Numerical estimation of stress and refractive power maps in healthy and keratoconus eyes.

Keratoconus is an eye condition caused by localized thinning of the corneal tissue, which leads to a characteristic cone-shaped protrusion of the cornea. We investigate the mechanical behavior of keratoconus and suspect keratoconus corneas versus healthy corneas by using patient-specific finite element models. Patient-specific geometries of the corneas are obtained from diagnostic images provided by corneal topographer, transformed into solid models, and discretized in hexahedral elements. For the diseased corneas, a suitable reduction of the stiffness is applied within a limited region of the cornea around the conus. After the identification of the stress-free configuration, the models are used to simulate pressurization tests up to 40 mmHg. The material parameters have been estimated within the stress-free configuration identification procedure. As expected, numerical results reveal a more compliant behavior for the diseased corneas in terms of apex displacement plots as a function of the intraocular pressure, with diseased corneas experiencing up to 44% increase in apex displacement compared to healthy corneas. The maps of the stress confirm, for the diseased corneas, a marked increase of the maximum tensile stress, on both anterior and posterior surfaces, to be ascribed mainly to the reduction of the corneal thickness. Stress maps also show, for keratoconus corneas, a marked increase of the ratio between posterior and anterior tensile stress in the conus. Numerical analyses are used to construct the refractive power maps, revealing clearly that the maximum dioptric power in keratoconus corneas is at the center of the cone-shape rather than at the apex.

On the Connection Between Geometry and Statically Determined Membrane Stresses in the Human Cornea.

Under the action of the intraocular pressure (IOP), the human cornea is stressed and deforms acquiring a quasi-spherical configuration. If the stressed configuration is known, and the cornea is regarded as a membrane, disregarding flexural behaviors with an equilibrium analysis only is possible to estimate the distribution of the average stress across the thickness. In the cornea, the action of the intraocular pressure is supported by collagen fibrils, immersed into an elastin-proteoglycan matrix, and organized in a very precise architecture to provide the necessary confinement and transparency to the light. With the goal of understanding the static consequences of shape modifications due to pathological dilatation (ectasia), we present a simplified stress analysis of the human cornea modeled as a membrane. A numerical investigation over 40 patient-specific corneas (20 normal and 20 ectatic) is carried out to establish a relationship between the physiological geometry and the distribution of the membrane stresses, and to assess the possibility to obtain information on the stress state based on topographic images only. Comparative analyses reveal that, with respect to normal corneas, in ectatic corneas the pattern of the principal stress lines is modified markedly showing a deviation from the hypothetical dominant orientation of the collagen fibrils. The rotation of the principal stress with respect to the fibril orientation can be thought as responsible of the transmission of a large amount of shear stresses onto the elastin-proteoglycan matrix. The anomalous loading of the matrix could be correlated to the evolution of time-dependent shape modifications leading to ectasia.

A microstructural model of cross-link interaction between collagen fibrils in the human cornea.

We propose a simplified micromechanical model of the fibrous reinforcement of the corneal tissue. We restrict our consideration to the structural function of the collagen fibrils located in the stroma and disregard the other all-important components of the cornea. The reinforcing structure is modelled with two sets of parallel fibrils, connected by transversal bonds within the single fibril family (inter-cross-link) and across the two families (intra-cross-link). The particular design chosen for this ideal structure relies on the fact that its ability to sustain loads is dependent on the degree of the cross-link and, therefore, on the density and stiffness of the bonds. We analyse the mechanical response of the system according to the type of interlacing and on the stiffness of fibres and bonds. Results show that the weakening of transversal bonds is associated with a marked increase of the deformability of the system. In particular, the deterioration of transversal bonds due to mechanical, chemical or enzymatic reasons can justify the loss of stiffness of the stromal tissue resulting in localized thinning and bulging typically observed in keratoconus corneas. This article is part of the theme issue 'Rivlin's legacy in continuum mechanics and applied mathematics'.

A modified approach to horizontal augmention of soft tissue around the implant: omega roll envelope flap. Description of surgical technique.

OBJECTIVE: The flap's design, as applied to implant surgery procedures for implant-prosthetic therapy, takes inspiration from the roll technique of Abrams (1980) and subsequent modifications. This article describes a modified flap design for the correction of horizontal alveolar mucosa defects in implant-supported rehabilitation with one-stage and two-stage approache. The omega roll envelope flap (OREF) is a roll flap combined with a modified pouch technique. The goal of this type of flap design is to correct localized horizontal alveolar ridge defects and augment peri-implant soft tissue thickness. DESIGN: OREF is a flap technique that avoids harvesting autologous connective tissue from another donor site by using the supracrestal connective tissue of the implant surgical site. The proposed technique allows for increased horizontal buccal soft tissue thickness during implant-prosthetic rehabilitation. DISCUSSION: The OREF technique is practical for one- and two-stage implant approaches, and when it is applied with an immediate non-functional loading procedure, this technique can optimize surgical and prosthesis chair times. This technique has shown advantages as maximizes the amount of connective tissue that can be rolled within the buccal flap. The OREF technique can be applied with a one-technique can be applied with a one-stage or two-stage implant-prosthetic approach.

Centella asiatica and lipoic acid, or a combination thereof, inhibit monocyte adhesion to endothelial cells from umbilical cords of gestational diabetic women.

BACKGROUND AND AIMS: Diabetes mellitus is associated with inflammatory endothelial activation and increased vascular leukocyte adhesion molecule expression, both playing a prominent role in the development of vascular complications. Centella asiatica (CA) and Lipoic Acid (LA) have shown anti-inflammatory and anti-oxidant properties in a variety of experimental models; however, their action on human umbilical vein endothelial cells (HUVECs), chronically exposed to hyperglycemia and pro-inflammatory environment during pregnancy, is still unknown. METHODS AND RESULTS: In HUVECs from umbilical cords of gestational diabetic (GD) or healthy (C) women, both CA and LA affected tumor necrosis factor-α (TNF-α)-induced inflammation, being associated with a significant decrease in vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression (western blot) and exposure (flow cytometry), as well as monocyte-HUVECs interaction (adhesion assay). Notably, this was associated with a significant reduction of an index of nitro-oxidative stress, such as the intracellular peroxynitrite levels (fluorescence detection by cytometric analysis), Mitogen-Activated Protein kinase (p44/42 MAPK) expression/phosphorylation levels and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB p65) cytoplasm-nucleus translocation (flow cytometry). Overall our results indicate that both CA and LA used separately, and even better when combined, are effective to reduce the inflammatory response in TNF-α-treated HUVECs. Notably, this was more significant in GD than in C-HUVECs and also evident at baseline. CONCLUSION: In conclusion, our in vitro study demonstrates that both CA and LA, or a combination thereof, are able to mitigate the potentially dangerous effects on the endothelium of chronic exposure to hyperglycemia in vivo.

Features of endothelial dysfunction in umbilical cord vessels of women with gestational diabetes.

BACKGROUND AND AIMS: Gestational diabetes (GDM) is associated with increased oxidative stress and overexpression of inflammatory cytokines, both of which might lead to endothelial dysfunction and vascular disease. As such, GDM could be viewed as a sort of 'short lived' metabolic syndrome. As umbilical cord vessels represent a suitable model for the study of vascular alterations brought about by GDM, the aim of the present work was to characterize the phenotype of human umbilical vein endothelial cells (HUVECs) chronically exposed to hyperglycaemia and to a pro-inflammatory environment during pregnancy so as to identify molecular modifications of cellular homoeostasis eventually impacting on endothelial dysfunction. METHODS AND RESULT: Tissue specimens and HUVECs were obtained from umbilical cords of GDMand control women. As compared to controls, GD-HUVEC exhibited enhanced monocyte adhesion and vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1(ICAM-1) expression and exposure on plasma membrane after tumour necrosis factor-alpha(TNF-α) stimulation (Western blot, flow cytometer). As compared to control cells, GD-HUVEC in basal conditions exhibited enhanced monocyte adhesion, nitric oxide synthase (NOS) expression and activity (eNOS Real-Time polymerase chain reaction, Western Blot for eNOS total protein and monomers/dimers ratio, conversion of [3H]-L-arginine in [3H]-L-citrulline), increased O(-)(2)egeneration together with increased NT levels (immunofluorescence) and reduced NO bioavailability(guanosine 3',5'-monophosphate (cGMP) production, EIA). Furthermore, immunohistochemistry revealed increased eNOS and NT immunoreactivity in GD umbilical cords. CONCLUSION: Endothelial cells exposed in vivo even transiently to hyperglycaemia, oxidative stress and inflammation exhibit durable pro-atherogenic modifications.

Transcriptome analysis of human primary endothelial cells (HUVEC) from umbilical cords of gestational diabetic mothers reveals candidate sites for an epigenetic modulation of specific gene expression.

Within the complex pathological picture associated to diabetes, high glucose (HG) has "per se" effects on cells and tissues that involve epigenetic reprogramming of gene expression. In fetal tissues, epigenetic changes occur genome-wide and are believed to induce specific long term effects. Human umbilical vein endothelial cells (HUVEC) obtained at delivery from gestational diabetic women were used to study the transcriptomic effects of chronic hyperglycemia in fetal vascular cells using Affymetrix microarrays. In spite of the small number of samples analyzed (n=6), genes related to insulin sensing and extracellular matrix reorganization were found significantly affected by HG. Quantitative PCR analysis of gene promoters identified a significant differential DNA methylation in TGFB2. Use of Ea.hy926 endothelial cells confirms data on HUVEC. Our study corroborates recent evidences suggesting that epigenetic reprogramming of gene expression occurs with persistent HG and provides a background for future investigations addressing genomic consequences of chronic HG.

Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD, and wild-type mice.

In this study, we investigated the effects of long-term (9-month) treatment with pioglitazone (PIO; 20 mg/kg/d) in two animal models of Alzheimer's disease (AD)-related neural dysfunction and pathology: the PS1-KI(M146V) (human presenilin-1 (M146V) knock-in mouse) and 3xTg-AD (triple transgenic mouse carrying AD-linked mutations) mice. We also investigated the effects on wild-type (WT) mice. Mice were monitored for body mass changes, fasting glycemia, glucose tolerance, and studied for changes in brain mitochondrial enzyme activity (complexes I and IV) as well as energy metabolism (lactate dehydrogenase (LDH)). Cognitive effects were investigated with the Morris water maze (MWM) test and the object recognition task (ORT). Behavioral analysis revealed that PIO treatment promoted positive cognitive effects in PS1-KI female mice. These effects were associated with normalization of peripheral gluco-regulatory abnormalities that were found in untreated PS1-KI females. PIO-treated PS1-KI females also showed no statistically significant alterations in brain mitochondrial enzyme activity but significantly increased reverse LDH activity.PIO treatment produced no effects on cognition, glucose metabolism, or mitochondrial functioning in 3xTg-AD mice. Finally, PIO treatment promoted enhanced short-term memory performance in WT male mice, a group that did not show deregulation of glucose metabolism but that showed decreased activity of complex I in hippocampal and cortical mitochondria. Overall, these results indicate metabolically driven cognitive-enhancing effects of PIO that are differentially gender-related among specific genotypes.

Mechanical characterization of porcine corneas.

An experimental program has been carried out in order to investigate the mechanical behavior of porcine corneas. We report the results of inflation tests on the whole cornea and uniaxial tests on excised corneal strips, performed on 51 fresh porcine eyes. Uniaxial tests have been performed on specimens cut from previously inflated corneas. The cornea behavior is characterized by means of elastic stiffness, measured on both average pressure-apex displacement and average uniaxial stress-strain curves; and by means of transversal contraction coefficient, peak stress, and failure stress measured on uniaxial stress-strain curves. Uniaxial tests performed on excised strips allowed to measure the anisotropy in the corneal stiffness and to compare the stiffness of the cornea with the one of the sclera. Viscous properties of the cornea have been obtained through uniaxial relaxation curves on excised corneal strips. The relevant geometrical parameters have been measured and, with the aid of the elastic thin shell theory, a stress-strain curve has been derived from the average inflation test data and compared with similar data available in the literature. The experimental system has been developed in view of future applications to the mechanical testing of both porcine and human corneas.

Counting of leukocytes in samples from G-CSF mobilized donors, leukapheresis products, and cord blood: the performances of an analyzer with dedicated profiles.

INTRODUCTION: Accurate white blood cell counting (WBC) and differential count by blood analyzers could allow a more informative characterization of granulocyte colony-stimulating factor (G-CSF) mobilized blood (MB), leukapheresis products (LP), and cord blood (CB). However, reliable counting by a blood cell analyzer in this setting is a major challenge owing to quali-quantitative abnormalities of blood cells. METHODS: We evaluated the performances of the analyzer Pentra DX 120 by Horiba ABX working with dedicated cell-gating profiles, which generate three-part differential counts in samples obtained from donors' MB, LP, and CB. The results of the analyzer were compared to counts obtained by flow cytometry and manual counts, the latter performed for reference validation and in the case of discrepant results between study and reference counts. RESULTS: Pentra DX 120 generated highly correlated counts (R > 0.91 in all cases) to those obtained by flow cytometry in all samples (MB, LP, and CB) with high degree of count accuracy in most cases and referred to WBC absolute count and differential count including lymphocytes (LYM) %, monocytes (MON) %, and polymorphonuclear leukocytes (PMN) %. Accuracy, judged by the difference between study and reference counts and expressed as percentage of reference count, ranged from 0.8% to 8.6%, and sporadic loss of accuracy occurred for MON % only in no more than 10% of CB samples. CONCLUSION: The ABX Pentra DX 120 provided accurate WBC count and differential count during MB, LP, and CB analyses and allowed a better characterization of donors' hematologic status and graft composition.

[Reduced nitric oxide bioavailability in chronic renal failure: a new factor of progression?]. / Ridotta biodisponibilità di ossido nitrico nell'insufficienza renale cronica: un nuovo fattore di progressione?

Nitric oxide (NO) is a gaseous free radical and an important molecular mediator of many physiologic processes in virtually every organ. NO is produced from L-arginine by nitric oxide synthase (NOS). This enzyme is expressed as 3 isoforms, all of which have been isolated from the kidney: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). At present it is very difficult to measure authentic nitric oxide in vivo; a way to circumvent the difficulties is to study the effects of NOS stimulation and subsequent nitric oxide release directly by measurement of the resulting changes in vascular tone. In the kidney and vasculature, NO plays fundamental roles in the control of systemic and intrarenal hemodynamics, the tubuloglomerular feedback response, pressure natriuresis, release of sympathetic neurotransmitters and renin, and tubular solute and water transport. Chronic renal failure (CRF) is a state of NO deficiency secondary to decreased NO production and/or increased bioinactivation of NO by reactive oxygen species. The purpose of this review is to examine the functions of NO in the kidney, and to discuss the effects of NO deficiency in the progression of chronic kidney disease.

Numerical modelling of fracture in human arteries.

We present 3D finite element models of atherosclerotic arteries, used to investigate the influence of the geometry and tissue properties on the plaque rupture caused by overexpansion. We adopted a geometry reconstructed from a contiguous set of in vitro magnetic resonance images of a damaged artery. The artery wall is divided in three layers (adventitia, media and intima) and is discretized into tetrahedral finite elements. The artery material is described with a hyperelastic two-fiber anisotropic model proposed by Holzapfel et al. 2000. A new constitutive framework for arterial wall mechanics and a comparative study of material models. J Elasticity 61(1):1-48, while the plaque is assumed to be transversely isotropic. Cracks induced by mechanical actions are represented through cohesive surfaces, and are allowed to develop along solid elements boundaries only. Fractures are explicitly introduced in the discretized model at the locations where the tensile strength of the material is reached.

The prominent role of p38 mitogen-activated protein kinase in insulin-mediated enhancement of VCAM-1 expression in endothelial cells.

Insulin levels are a marker for cardiovascular events, but the link between hyperinsulinemia and atherosclerosis is poorly understood. We previously showed that insulin increases monocyte-endothelial interactions and the endothelial expression of the pro-atherogenic vascular cell adhesion molecule-1 (VCAM-1). The aim of this study is to examine molecular mechanisms involved in the effect of insulin on VCAM-1 expression. Human umbilical vein endothelial cells (HUVEC) were incubated with insulin (0-24 h)+/- inhibitors of signaling pathways potentially involved. At pathophysiological concentrations (10(-9)-10(-7) M), insulin selectively induced VCAM-1 expression. The p38 mitogen activated protein(MAP) kinase inhibitors SB203580 and SB202190, and partially the c-Jun NH2-terminal kinase (JNK) inhibitor SP600127, decreased insulin effect on VCAM-1. Gene silencing by small interfering RNA significantly reduced the expression of p38MAP kinase, and this was accompanied by suppression of insulin-stimulated VCAM-1 expression. Treatment with insulin also led to the activation of NF-KB and induction of IKB-alpha phosphorylation, thus accounting for NF-KB translocation into the nucleus. Co-treatment of HUVEC with insulin and SB202190 strongly reverted the stimulatory effect of insulin on NF-KB activation, thus establishing a link between NF-KB activation and p38MAPkinase-mediated induction of VCAM-1 by insulin. In conclusion, pathophysiological insulin concentrations increase VCAM-1 expression and activate NF-KB. This mostly occurs through stimulation of p38MAP kinase.

Age-dependent changes in the expression of superoxide dismutases and catalase are associated with ultrastructural modifications in human granulosa cells.

Limited knowledge exists about changes in follicle quality associated with age. The aim of this work was to investigate whether ageing may cause oxidative stress-mediated alterations in human granulosa cells (GCs) from periovulatory follicles. GCs employed in this study were obtained from follicular aspirates of 20 younger women (range 27-32 years) and 20 older women (range 38-41 years) undergoing an IVF treatment. Results obtained from comparative RT-PCR analysis revealed that the mean relative levels of mRNAs coding for superoxide dismutases, Cu, ZnSOD (SOD1), MnSOD (SOD2) and catalase were significantly decreased in women > or =38 years (P < 0.05, Student's t-test). These changes were associated with a reduced expression of SOD1, SOD2 and catalase at the protein level. When examined at an ultrastructural level, most of the GCs from this group showed defective mitochondria and fewer lipid droplets than those observed in the younger group. These results indicate that GCs from older patients suffer from age-dependent oxidative stress injury and are taken as an evidence for reduced defence against reactive oxygen species (ROS) in GCs during reproductive ageing.

A model for the human cornea: constitutive formulation and numerical analysis.

Abstract The human cornea (the external lens of the eye) has the macroscopic structure of a thin shell, originated by the organization of collagen lamellae parallel to the middle surface of the shell. The lamellae, composed of bundles of collagen fibrils, are responsible for the experimentally observed anisotropy of the cornea. Anomalies in the fibril structure may explain the changes in the mechanical behavior of the tissue observed in pathologies such as keratoconus. We employ a fiber-matrix constitutive model and propose a numerical model for the human cornea that is able to account for its mechanical behavior in healthy conditions or in the presence of keratoconus under increasing values of the intraocular pressure. The ability of our model to reproduce the behavior of the human cornea opens a promising perspective for the numerical simulation of refractive surgery.

Insulin enhances vascular cell adhesion molecule-1 expression in human cultured endothelial cells through a pro-atherogenic pathway mediated by p38 mitogen-activated protein-kinase.

AIMS/HYPOTHESIS: Although hyperinsulinaemia in Type 2 diabetes in states of insulin resistance is a risk factor for atherosclerotic vascular disease, underlying mechanisms are poorly understood. We tested the hypothesis that insulin increases monocyte-endothelial interactions, which are implicated in atherosclerosis. METHODS: We treated human umbilical vein endothelial cells with insulin (10(-10) to 10(-7) mol/l) for 0 to 24 h. To dissect potentially implicated signal transduction pathways, we treated endothelial cells with known pharmacological inhibitors of two distinct insulin signalling pathways: the phosphatidylinositol-3'-kinase (PI3'-kinase) inhibitor wortmannin (3 x 10(-8) to 10(-6) mol/l), involved in insulin-induced endothelial nitric oxide synthase stimulation, and the p38 mitogen-activated protein (p38MAP) kinase inhibitor SB-203580 (10(-7) to 2 x 10(-6) mol/l). We measured adhesion molecule expression by cell surface enzyme immunoassays and U937 monocytoid cell adhesion in rotational adhesion assays. RESULTS: At pathophysiological concentrations (10(-9) to 10(-7) mol/l), insulin concentration-dependently induced vascular cell adhesion molecule (VCAM)-1 (average increase: 1.8-fold) peaking at 16 h. By contrast, the expression of intercellular adhesion molecule-1 and E-selectin were unchanged. The effect on VCAM-1 was paralleled by increased U937 cell adhesion. In the absence of cytotoxicity, wortmannin significantly potentiated the effect of insulin alone on VCAM-1 surface expression and monocytoid cell adhesion, whereas SB-203580 (10(-6) mol/l) completely abolished such effects. CONCLUSIONS/INTERPRETATION: These observations indicate that insulin promotes VCAM-1 expression in endothelial cells through a p38MAP-kinase pathway, amplified by the PI3'-kinase blockage. This could contribute to explaining the increased atherosclerosis occurring in subjects with hyperinsulinaemia, or in states of insulin resistance, which feature a defective PI3'-kinase pathway.

Autologous bone marrow transplantation with negative immunomagnetic purging for aggressive B-cell non-Hodgkin's lymphoma in first complete remission.

To evaluate the effect on survival of negative immunomagnetic purging in aggressive B-cell non-Hodgkin's lymphoma (NHL), 20 patients retrospectively staged according to the age-adjusted International Prognostic Index as high-intermediate (11 patients) or high-risk (9 patients) received autologous bone marrow transplantation (ABMT) in first complete remission (CR1). All patients received six to eight cycles of a F-MACHOP-like protocol as induction treatment and then underwent high-dose chemotherapy (HDC) with a CBV-like regimen. Negative purging included a panel of monoclonal antibodies against B-cell antigens and immunomagnetic beads. The data were compared to a historical control of 18 patients with the same characteristics treated in our institution who received unpurged bone marrow support. The median yield of mononuclear cells (MNC), colony-forming units-granulocyte/macrophage (CFU-GM), and CD34+ cells after purging were 52%, 49%, and 57%, respectively. The median B-cell depletion after negative selection was 1.8 logs. All patients obtained a complete engraftment with no significant differences between the purged and unpurged group. Two toxic deaths (one for each group) were observed and the main extrahematological toxicities were mucositis, vomiting, and diarrhea. The event-free survival (EFS) and overall survival (OS) at 3 years for the whole group of 38 patients were 73% (95% CI: 59-88%) and 81% (95% CI, 68-94%), respectively. The comparison between patients receiving purged marrow and patients receiving unmanipulated marrow indicated no significant survival differences between the two groups both for EFS 84% (95% CI: 67-100%) vs 61% (95%CI: 39-84%) ( P=0.12) and OS 84% (95% CI: 69-100%) vs 71% (95% CI: 50-93%) ( P=0.58). Our report shows that HDC followed by reinfusion of autologous bone marrow can produce long EFS and OS in high-intermediate and high-risk patients with B-cell NHL transplanted in CR1, but was not be able to demonstrate a significant clinical advantage using immunomagnetic purged marrow. However, the use of ex vivo negative purging combined with innovative treatment modalities (peripheral blood stem cell transplant, in vivo administration of monoclonal antibodies) needs to be explored.

Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects.

Plasma plasminogen activator inhibitor type 1 (PAI-1) increases in diabetes, and this might contribute to decreased fibrinolysis and accelerated atherosclerosis. Increased PAI-1 levels in the vessel wall could decrease local fibrinolysis and elevate thrombus formation and the unfavorable evolution of atherosclerotic plaques. High glucose increases PAI-1 synthesis in arterial wall cells in culture, and aortic wall PAI-1 levels have been found to be elevated in diabetic animals. However, arterial wall PAI-1 levels have not been investigated in diabetic subjects. Therefore, the aim of this study was to determine the effect of diabetes on PAI-1 levels in the arterial wall. Blood samples and small tissue specimens from the mammary artery were obtained from 11 diabetic and 10 nondiabetic subjects who underwent coronary artery bypass graft surgery. PAI-1 antigen localization in the arterial wall was obtained by immunohistochemistry and was read by laser scanning confocal microscopy; plasma fibrinolytic activity was measured by lysis of fibrin plates; and PAI-1 activity was assessed by a chromogenic method. PAI-1-related immunofluorescence was increased in the arterial wall of diabetic patients, whereas plasma fibrinolysis was reduced. These data provide evidence that diabetes is associated with increased PAI-1 in the arterial wall. This might be an important factor for increased cardiovascular risk and unfavorable plaque evolution in diabetes.

Costs of high-dose chemotherapy and peripheral blood progenitor cell autograft for breast cancer.

The aim of the study was to analyze the real cost of single or tandem high-dose chemotherapy (HDC) and peripheral blood progenitor cell autologous transplant (PBPCT) in patients with breast cancer. We analyzed the costs of 40 PBPCT performed in 20 patients. Tandem transplant was planned for each patient. Resources used and direct costs were identified for each patient. The study was carried out using the hospital perspective and monetary values were reported in 1999 Euro. The mean cost of whole procedure for single transplant was 20,816.63 Euro, while the mean cost of tandem transplant was 38,770.83 Euro. The cost distribution in the two groups was similar: the most expensive phase of procedure was the supportive phase post transplant (about 60% of total cost), with the categories of cost most represented being professional fees (about 28%) and pharmacy (about 35%). Awaiting more convincing trials of the clinical advantage of HDC in breast cancer, our analytical evaluation of transplant costs for different therapeutic options, single or tandem, permits identification of the most expensive categories in order to intervene for cost savings.