC) blends, and that this preference affects offspring fitness. Female preference is positively genetically correlated with offspring fitness, indicating that females have gained genetic benefits from their choice of males. Despite male CHCs experiencing strong sexual selection, the genes underlying attractive CHCs also conferred lower offspring fitness, suggesting a balance between sexual selection and natural selection may have been reached in this population.