Beneficial Effect of Successful Simultaneous Pancreas-Kidney Transplantation on Plasma Profile of Metalloproteinases in Type 1 Diabetes Mellitus Patients.

It is not fully elucidated whether the restoring of normal glucose metabolism after successful simultaneous pancreas-kidney transplantation (SPK) improves vascular wall morphology and function in type 1 diabetic (T1D) patients. Therefore, we compared arterial stiffness, assessed by pulse wave velocity (PWV), carotid intima-media thickness (IMT), and biomarkers of arterial wall calcification in T1D patients after SPK or kidney transplantation alone (KTA). In 39 SPK and 39 KTA adult patients of similar age, PWV, IMT, circulating matrix metalloproteinases (MMPs) and calcification biomarkers were assessed at median 83 months post transplantation. Additionally, carotid plaques were visualized and semi-qualitatively classified. Although PWV and IMT values were similar, the occurrence of atherosclerotic plaques (51.3 vs. 70.3%, p < 0.01) and calcified lesions (35.9 vs. 64.9%, p < 0.05) was lower in SPK patients. There were significantly lower concentrations of MMP-1, MMP-2, MMP-3, and osteocalcin in SPK subjects. Among the analyzed biomarkers, only logMMP-1, logMMP-2, and logMMP-3 concentrations were associated with log HbA1c. Multivariate stepwise backward regression analysis revealed that MMP-1 and MMP-3 variability were explained only by log HbA1c. Normal glucose metabolism achieved by SPK is followed by the favorable profile of circulating matrix metalloproteinases, which may reflect the vasoprotective effect of pancreas transplantation.

The Pathogenesis and Diagnosis of Thromboangiitis obliterans: Is It Still a Mystery?

Thromboangiitis obliterans (TAO) is a rare disease of unknown etiology that results in the occlusion of limb arteries located distally to the elbow and knee. Despite the fact that more than one hundred years have passed since its first description, knowledge on the pathogenesis of TAO and precipitating factors is still limited. Due to a lack of decisive noninvasive diagnostic methods and geographical differences in the prevalence of this condition, data on TAO epidemiology also remains sparse. This review presents important evidence on the pathogenesis and the course of the condition, as well as diagnostic modalities, with a focus on differential diagnosis. Theories on the pathogenesis of TAO include the theory of an infectious disease, coagulation disorders and injury to vascular endothelium resulting in activation of the inflammatory response. Differential diagnosis should exclude thoracic outlet syndrome, blue toe syndrome, infectious endocarditis, popliteal entrapment syndrome, Takayasu disease, primary and secondary systemic vasculitis, antiphospholipid syndrome, infection with the anaerobic Clostridium sp. bacilli and some less common conditions.

Vasculitis in systemic lupus erythematosus (SLE)--assessment of peripheral blood mononuclear cell activation and the degree of endothelial dysfunction: initial report.

BACKGROUND: Inflammatory-immune changes in the vascular endothelium are one of the main factors initiating vessel wall damage. Enhanced expression of endothelial adhesion molecules and their receptors on the surface of circulating leukocytes seems to play an important role in the pathogenesis of vasculitis. Increasing evidence indicates endothelial cell activation/damage in SLE. In patients with SLE complicated by vasculitis, enhanced expression of integrin activation markers on the surface of peripheral blood mononuclear cells (PBMCs) has been reported. It seems relevant to assess the mechanisms of inflammatory response involving PBMCs and endothelial cells at particular stages of SLE microangiopathy. AIM: The main aim was to assess the surface expressions of the integrin adhesion molecules VLA-4 (CD49d) and LFA-1 (CD11a) on PBMCs as well as the number of circulating endothelial cells (CECs) in patients with SLE and complications related to inflammatory microangiopathy and to determine whether these parameters vary depending on disease activity. PATIENTS: Twenty-nine women with SLE (mean age: 38.72+/-10.23 years) were divided into subgroup I: those with severe disease activity according to the modified disease activity index SLEDAI, characterized by the presence of inflammatory microangiopathy-related complications such as systemic central nervous system affection and/or vasculitis and/or nephritis (15 women, mean age: 38.33+/-11.02 years), and subgroup II: patients with mild or moderate disease activity according to SLEDAI and without vascular complications (14 women, mean age: 39.14+/-9.72 years). METHODS: Expressions of VLA-4 and LFA-1 on the surface of peripheral blood lymphocytes and monocytes were assessed by flow cytometry using monoclonal antibodies. CECs (a marker of endothelial damage) were isolated from peripheral blood with anti-CD146(S-Endo 1)-coated immunomagnetic Dynabeads. Tests for the lupus anticoagulant, antinuclear antibody, anti-dsDNA, and anticardiolipin antibody were performed in every study subject by ELISA. Erythrocyte sedimentation rate and serum levels of fibrinogen, C-reactive protein, the complement components C3 and C4, urea, creatinine, and uric acid were determined by standard methods. Peripheral blood counts and a general urinalysis were also performed. RESULTS: The mean CEC count was significantly higher in SLE patients than in the control group (15.29+/-12.10 vs. 3.08+/-1.46 cells/ml, p<0.001). CEC counts was notably elevated in patient subgroup II compared with the control group (9.14+/-5.16 vs. 3.08+/-1.46 cells/ml, p<0.05) and in subgroup I compared with subgroup II (21.03+/-13.96 vs. 9.14+/-5.19 cell/ml, p<0.05). In patients with severe SLE flares, CEC count visibly correlated with disease activity assessed by SLEDAI score (R=0.92, p<0.001). The expressions of VLA-4 and LFA-1 on peripheral blood lymphocytes in both patient subgroups were significantly higher than in the control group (subgroup I vs. controls: 1.70+/-1.56 vs. 0.39+/-0.26%, p<0.05, and 1.97+/-2.60 vs. 0.67+/-0.83%, p<0.05; subgroup II vs. controls: 1.71+/-1.04 vs. 0.39+/-0.26%, p<0.001, and 3.32+/-2.48 vs. 0.67+/-0.83%, p<0.05, for VLA-4 and LFA-1, respectively). There was no significant difference between the two subgroups of patients (1.70+/-1.56 vs. 1.71+/-1.04%, p>0.05, and 1.97+/-2.60 vs. 3.32+/-2.48%, p>0.05, respectively). Similarly, the surface expression of LFA-1 on circulating monocytes in patients in both subgroups was notably enhanced over that of the control group (91.44+/-16.00 vs. 84.95+/-19.86%, p<0.05, and 90.11+/-10.34 vs. 84.95+/-19.86%, p<0.05, in subgroups I and II respectively) and was comparable in both subgroups of patients (91.44+/-16.00 vs. 90.11+/-10.33%, p>0.05). The surface expression of VLA-4 on peripheral blood monocytes was considerably higher in patients with severe disease activity than in the control group and in patients with less active disease (77.10+/-13.56 vs. 64.90+/-19.13%, p<0.05, and 77.10+/-13.56 vs. 63.40+/-20.95%, p<0.05, respectively). However, there was no significant difference between patients with mild or moderate disease activity and the control group (63.40+/-20.95 vs. 64.90+/-19.13%, p>0.05). CONCLUSIONS: 1) The number of CECs increases in the course of SLE and correlates with disease activity, indicating progressive endothelial damage.2) The expressions of VLA-4 and LFA-1 on the surface of peripheral blood lymphocytes as well as that of LFA-1 on circulating monocytes are enhanced in SLE patients regardless of disease activity. 3) The expression of VLA-4 on the surface of circulating monocytes is enhanced only in patients with severe disease activity, characterized by the presence of complications connected with inflammatory microangiopathy, which may indicate that the upregulation of VLA-4 expression in monocytes plays a leading role in the pathogenesis of vasculitis in SLE.

[New therapeutic approach in patients with type 2 diabetes based on glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP)]. / Nowe perspektywy terapii chorych na cukrzyce typu 2 oparte na glukagonopodobnym peptydzie 1 (GLP-1) i zoladkowym peptydzie hamujacym (GIP).

Inadequate secretion of insulin is a very early element in the development of type 2 diabetes and its progression is due to declining beta-cell function. This beta-cell defect is partly related to beta-cell loss, but endocrine regulation of islet function could also be involved. A number of recent studies have highlighted the role of the so-called incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP) in beta-cell function and development. Up to two- thirds of the insulin normally secreted in connection with meal intake is thought to be due to the insulinotropic actions of these hormones. Although patients with type 2 diabetes have been demonstrated to exhibit an almost total loss of incretin effect, the glucose-lowering actions of exogenous GLP-1 are well preserved. New therapeutic strategies under investigation include the search for novel agents able to utilize the incretin axis in patients with type 2 diabetes. Two strategies have been applied: the first is treatment with GLP-1, either with chronic infusions or with analogues with diminished clearance, and the second is inhibiting dipeptidyl peptidase IV, the enzyme that inactivates both GLP-1 and GIP in vivo. Inhibition of DP- IV has been shown to raise circulating active incretin levels and thus increase the effective concentrations of these peptides reaching target tissues. Apart from their glucose-dependent manner of stimulating insulin secretion, GLP-1, its analogues, and GIP have been demonstrated to stimulate beta-cell growth, differentiation, proliferation, and survival. Similarly, studies in both humans and in animal models have established DP-IV inhibition as a promising therapeutic approach for the treatment of type 2 diabetes, resulting in an enhancement of glucose tolerance, insulin sensitivity, and beta-cell glucose responsiveness.

Mutational load and the transition between diploidy and haploidy in experimental populations of the yeast Saccharomyces cerevisiae.

Mutations were accumulated over hundreds of generations in a mutator strain of yeast in a constant laboratory environment. This ensured that mutations were frequent and that the quality of environment remained unchanged. Mutations were accumulated in asexual populations of diploids but their impact on fitness was tested both for the diploid clones and for haploid clones derived from them. Dozens of harmful and lethal mutations accumulated in diploids, but important phenotypic traits, such as maximum growth rate, did not deteriorate by more than 10%. There were no signs of decline in population size. In strong contrast, the populations of haploids derived from the diploids suffered from high mortality; their density was reduced by more than three orders of magnitude. These findings indicate how ineffective natural selection can be in removing deleterious mutations from populations of clonally reproducing diploids. They also suggest that phenotypic assays of heterozygous diploids may be of little value as indicators of increasing genetic degeneration.

[The role of anti-endothelial cell antibodies in the pathogenesis of atherosclerosis and diabetic angiopathy]. / Rola przeciwcial przeciwko komórkom sródblonka naczyn (AECA) w patogenezie zmian miazdzycowych i angiopatii cukrzycowej.

Anti-endothelial cell antibodies (AECA) are a heterogeneous group of autoantibodies directed against antigens located on endothelial cells. AECA can be detected in a wide variety of clinically distinct diseases in which the common feature appears to be immune, inflammatory-mediated damage to the vessel wall. In in vitro studies it has been demonstrated that AECA possess functional properties, such as endothelial cell activation leading to the induction of a pro-inflammatory/pro-coagulant phenotype of the endothelial cells. Increasing evidence is accumulating on the possibility that AECA may play an important role in the development or progression of atherosclerotic lesions. Moreover, it has been suggested that AECA may contribute to the instability of angina and postangioplasty intimal proliferation, associated with the high restenosis rate after PTCA (percutaneous transluminal coronary angioplasty). In diabetes these autoantibodies seem to be involved in the complex pathogenesis of diabetic vascular complications.