Endothelin-1 actions on vascular smooth muscle cell functions as a target for the prevention of atherosclerosis

The formation and progression of atherosclerotic plaques followed by rupture, thrombus formation and vessel blockage leads to ischemic tissue damage and the clinical condition underlying most cardiovascular disease. Therapeutic agents for the prevention of atherosclerosis have all targeted epidemiologically-identified and relatively easily measured risk factors (e.g. lipids and blood pressure). This strategy has proven somewhat effective but is of less than optimal efficacy as rates of cardiovascular disease remain high. Treatment targeting the mechanisms of atherosclerosis in the vessel wall is a conceptually attractive proposition to complement the risk factor directed strategy. Vascular smooth muscle cells (VSMC) are the major cellular component of the vascular media and migration and proliferation leads to the formation of the neointima the development of which renders the vessels particularly sensitive to atherosclerosis. Numerous hormones and growth factors act on VSMC to cause migration, proliferation and the secretion of extracellular matrix and modulation or dysfunction of these processes is the most likely cause of atherosclerosis. Endothelin-1 (ET-1) is a 21 amino acid peptide that acts on 7 transmembrane G protein coupled receptors to elicit a plethora of responses that can modulate the behaviour of VSMCs and thus impact on the development of atherosclerosis. ET-1 is elevated in atherosclerotic plaques. People with diabetes have accelerated atherosclerosis and also show elevated plasma levels of ET-1. This review addresses the actions of ET-1 on VSMC and the signalling pathways through which it mediates its effects as the latter represent potential therapeutic targets for the prevention of atherosclerosis.     

Phosphorylated troglitazone activates PPARgamma and inhibits vascular smooth muscle cell proliferation and proteoglycan synthesis

Phosphorylation of alpha-tocopherol produces an entity with enhanced antiatherogenic properties. Troglitazone, an alpha-tocopherol derivative of a 2,4-thiazolidinedione nucleus, is an antidiabetic agent that shows fatal idiosyncratic hepatotoxicity, a property not shared by later agents. We investigated the effects of phosphorylation of troglitazone (to yield "phosphoglitazone") on the biochemical pharmacologic properties of troglitazone. We investigated its ability to act as a PPARgamma agonist and to inhibit 2 atherogenic properties of vascular smooth muscle cells (vSMC)-proliferation and proteoglycan synthesis. PPARgamma activity was assessed in a transfection assay. Proliferation was assessed by [H]-thymidine incorporation and cell counting and proteoglycan synthesis by [S]-sulfate incorporation using human vSMCs stimulated with platelet-derived growth factor (PDGF; 50 ng/mL) and transforming growth factor (TGF)-beta (2 ng/mL). Phosphoglitazone was a full agonist for PPARgamma with a potency and efficacy similar to troglitazone. Phosphoglitazone also inhibited cell proliferation and proteoglycan synthesis with potency similar to troglitazone. We conclude that phosphorylation retains the pharmacologic activity of troglitazone while decreasing its lipophilicity and therefore potentially its toxicity. A phosphorylated derivative of a 2,4-thiazolidinedione warrants further investigation as a potential new therapeutic agent for the treatment of insulin resistance and Type 2 diabetes.     

Synovial chondromatosis of the subtalar joint: a case report and review of the literature

Synovial chondromatosis is an uncommon disorder characterized by the formation of multiple cartilaginous nodules within the synovium and most commonly affects large joints, such as the knee and hip. Diagnosis in synovial chondromatosis is generally confirmed by histology after clinical and radiologic examination. Diagnosis may sometimes be difficult because synovial chondromatosis resembles a soft-tissue mass and may give no radiologic findings. We describe a case of synovial chondromatosis stemming from the subtalar joint, in which diagnosis was difficult clinically and radiologically. The patient presented with pain in the ankle and with a soft-tissue mass. This case is presented with a review of the literature on subtalar joint involvement of synovial chondromatosis.     

Spondyloenchondrodysplasia Due to Mutations in <Emphasis Type="Italic">ACP5</Emphasis>: A Comprehensive Survey

Purpose

Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases.

Methods

We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.

Results

We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.

Conclusions

Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.

     

Adapting anatomy teaching to surgical trends: a combination of classical dissection,medical imaging,and 3D-printing technologies

Purpose

Many regions worldwide report difficulties in recruiting applicants to surgery. One strategy proposed to reverse this trend consists of early exposure of medical students to the field. Against this backdrop, the present study presents an innovative approach for anatomy teaching, integrating a surgically relevant trend: 3D printing.

Methods

Whole-body computed tomography (CT) was made of two cadavers. Twelve students performed measurements and 3D reconstructions of selected anatomical structures (Osirix, Mimics). 3D printed (3DP) models were obtained (ZPrinter 310 Plus), and the students completed the analogous measurements on these replicas. Finally, classical anatomical dissection was performed and the same parameters were measured. The differences between the values obtained by the three modalities were submitted to standard statistical analysis (Wilcoxon two-tail paired test).

Results

Qualitative comparison of the digital 3D reconstructions based on the students’ manual CT segmentation and the anatomical reality showed excellent correlation. Quantitatively, the values measured on the CT images and the physical models created by 3D printing differed from those measured on the cadavers by less than 2 mm. Students were highly appreciative of the approach (CT, 3DP, cadaver). Their average satisfaction score was 5.8 on a 1–6 scale.

Conclusions

This study shows that the approach proposed can be achieved. The results obtained also show that CT-based 3D printed models are close to the authentic anatomic reality. The program allows early and interactive exposure of medical students to a surgically relevant trend—in this case 3D printing.

     

Effect of thiamine pyrophosphate on retinopathy induced by hyperglycemia in rats: A biochemical and pathological evaluation

Purpose:Information is lacking on the protective effects of thiamine pyrophosphate (TPP) against hyperglycemia-induced retinopathy in rats. This study investigated the biochemical and histopathological aspects of the effect of TPP on hyperglycemia-induced retinopathy induced by alloxan in rats.Results:TPP prevented hyperglycemia by increasing the amount of malondialdehyde and decreasing endogen antioxidants, including total glutathione, glutathione reductase, glutathione S-transferase and superoxide dismutase. In addition, the amounts of the DNA oxidation product 8-hydroxyguanine were significantly lower in the retinas of the DTPG compared to the DCG. In the retinas of the DCG, there was a marked increase in vascular structures and congestion, in addition to edema. In contrast, little vascularization and edema were observed in the DTPG, and there was no congestion. The results suggest that TPP significantly reduced the degree of hyperglycemia-induced retinopathy.Conclusions:The results of this study indicate that TPP may be useful for prophylaxis against diabetic retinopathy.